BioMed Research International: Oncology http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Treatment for Intramuscular Lipoma Frequently Confused with Sarcoma: A 6-Year Restrospective Study and Literature Review Wed, 10 Dec 2014 00:11:22 +0000 http://www.hindawi.com/journals/bmri/2014/867689/ Introduction. Intramuscular lipoma is a very rare form of lipoma, known to be categorized as an infiltrating lipoma due to its tendencies to infiltrate the muscle or the synovium. Contrary to other subcutaneous lipomas, even after surgical removal, the rate of local recurrence ranges at a high rate from 50∼80% and differential diagnosis with liposarcoma is very difficult. Patients and Methods. A retrospective chart review was conducted for a total of 27 patients. Before performing a surgery based on the types of mass, a radiologic imaging study was performed. An intraoperative frozen biopsy was performed on every patient and the results were compared. The progress was monitored every 3 to 6 months for recurrence or struggles with rehabilitation. Results. There were 13 male and 14 female patients with an average age of 54.6. The average tumor size was 8.2 cm (1.1 cm∼31.6 cm). Excision was performed using a wide excision. All 27 individuals were initially diagnosed as intramuscular lipoma; however, 1 of the patients was rediagnosed as liposarcoma in the final checkup. The patients had an average of 3 years and 1 month of follow-up and did not suffer recurrences. Conclusion. Thus, it is essential that a frozen biopsy is performed during the surgery in order to identify its malignancy. And a wide excision like malignant tumor operation is a principle of treatment. Hyun Ho Han, Jong Yun Choi, Bommie F. Seo, Suk-Ho Moon, Deuk Young Oh, Sang Tae Ahn, and Jong Won Rhie Copyright © 2014 Hyun Ho Han et al. All rights reserved. CCR7 Regulates Cell Migration and Invasion through JAK2/STAT3 in Metastatic Squamous Cell Carcinoma of the Head and Neck Mon, 27 Oct 2014 11:51:38 +0000 http://www.hindawi.com/journals/bmri/2014/415375/ Squamous cell carcinoma of the head and neck (SCCHN) frequently involves metastasis at diagnosis. Our previous research has demonstrated that CCR7 plays a key role in regulating SCCHN metastasis, and this process involves several molecules, such as PI3K/cdc42, pyk2, and Src. In this study, the goals are to identify whether JAK2/STAT3 also participates in CCR7’s signal network, its relationship with other signal pathways, and its role in SCCHN cell invasion and migration. The results showed that stimulation of CCL19 could induce JAK2/STAT3 phosphorylation, which can be blocked by Src and pyk2 inhibitors. After activation, STAT3 was able to promote low expression of E-cadherin and had no effect on vimentin. This JAk2/STAT3 pathway not only mediated CCR7-induced cell migration but also mediated invasion speed. The immunohistochemistry results also showed that the phosphorylation of STAT3 was correlated with CCR7 expression in SCCHN, and CCR7 and STAT3 phosphorylation were all associated with lymph node metastasis. In conclusion, JAk2/STAT3 plays a key role in CCR7 regulating SCCHN metastasis. Fa-Yu Liu, Jawad Safdar, Zhen-Ning Li, Qi-Gen Fang, Xu Zhang, Zhong-Fei Xu, and Chang-Fu Sun Copyright © 2014 Fa-Yu Liu et al. All rights reserved. Downregulation of MDR1 Gene by Cepharanthine Hydrochloride Is Related to the Activation of c-Jun/JNK in K562/ADR Cells Thu, 16 Oct 2014 08:40:31 +0000 http://www.hindawi.com/journals/bmri/2014/164391/ The purpose of the study was to determine the signal transduction mechanism of cepharanthine hydrochloride (CH) on reversing tumor multidrug resistance. RT-PCR and Western blot analysis were used to determine the effects of CH on the expression of MDR1 mRNA and P-glycoprotein in K562/ADR cells when CH was used alone and combined with SP600125, a JNK inhibitor, to explore the effects of CH on JNK pathway. Western blot analysis was used to determine the effects of CH on c-Jun protein expression and phosphorylation, to explore the regulating effects of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins. Our results showed that the inhibitory effect of CH on MDR1 mRNA increased with the concentrations of CH (5.0, 10.0, and 20.0 μM) and the inhibitory effects of CH on MDR1 mRNA and P-glycoprotein increased with the incubation time of CH (0, 12, 24, 36, and 48 hours). The inhibitory effect was weakened after CH combined with SP600125. The expressions of c-Jun and p-c-Jun proteins increased with the incubation time of CH (0, 6, 12, and 24 hours). These findings suggest that CH downregulated the expressions of MDR1 mRNA and P-glycoprotein in a time and concentration manner; the mechanism may be mediated via activating c-Jun/JNK pathway. Li Han, Yafeng Wang, Xiaojuan Guo, Yubing Zhou, Jingmin Zhang, Ning Wang, Jinhua Jiang, Fang Ma, and Qingduan Wang Copyright © 2014 Li Han et al. All rights reserved. Tumor Suppression and Promotion by Autophagy Thu, 18 Sep 2014 12:53:15 +0000 http://www.hindawi.com/journals/bmri/2014/603980/ Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer. Yenniffer Ávalos, Jimena Canales, Roberto Bravo-Sagua, Alfredo Criollo, Sergio Lavandero, and Andrew F. G. Quest Copyright © 2014 Yenniffer Ávalos et al. All rights reserved. The Importance of Autophagy Regulation in Breast Cancer Development and Treatment Wed, 17 Sep 2014 05:11:20 +0000 http://www.hindawi.com/journals/bmri/2014/710345/ Breast cancer (BC) is a potentially life-threatening malignant tumor that still causes high mortality among women. One of the mechanisms through which cancer development could be controlled is autophagy. This process exerts different effects during the stages of cancer initiation and progression due to the occurring superimposition of signaling pathways of autophagy and carcinogenesis. Chronic inhibition of autophagy or autophagy deficiency promotes cancer, due to instability of the genome and defective cell growth and as a result of cell stress. However, increased induction of autophagy can become a mechanism which allows tumor cells to survive the conditions of hypoxia, acidosis, or chemotherapy. Therefore, in the development of cancer, autophagy is regarded as a double-edged sword. Determination of the molecular mechanisms underlying autophagy regulation and its role in tumorigenesis is an essential component of modern anticancer strategies. Results of scientific studies show that inhibition of autophagy may enhance the effectiveness of currently used anticancer drugs and other therapies (like radiotherapy). However, in some cases, the promotion of autophagy can induce death and, hence, elimination of the cancer cells and reduction of tumor size. This review summarizes the current knowledge on autophagy regulation in BC and up-to-date anticancer strategies correlated with autophagy. Joanna Magdalena Zarzynska Copyright © 2014 Joanna Magdalena Zarzynska. All rights reserved. Radiation Oncology In Vitro: Trends to Improve Radiotherapy through Molecular Targets Mon, 15 Sep 2014 05:26:54 +0000 http://www.hindawi.com/journals/bmri/2014/461687/ Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements. Natália Feofanova, Jony Marques Geraldo, and Lídia Maria de Andrade Copyright © 2014 Natália Feofanova et al. All rights reserved. Curcumin: A Potential Candidate in Prevention of Cancer via Modulation of Molecular Pathways Wed, 10 Sep 2014 12:30:34 +0000 http://www.hindawi.com/journals/bmri/2014/761608/ Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways. Arshad H. Rahmani, Mohammad A. Al Zohairy, Salah M. Aly, and Masood A. Khan Copyright © 2014 Arshad H. Rahmani et al. All rights reserved. KML001, a Telomere-Targeting Drug, Sensitizes Glioblastoma Cells to Temozolomide Chemotherapy and Radiotherapy through DNA Damage and Apoptosis Wed, 10 Sep 2014 09:25:16 +0000 http://www.hindawi.com/journals/bmri/2014/747415/ Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated γ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma. Seon Rang Woo, Yunhee Ham, Wonyoung Kang, Heekyoung Yang, Sujong Kim, Juyoun Jin, Kyeung Min Joo, and Do-Hyun Nam Copyright © 2014 Seon Rang Woo et al. All rights reserved. Four-Dimensional Computed Tomography Based Respiratory-Gated Radiotherapy with Respiratory Guidance System: Analysis of Respiratory Signals and Dosimetric Comparison Sun, 07 Sep 2014 11:22:36 +0000 http://www.hindawi.com/journals/bmri/2014/306021/ Purpose. To investigate the effectiveness of respiratory guidance system in 4-dimensional computed tomography (4DCT) based respiratory-gated radiation therapy (RGRT) by comparing respiratory signals and dosimetric analysis of treatment plans. Methods. The respiratory amplitude and period of the free, the audio device-guided, and the complex system-guided breathing were evaluated in eleven patients with lung or liver cancers. The dosimetric parameters were assessed by comparing free breathing CT plan and 4DCT-based 30–70% maximal intensity projection (MIP) plan. Results. The use of complex system-guided breathing showed significantly less variation in respiratory amplitude and period compared to the free or audio-guided breathing regarding the root mean square errors (RMSE) of full inspiration (), full expiration (), and period (). The dosimetric parameters including , , , , , and of normal liver or lung in 4DCT MIP plan were superior over free breathing CT plan. Conclusions. The reproducibility and regularity of respiratory amplitude and period were significantly improved with the complex system-guided breathing compared to the free or the audio-guided breathing. In addition, the treatment plan based on the 4D CT-based MIP images acquired with the complex system guided breathing showed better normal tissue sparing than that on the free breathing CT. Jung Ae Lee, Chul Yong Kim, Dae Sik Yang, Won Sup Yoon, Young Je Park, Suk Lee, and Young Bum Kim Copyright © 2014 Jung Ae Lee et al. All rights reserved. Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis Mon, 01 Sep 2014 10:38:37 +0000 http://www.hindawi.com/journals/bmri/2014/639058/ Lymphangiogenesis is a very early step in lymphatic metastasis. It is regulated and promoted not only by the tumor cells themselves, but also by cells of the tumor microenvironment, including cancer associated fibroblasts, mesenchymal stem cells, dendritic cells, or macrophages. Even the extracellular matrix as well as cytokines and growth factors are involved in the process of lymphangiogenesis and metastasis. The cellular and noncellular components influence each other and can be influenced by the tumor cells. The knowledge about mechanisms behind lymphangiogenesis in the tumor microenvironmental crosstalk is growing and offers starting points for new therapeutic approaches. Simona L. Schlereth, Nasrin Refaian, Sandra Iden, Claus Cursiefen, and Ludwig M. Heindl Copyright © 2014 Simona L. Schlereth et al. All rights reserved. Viola tricolor Induces Apoptosis in Cancer Cells and Exhibits Antiangiogenic Activity on Chicken Chorioallantoic Membrane Thu, 28 Aug 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/625792/ In the present study, the cytotoxic and apoptogenic properties of hydroalcoholic extract and ethyl acetate (EtOAc), n-butanol, and water fractions (0–800 μg/mL) of Viola tricolor were investigated in Neuro2a mouse neuroblastoma and MCF-7 human breast cancer cells. In addition, antiangiogenic effect of EtOAc fraction was evaluated on chicken chorioallantoic membrane (CAM). The quality of EtOAc fraction was also characterized using high performance liquid chromatography (HPLC) fingerprint. Cytotoxicity assay revealed that EtOAc fraction was the most potent among all fractions with maximal effect on MCF-7 and minimal toxicity against normal murine fibroblast L929 cells. Apoptosis induction by EtOAc fraction was confirmed by increased sub-G1 peak of propidium iodide (PI) stained cells. This fraction triggered the apoptotic pathway by increased Bax/Bcl-2 ratio and cleaved caspase-3 level. Moreover, treatment with EtOAc fraction significantly decreased the diameter of vessels on CAM, while the number of newly formed blood vessels was not suppressed significantly. Analysis of quality of EtOAc fraction using HPLC fingerprint showed six major peaks with different retention times. The results of the present study suggest that V. tricolor has potential anticancer property by inducing apoptosis and inhibiting angiogenesis. Hamid Reza Sadeghnia, Taghi Ghorbani Hesari, Seyed Mohsen Mortazavian, Seyed Hadi Mousavi, Zahra Tayarani-Najaran, and Ahmad Ghorbani Copyright © 2014 Hamid Reza Sadeghnia et al. All rights reserved. Assessment of Tumor Cells in a Mouse Model of Diffuse Infiltrative Glioma by Raman Spectroscopy Wed, 27 Aug 2014 10:36:39 +0000 http://www.hindawi.com/journals/bmri/2014/860241/ Glioma of infiltrative nature is challenging for surgeons to achieve tumor-specific and maximal resection. Raman spectroscopy provides structural information on the targeted materials as vibrational shifts. We utilized Raman spectroscopy to distinguish invasive tumors from normal tissues. Spectra obtained from replication-competent avian sarcoma-(RCAS-) based infiltrative glioma cells and glioma tissues (resembling low-grade human glioma) were compared with those obtained from normal mouse astrocytes and normal tissues. In cell analysis, the spectra at 950–1000, 1030, 1050–1100, 1120–1130, 1120–1200, 1200–1300, 1300–1350, and 1450 cm−1 were significantly higher in infiltrative glioma cells than in normal astrocytes. In brain tissue analysis, the spectra at 1030, 1050–1100, and 1200–1300 cm−1 were significantly higher in infiltrative glioma tissues than in normal brain tissues. These spectra reflect the structures of proteins, lipids, and DNA content. The sensitivity and specificity to predict glioma cells by distinguishing normal cells were 98.3% and 75.0%, respectively. Principal component analysis elucidated the significance of spectral difference between tumor tissues and normal tissues. It is possible to distinguish invasive tumors from normal tissues by using Raman spectroscopy. Kuniaki Tanahashi, Atsushi Natsume, Fumiharu Ohka, Hiroyuki Momota, Akira Kato, Kazuya Motomura, Naoki Watabe, Shuichi Muraishi, Hitoshi Nakahara, Yahachi Saito, Ichiro Takeuchi, and Toshihiko Wakabayashi Copyright © 2014 Kuniaki Tanahashi et al. All rights reserved. New Biomarkers to Predict the Evolution of In Situ Breast Cancers Tue, 26 Aug 2014 10:32:40 +0000 http://www.hindawi.com/journals/bmri/2014/159765/ Background. Genomic studies have shown that gene expression profiles are similar in in situ (CIS) and invasive breast cancers, suggesting that several biofunctional modifications of the transformation process occur before or during the development of CIS lesion. Methods. We investigated 3 biomarkers in 44 patients with CIS: TG2 (transglutaminase 2), HJURP (Holliday junction recognition protein), and HIF-1α (hypoxia inducible factor-1 alpha). Results. TG2 was more highly expressed than the other two markers and significantly more so in stromal than in tumor cells. HIF-1α evaluation showed a higher expression in both tumor and stromal cells in patients with relapsed G3 tumors, indicating a potential role of this marker in CIS evolution. A greater than sevenfold higher risk of relapse was observed in patients highly expressing HJURP in stroma and a tenfold higher recurrence risk was seen in those with a higher stromal HIF-1α expression. An important increase in risk accuracy (AUC 0.80) was obtained when HIF-1α and HJURP were evaluated together. Conclusions. Despite the limited number of relapsed patients, we formulated some hypotheses on the factors responsible for malignant evolution and recurrence which are now being tested in a large case series with a longer follow-up. S. Bravaccini, M. M. Tumedei, E. Scarpi, W. Zoli, C. Rengucci, L. Serra, A. Curcio, F. Buggi, S. Folli, A. Rocca, R. Maltoni, M. Puccetti, D. Amadori, and R. Silvestrini Copyright © 2014 S. Bravaccini et al. All rights reserved. Involvement of p53 Mutation and Mismatch Repair Proteins Dysregulation in NNK-Induced Malignant Transformation of Human Bronchial Epithelial Cells Mon, 18 Aug 2014 09:14:35 +0000 http://www.hindawi.com/journals/bmri/2014/920275/ Genome integrity is essential for normal cellular functions and cell survival. Its instability can cause genetic aberrations and is considered as a hallmark of most cancers. To investigate the carcinogenesis process induced by tobacco-specific carcinogen NNK, we studied the dynamic changes of two important protectors of genome integrity, p53 and MMR system, in malignant transformation of human bronchial epithelial cells after NNK exposure. Our results showed that the expression of MLH1, one of the important MMR proteins, was decreased early and maintained the downregulation during the transformation in a histone modification involved and DNA methylation-independent manner. Another MMR protein PMS2 also displayed a declined expression while being in a later stage of transformation. Moreover, we conducted p53 mutation analysis and revealed a mutation at codon 273 which led to the replacement of arginine by histidine. With the mutation, DNA damage-induced activation of p53 was significantly impaired. We further reintroduced the wild-type p53 into the transformed cells, and the malignant proliferation can be abrogated by inducing cell cycle arrest and apoptosis. These findings indicate that p53 and MMR system play an important role in the initiation and progression of NNK-induced transformation, and p53 could be a potential therapeutic target for tobacco-related cancers. Ying Shen, Shuilian Zhang, Xiaobin Huang, Kailin Chen, Jing Shen, and Zhengyang Wang Copyright © 2014 Ying Shen et al. All rights reserved. CC Chemokine Ligand 18 Correlates with Malignant Progression of Prostate Cancer Sun, 17 Aug 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/230183/ Background and Aim. CC chemokine ligand 18 (CCL18) promotes malignant behaviors of various human cancer types. However, its involvement in human prostate cancer has not been fully elucidated. The aim of this study was to investigate the role of CCL18 in PCa. Methods. Expression of CCL18 at mRNA and protein levels was detected using real-time qRT-PCR and immunohistochemistry analysis. We analyzed the associations of CCL18 expression with clinical features of human PCa. The effects of PCa cell migration, invasion, and apoptosis were tested. The efficiency of CCL18 on prostate tumor growth was assessed in a subcutaneous xenograft model. Results. CCL18 expression was upregulated (both ) in PCa tissues compared with those in noncancerous prostate tissues. CCL18 upregulation was correlated with high Gleason score () of patients with PCa. rCCL18 stimulation in PCa cells promoted cell migration and invasion but decreased DU145 cells apoptosis rate. Furthermore, subcutaneous homografts models showed the increased tumor growth and tumor vascularization with the CCL18 stimulation, and the expression of Ki67, PCNA, and CD31 in CCL18 stimulation mice was also significantly increased. Conclusions. Our data offer the convincing evidence that the upregulation of CCL18 may be involved in the malignant progression of PCa. Guo Chen, Yu-xiang Liang, Jian-guo Zhu, Xin Fu, Yan-fei Chen, Ru-jun Mo, Liang Zhou, Hao Fu, Xue-cheng Bi, Hui-chan He, Sheng-bang Yang, Yong-ding Wu, Fu-neng Jiang, and Wei-de Zhong Copyright © 2014 Guo Chen et al. All rights reserved. Evaluating the Therapeutic Dose Distribution of Intensity-Modulated Radiation Therapy for Head and Neck with Cone-Beam Computed Tomography Image: A Methodological Study Sun, 17 Aug 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/326532/ An approximate correction method for the CT value-electron density curve of CBCT was established, through comparison and fitting with FBCT images, and applied to evaluate the therapeutic dose of IMRT. The precision of using CBCT for plan calculation was validated by comparing the dose distribution between CBCT- and FBCT-based IMRT plans. Also setup deviations were simulated to evaluate the ability of the CBCT-based calculation for detecting the dose errors caused by positioning deviation. The gamma comparison between CBCT- and FBCT-based dose computations showed that the pass rates of (2%, 2 mm) criteria were better than 97.60 ± 0.83% and 97.74 ± 2.08% in the phantom and 10 NPC cases. When setup deviation was introduced into CBCT-based dose calculation, the gamma pass rate significantly decreased while the volumetric doses of the targets and some normal organs exhibited different changes compared to the original plan. Our results validated the above CT value-electron density correction which reduced the difference between CBCT- and FBCT-based IMRT plan calculation for NPC to less than 2%. Online CBCT-based dose calculation can be used to reflect and evaluate the dose distribution discrepancy caused by setup deviation and structure changes during the treatment, ensuring more effective quality control of IMRT treatment. Guang-shun Zhang, Shao-min Huang, Cui Chen, Sen-kui Xu, Dan-dan Zhang, and Xiao-wu Deng Copyright © 2014 Guang-shun Zhang et al. All rights reserved. Anticancer, Anti-Inflammatory, and Analgesic Activities of Synthesized 2-(Substituted phenoxy) Acetamide Derivatives Thu, 14 Aug 2014 09:18:38 +0000 http://www.hindawi.com/journals/bmri/2014/386473/ The aphorism was to develop new chemical entities as potential anticancer, anti-inflammatory, and analgesic agents. The Leuckart synthetic pathway was utilized in development of novel series of 2-(substituted phenoxy)-N-(1-phenylethyl)acetamide derivatives. The compounds containing 1-phenylethylamine as basic moiety attached to substituted phenols were assessed for their anticancer activity against MCF-7 (breast cancer), SK-N-SH (neuroblastoma), anti-inflammatory activity, and analgesic activity. These investigations revealed that synthesized products 3a–j with halogens on the aromatic ring favors as the anticancer and anti-inflammatory activity. Among all, compound 3c N-(1-(4-chlorophenyl)ethyl)-2-(4-nitrophenoxy)acetamide exhibited anticancer, anti-inflammatory, and analgesic activities. In conclusion, 3c may have potential to be developed into a therapeutic agent. Priyanka Rani, Dilipkumar Pal, Rahul Rama Hegde, and Syed Riaz Hashim Copyright © 2014 Priyanka Rani et al. All rights reserved. miR-375 Suppresses IGF1R Expression and Contributes to Inhibition of Cell Progression in Laryngeal Squamous Cell Carcinoma Tue, 12 Aug 2014 08:55:23 +0000 http://www.hindawi.com/journals/bmri/2014/374598/ MicroRNAs (miRNAs) are small noncoding RNA molecules which are involved in tumorigenesis and development. To investigate their role in primary laryngeal squamous cell carcinoma (LSCC), miRNA GeneChips were used to screen the differentially expressed miRNA, and then validated by real-time quantitative PCR in LSCC samples, we found that miR-375 was frequently downregulated in primary LSCC tissues. The tumor-suppressive effect of miR-375 was determined by in vitro assays; through gain-of-function studies we demonstrated that miR-375 can inhibit LSCC cell (SNU-48 and SNU-899) proliferation, motility, and invasion, and promote their apoptosis. In addition, bioinformatics tools TargetScan, PicTar, and Miranda were used to investigate the potential target of miR-375; bioinformatics analysis and dual-luciferase reporter assay indicated that IGF1R was a novel direct target of miR-375. Ectopic transfection of miR-375 led to a significant reduction in IGF1R and its downstream signaling molecule AKT at both the mRNA and protein levels in LSCC cells. Our results suggested that downregulation of miR-375 is one of the molecular mechanisms for the development and progression of LSCC by directly targeting IGF1R and affecting its downstream AKT signaling pathways. Furthermore, miR-375 and IGF1R may serve as a novel therapeutic target for LSCC. Jie Luo, Jianhui Wu, Zenghong Li, Hao Qin, Bin Wang, Thian-Sze Wong, Weiqiang Yang, Qing-Ling Fu, and Wenbin Lei Copyright © 2014 Jie Luo et al. All rights reserved. Invasive Potential of Melanoma Cells Correlates with the Expression of MT1-MMP and Regulated by Modulating Its Association with Motility Receptors via N-Glycosylation on the Receptors Mon, 11 Aug 2014 12:50:36 +0000 http://www.hindawi.com/journals/bmri/2014/804680/ Matrix remodeling and invasion of basement membrane are the major determinants of malignant progression. Matrix degrading enzymes play a pivotal role in this process and have been shown to be regulated at multiple levels. Using high metastatic B16F10 and its invasive variant B16BL6 cells, we previously demonstrated that the expression of β1,6 branched N-oligosaccharides promotes cellular adhesion on different matrix components which in turn induces secretion of MMP9. The present investigations report that although the two cell lines do not differ in the expression of uPAR, expression of MT1-MMP is significantly higher on B16BL6 cells. Analysis of the transcripts of tissue inhibitors of matrix metalloproteinases (TIMPs) showed that expression of both TIMP1 and TIMP2 correlates negatively with the invasive potential of cells. CD44 and β1 integrin, the two important receptors involved in motility, were identified to carry β1,6 branched N-oligosaccharides in an invasive potential dependent manner. However, their glycosylation status did not appear to influence their surface expression. Although glycosylation on CD44 had no effect, that on β1 integrin significantly affected association of β1 integrin with MT1-MMP. The results thus demonstrate that the cancer cells use multiple mechanisms for degradation of matrix in a controlled manner to couple it with movement for effective invasion. Amit Ranjan and Rajiv D. Kalraiya Copyright © 2014 Amit Ranjan and Rajiv D. Kalraiya. All rights reserved. Tobacco Exposure by Various Modes May Alter Proinflammatory (IL-12) and Anti-Inflammatory (IL-10) Levels and Affects the Survival of Prostate Carcinoma Patients: An Explorative Study in North Indian Population Thu, 07 Aug 2014 11:00:54 +0000 http://www.hindawi.com/journals/bmri/2014/158530/ Objective. Inflammation is an important hallmark of all cancers and net inflammatory response is determined by a delicate balance between pro- and anti-inflammatory cytokines, which may be affected by tobacco exposure, so the present study was designed to explore the effect of various modes of tobacco exposure on interleukin-12 (IL-12) and interleukin-10 (IL-10) inflammatory cytokine levels and survival in prostate carcinoma (PCa) patients. Methods. 285 cancer patients and equal controls with 94 BPH (benign prostatic hyperplasia) were recruited; baseline levels of serum IL-12 and IL-10 were measured and analyzed in various tobacco exposed groups by appropriate statistical tool. Five-year survivals of patients were analyzed by Log-rank (Mantel-Cox) test (graph pad version 5). Results. The expression of serum proinflammatory (IL-12) and anti-inflammatory (IL-10) cytokines was correlated with tobacco exposed group as smokers, chewers, and alcohol users have shown significantly higher levels () with significantly lower median survivals (27.1 months, standard error = 2.86, and 95% CI: 21.4–32.62); than nonusers. Stages III and IV of tobacco addicted patients have also shown significantly increased levels of IL-12 and IL-10. Conclusions. IL-12 and IL-10 seem to be affected by various modes of tobacco exposure and inflammation also affects median survival of cancer patients. Shailendra Dwivedi, Apul Goel, Sanjay Khattri, Anil Mandhani, Praveen Sharma, and Kamlesh Kumar Pant Copyright © 2014 Shailendra Dwivedi et al. All rights reserved. The Impact of Uterine Radiation on Subsequent Fertility and Pregnancy Outcomes Wed, 06 Aug 2014 10:27:30 +0000 http://www.hindawi.com/journals/bmri/2014/482968/ Future fertility is of paramount importance to younger cancer survivors. Advances in assisted reproductive technology mean that young women treated with radiation involving the uterus may require clinical guidance regarding whether to attempt a pregnancy themselves. We performed a review of the literature regarding radiation involving uterus (total body irradiation (TBI) and pelvic radiation), fertility, and pregnancy outcomes to come up with a recommendation for our patients. Limited evidence suggests lower fecundity and an increased incidence of pregnancy complications after uterine radiation. Higher radiation doses and direct uterine radiation both significantly increase the risk of an adverse pregnancy outcome. Uterine radiation doses of <4 Gy do not appear to impair uterine function. Adult TBI data (usually 12 Gy) suggest pregnancy is possible but with lower fecundity and more complications. Although there is no clear data indicating the dose of radiation to the uterus, above which a pregnancy would not be sustainable, we suggest patients receiving >45 Gy during adulthood and >25 Gy in childhood be counselled to avoid attempting pregnancy. There is preliminary evidence that menopausal hormone therapy and a combination of pentoxifylline and tocopherol may improve uterine function following irradiation. Wan Tinn Teh, Catharyn Stern, Sarat Chander, and Martha Hickey Copyright © 2014 Wan Tinn Teh et al. All rights reserved. Clinical Outcomes and Prognostic Factors of 695 Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Radiotherapy Tue, 05 Aug 2014 13:20:53 +0000 http://www.hindawi.com/journals/bmri/2014/814948/ Objective. The 5-year clinical outcomes and prognostic factors of nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiotherapy (IMRT) were evaluated. Methods. Six hundred ninety five NPC patients primarily treated with IMRT in Sichuan Cancer Hospital from January, 2003 to December, 2006 were analyzed retrospectively, including 540 males and 155 females. The prescription dose was delivered as follows: gross target volume (GTVnx) 67–76 Gy in 30–33 fractions, positive neck lymph nodes (GTVln-R/L) 60–70 Gy in 30–33 fractions, high-risk clinical target volume (CTV1) 60–66 Gy, low-risk clinical target volume (CTV2) 54–60 Gy, and clinical target volume of cervical lymph node regions (CTVln) 50–55 Gy. Results. The 5-year local control (LC), regional control, distant metastasis-free survival (DMFS), disease free survival, disease specific survival, and overall survival (OS) rates were 89.8%, 95.2%, 74.1%, 69.6%, 83.2%, and 77.1%. The 5-year DMFS of IMRT and IMRT combined with chemotherapy was 62.1% and 70.9%, the OS of them was 72.9% and 79.1%. The incidence of grade 3 acute and late toxicity was 38.3% and 4.2%, respectively. Conclusion. The 5-year LC and OS rate of NPC treated with IMRT was 89.8% and 77.1%. The clinical stage, N stage, volume of GTVnx, and chemotherapy were the main prognostic factor for the OS. Distant metastasis was the main pattern of failure. Weidong Wang, Mei Feng, Zixuan Fan, Jie Li, and Jinyi Lang Copyright © 2014 Weidong Wang et al. All rights reserved. In Vitro and In Vivo Effects of Suppressor of Cytokine Signalling 7 Knockdown in Breast Cancer: The Influence on Cellular Response to Hepatocyte Growth Factor Mon, 04 Aug 2014 11:30:59 +0000 http://www.hindawi.com/journals/bmri/2014/648040/ Purpose. Suppressor of cytokine signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with phospholipase Cγ-1 (PLCγ-1), a key downstream mediator of the hepatocyte growth factor (HGF)/C-MET axis. Here, we report our observations of the effect of knocking down SOCS7 gene on the behaviour of breast cancer cells both in vitro and in vivo and to elucidate whether this involves HGF/C-MET pathway using the PLCγ-1 blocker U73122. Methods. MCF7 and MDA-MB-231 breast cancer cells were transfected with anti-SOCS7 ribozymal transgene, to create sublines with SOCS7 knockdown. The in vitro growth and migration of the cells were evaluated in basic conditions and with HGF and U73122 treatment using growth assays, scratch-wound, and electrical cell impedance sensing (ECIS) migration assays. MCF7 and MDA-MB-231 in vivo tumour xenograft growth were also studied. Results. Basal in vitro growth and migration of both cellular lines and the in vivo MCF7 xenograft growth were significantly enhanced with SOCS7 knockdown. In vitro HGF treatment has further influenced the growth and migration when SOCS7 gene was knocked-down in both cellular lines . PLCγ-1 pharmacological inhibition of the HGF/C-MET cascade during their in vitro growth and migration seemed to only occur when SOCS7 gene was knocked down. Conclusions. We report a unique regulatory role for SOCS7 in controlling the malignant behaviour of breast cancer lines MCF7 and MDA-MB-231 in vitro and the MCF7 tumour xenografts in vivo. We also report a regulatory role for SOCS7 during the in vitro HGF-induced growth and migration in these cells as HGF treatment and SOCS7 loss have synergistically enhanced these functions. This SOCS7 knockdown-attributed effect could be due to a precise anti-PLCγ-1 role. Walid Sasi, Lin Ye, Wen G. Jiang, Anup K. Sharma, and Kefah Mokbel Copyright © 2014 Walid Sasi et al. All rights reserved. Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Sequential versus Simultaneous Integrated Photon Boost Mon, 04 Aug 2014 09:13:43 +0000 http://www.hindawi.com/journals/bmri/2014/827475/ Background. Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. Methods. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. Results. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. Conclusions. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine. Hilde Van Parijs, Truus Reynders, Karina Heuninckx, Dirk Verellen, Guy Storme, and Mark De Ridder Copyright © 2014 Hilde Van Parijs et al. All rights reserved. Epithelial-Mesenchymal Transition and Somatic Alteration in Colorectal Cancer with and without Peritoneal Carcinomatosis Sun, 03 Aug 2014 06:37:34 +0000 http://www.hindawi.com/journals/bmri/2014/629496/ Colorectal cancer is highly metastatic even when the tumors are small. To disseminate, cells use a complex and multistage process known as the epithelial-mesenchymal transition, in which epithelial phenotype is transformed into mesenchymal phenotype. The objective of this study is to describe the epithelial-mesenchymal transition in terms of gene expression profile and somatic alterations in samples of colorectal cancer with or without peritoneal carcinomatosis. We analyzed samples taken from 38 patients with colorectal cancer (stages II-IV) and samples from 20 patients with colorectal cancer complicated by peritoneal carcinomatosis. The expression of ZEB1, ZEB2, CDH1, VIM, and SNAI1 was analyzed by real-time PCR. KRAS/BRAF mutations were mapped using sequencing. Microsatellite instability was evaluated by fragment analysis. Epithelial-mesenchymal transition was detected in 6 out of 38 samples of colorectal cancer (stages II-IV), 7 out of 20 tumors from patients with peritoneal carcinomatosis, and 19 out of 20 samples taken from carcinomatous nodules. Tumors of the mesenchymal subtype displayed high frequency of somatic mutations, microsatellite stability, and low degree of differentiation. The identification of epithelial-mesenchymal transition may be used as a marker of high metastatic potential, which is particularly relevant at early stages of tumor growth. Y. A. Shelygin, N. I. Pospekhova, V. P. Shubin, V. N. Kashnikov, S. A. Frolov, O. I. Sushkov, S. I. Achkasov, and A. S. Tsukanov Copyright © 2014 Y. A. Shelygin et al. All rights reserved. Childhood Renal Tumor: A Report from a Chinese Children’s Cancer Group Thu, 24 Jul 2014 11:29:11 +0000 http://www.hindawi.com/journals/bmri/2014/894341/ Here we investigated the establishment of multicenter cooperative treatment groups in China, as well as radiotherapy compliance and effectiveness among children with renal tumors. Medical records were reviewed for 316 children with renal tumors diagnosed by a multicenter cooperative group from 14 hospitals in China from 1998 to 2012. Median patient age was 29.5 months (range, 2–173 months old), and male-to-female ratio was 1.4 : 1. After a median follow-up of 22 months (range, 1–177 months), five-year event-free survival rates were 72% overall; 76.1% for favorable histology (251 cases); 59% for unfavorable histology (27 cases); and 91%, 75%, 71%, 53%, and 48.5%, respectively for Stages I, II, III, IV, and V. Following standardized criteria, radiation therapy was indicated for 153 patients, among whom five-year event-free survival was 72.8% for the 95 who received radiation and 24% for the 58 patients who did not. Our results are reasonable but can be further improved and show the feasibility of a multicenter cooperative group model for childhood renal tumor treatment in China. Radiation therapy is important for stage III and IV patients but remains difficult to implement in some parts of China. Government management departments and medical professionals must pay attention to this situation. This clinical trial is registered with ChiCTR-PRCH-14004372. Jiaoyang Cai, Ci Pan, Qin Lu, Jie Yan, Xiuli Ju, Futian Ma, Yiping Zhu, Qiuling Liu, Lirong Sun, Lian Jiang, Lizhi Cao, Fu Li, Zhigang Liu, Lijing Qiao, Dongsheng Huang, Xin Tian, and Jingyan Tang Copyright © 2014 Jiaoyang Cai et al. All rights reserved. Implementation of Incident Learning in the Safety and Quality Management of Radiotherapy: The Primary Experience in a New Established Program with Advanced Technology Tue, 22 Jul 2014 08:41:37 +0000 http://www.hindawi.com/journals/bmri/2014/392596/ Objective. To explore the implementation of incident learning for quality management of radiotherapy in a new established radiotherapy program. Materials and Methods. With reference to the consensus recommendations by American Association of Physicist in Medicine, an incident learning system was specifically established for reporting, investigating, and learning of individual incidents. The incidents that occurred in external beam radiotherapy from February, 2012, to February, 2014, were reported. Results. A total of 28 near misses and 5 incidents were reported. Among them, 5 originated in imaging for planning, 25 in planning, and 1 in plan transfer, commissioning, and delivery, respectively. One near miss/incident was classified as wrong patient, 7 wrong sites, 6 wrong laterality, and 5 wrong dose. Five reported incidents were all classified as grade 1/2 of dosimetric severity, 1 as grade 0, and the other 4 as grade 1 of medical severity. For the causes/contributory factors, negligence, policy not followed, and inadequate training contributed to 19, 15, and 12 near misses/incidents, respectively. The average incident rate per 100 patients treated was 0.4. Conclusion. Effective implementation of incident learning can reduce the occurrence of near misses/incidents and enhance the culture of safety. Ruijie Yang, Junjie Wang, Xile Zhang, Haitao Sun, Yang Gao, Lu Liu, and Lei Lin Copyright © 2014 Ruijie Yang et al. All rights reserved. Potassium Channel Ether à go-go1 Is Aberrantly Expressed in Human Liposarcoma and Promotes Tumorigenesis Sun, 20 Jul 2014 11:52:17 +0000 http://www.hindawi.com/journals/bmri/2014/345678/ The ether à go-go1 (Eag1) channel is overexpressed in a variety of cancers. However, the expression and function of Eag1 in liposarcoma are poorly understood. In the present study, the mRNA expression of Eag1 in different adipose tissue samples was examined by real-time PCR. Then, the protein expression of Eag1 in 131 different adipose tissues from 109 patients was detected by immunohistochemistry. Next, the associations between Eag1 expression and clinicopathological features of liposarcoma were analyzed. In addition, the effects of Eag1 on liposarcoma cell proliferation and cycle were evaluated by CCK-8, colony formation, xenograft mouse model, and flow cytometry, respectively. Finally, the activation of p38 mitogen-activated protein kinase (MAPK) was detected by Western blot analysis to explain the detailed mechanisms of oncogenic potential of Eag1 in liposarcoma. It was found that Eag1 was aberrantly expressed in over 67% liposarcomas, with a higher frequency than in lipoma, hyperplasia, inflammation, and normal adipose tissues. However, Eag1 expression was not correlated with clinicopathological features of liposarcoma. Eag1 inhibitor imipramine or Eag1-shRNA significantly suppressed the proliferation of liposarcoma cells in vitro and in vivo, accompanying with accumulation of cells in the G1 phase. These results suggest that Eag1 plays an important role in regulating the proliferation and cell cycle of liposarcoma cells and might be a potential therapeutic target for liposarcoma. Jin Wu, Daixing Zhong, Yujian Wei, Xinyu Wu, Liangqi Kang, and Zhenqi Ding Copyright © 2014 Jin Wu et al. All rights reserved. Preclinical and Clinical Effects of Mistletoe against Breast Cancer Sun, 20 Jul 2014 07:43:17 +0000 http://www.hindawi.com/journals/bmri/2014/785479/ Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL), remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients. Mohsen Marvibaigi, Eko Supriyanto, Neda Amini, Fadzilah Adibah Abdul Majid, and Saravana Kumar Jaganathan Copyright © 2014 Mohsen Marvibaigi et al. All rights reserved. Effects of Parity and Serum Prolactin Levels on the Incidence and Regression of DMBA-Induced Tumors in OFA hr/hr Rats Thu, 17 Jul 2014 07:58:28 +0000 http://www.hindawi.com/journals/bmri/2014/210424/ Prolactin (PRL) is a key player in the development of mammary cancer. We studied the effects of parity or hyperprolactinemia on mammary carcinogenesis in OFA hr/hr treated with 7,12-dimethylbenzanthracene. They were divided into three groups: nulliparous (Null), primiparous (PL, after pregnancy and lactation), and hyperprolactinemic rats (I, implanted in the arcuate nucleus with 17β-estradiol). The tumor incidence was similar in the three groups. However, a higher percentage of regressing tumors was evident in the PL group. Serum PRL, mammary development, and mammary β-casein content were higher in I rats compared to Null. The expression of hormone receptors was similar in the different groups. However, mammary tissue from PL rats bearing tumors had increased expression of PRL and estrogen alpha receptors compared to rats free of tumors. Our results suggest that serum PRL levels do not have relevance on the incidence of tumors, probably because the low levels of PRL in OFA rats are not further decreased by PL like in other strains. However, supraphysiological levels of PRL affect carcinogenesis. PL induces regression of the tumors due to the differentiation produced on the mammary cells. Alterations in the expression of hormonal receptors may be involved in progression and regression of tumors. Corina V. Sasso, Flavia E. Santiano, Constanza M. López-Fontana, Virginia Pistone-Creydt, Marcelo E. Ezquer, María B. Hapon, Graciela A. Jahn, and Rubén W. Carón Copyright © 2014 Corina V. Sasso et al. All rights reserved. The Evolving Role of Radiosurgery in the Management of Radiation-Induced Meningiomas: A Review of Current Advances and Future Directions Thu, 17 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/107526/ Meningiomas are among the most common primary adult brain tumors, which arise either spontaneously or secondary to environmental factors such as ionizing radiation. The latter are referred to as radiation-induced meningiomas (RIMs) which, while much less common than their spontaneous counterparts, are challenging from a management point of view. Similar to spontaneous meningiomas, the optimal management of RIMs is complete surgical resection. However, given their high grade, multiplicity, tendency to invade bone and venous sinuses, and high recurrence rate, this cannot always be accomplished safely. Therefore, other therapeutic modalities, such as stereotactic radiosurgery, have emerged. In the current review, we provide an overview of the historical outcomes achieved for RIMs through radiosurgery and microsurgical resection. Furthermore, we provide a discussion of clinical and radiological parameters that affect the decision-making process with regard to the management of RIMs. We also provide an outline of recent changes in our understanding of RIMs, based on molecular and genetic markers, and how these will change our management perspective. We conclude the review by summarizing some of the current obstacles in the management of RIMs with SRS and how current and future research can address these challenges. Alireza Mansouri, Jetan Badhiwala, Sheila Mansouri, and Gelareh Zadeh Copyright © 2014 Alireza Mansouri et al. All rights reserved. The Different Dose-Volume Effects of Normal Tissue Complication Probability Using LASSO for Acute Small-Bowel Toxicity during Radiotherapy in Gynecological Patients with or without Prior Abdominal Surgery Wed, 16 Jul 2014 12:52:00 +0000 http://www.hindawi.com/journals/bmri/2014/143020/ Purpose. To develop normal tissue complication probability (NTCP) model with least absolute shrinkage and selection operator (LASSO) to analyze dose-volume effects that influence the incidence of acute diarrhea among gynecological patients with/without prior abdominal surgery. Methods and Materials. Ninety-five patients receiving gynecologic radiotherapy (RT) were enrolled. The endpoint was defined as the grade 2+ acute diarrhea toxicity during treatment. We obtained the range of small-bowel volume in V4 Gy to V40 Gy of dose. Results. The number of patients experiencing grade 2+ acute diarrhea toxicity was 23/61 (38%) in the group without abdominal surgery (group 0) and 17/34 (50%) patients with abdominal surgery (group 1). The most significant predictor was found for the logistic NTCP model with V16 Gy as the cutoff dose for group 0 and V40 Gy for group 1. Logistic regression NTCP model parameters were TV10 ≈ 290 cc for V16 Gy and TV10 ≈ 75 cc for V40 Gy, respectively. Conclusion. To keep the incidence of grade 2+ acute small-bowel toxicity below 10%, we suggest that small-bowel volume above the prescription dose (V16 Gy) should be held to <290 cc for patients without abdominal surgery, and the prescription dose (V40 Gy) should be maintained <75 cc for patients with abdominal surgery. Tsair-Fwu Lee and Eng-Yen Huang Copyright © 2014 Tsair-Fwu Lee and Eng-Yen Huang. All rights reserved. MicroRNA Expression in Salivary Supernatant of Patients with Pancreatic Cancer and Its Relationship with ZHENG Mon, 14 Jul 2014 10:56:01 +0000 http://www.hindawi.com/journals/bmri/2014/756347/ In traditional Chinese medicine (TCM), diagnosis and prescriptions are based on the signs and symptoms which are recognized as ZHENG. The cornerstone of TCM is to differentially treat one ZHENG from others, which is also known as syndrome differentiation, and this relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. However, the biomolecular basis of the ZHENG remains unclear. In this study, the expressions of 384 cancer-related miRNAs in salivary supernatant of patients with pancreatic cancer were assessed by miRNA polymerase chain reaction (PCR) array, and the different expression patterns of miRNA in three different groups of ZHENG were studied with use of real-time quantitative PCR (qRT-PCR). Some miRNAs were found to be specifically expressed in some ZHENGs, for instance, miR-17, miR-21, and miR-181b in Shi-Re ZHENG and miR-196a in Pi-Xu ZHENG. This indicates that these miRNAs may play important roles in different ZHENG condition. Therefore, this study to some extent revealed the molecular basis of TCM ZHENG in pancreatic cancer. Song Gao, Lian-Yu Chen, Peng Wang, Lu-Ming Liu, and Zhen Chen Copyright © 2014 Song Gao et al. All rights reserved. The Roles of CD73 in Cancer Mon, 14 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/460654/ Purinergic signaling has emerged as an important player in cancer progression and is regulated by a series of nucleotidases. Among the enzyme cascade, CD73, which catelyzes AMP breakdown to adenosine, has been found to be overexpressed in many types of cancer. Various factors and mechanisms are employed to regulate expression of CD73. Accumulating studies have shown that CD73 is a key regulatory molecule of cancer cells proliferation, migration and invasion in vitro, tumor angiogenesis, and tumor immune escape in vivo. With such important roles in cancer, CD73 has become an appealing therapy target. Recent evidences in mice models demonstrated that targeted blockade of CD73 could be a favorable therapeutic approach for cancer patients in the future. In this review, we will summarize the multiple roles of CD73 in cancer development, including its clinical significance, its promotive effects on tumor growth, metastasis, and angiogenesis, and its suppressive effects on immune response, regulatory mechanisms of CD73 expression, and current situation of anti-CD73 cancer therapy. Zhao-wei Gao, Ke Dong, and Hui-zhong Zhang Copyright © 2014 Zhao-wei Gao et al. All rights reserved. Left-Sided Whole Breast Irradiation with Hybrid-IMRT and Helical Tomotherapy Dosimetric Comparison Sun, 13 Jul 2014 12:03:48 +0000 http://www.hindawi.com/journals/bmri/2014/741326/ Purpose. Limited-tomotherapy and hybrid-IMRT treatment techniques were compared for reductions in ipsilateral and contralateral lung, heart, and contralateral breast radiation doses. Methods and Materials. Thirty consecutively treated left-sided early-stage breast cancer patients were scheduled for lTomo and hIMRT. For the hIMRT plan conventional tangential-field and four-field IMRT plans were combined with different weightings in the prescribed dose. For the lTomo plan a geometrically limited arc was designed for the beamlet entrance. A of 50.4 Gy in 28 fractions was used for the PTV. The dose coverage, homogeneity index, conformity index of the target, and the dose volumes of critical structures were compared. Results. Both modalities presented similar target coverage. The homogeneity and conformity were improved for lTomo with and , respectively. In the lTomo plan a concave dose distribution was generated with significant dose reductions in both high and low dose regions for ipsilateral lung and heart (). Conclusions. lTomo plan can have similar dose coverage and better homogeneity and conformity to the target. By properly designing the directionally and completely blocked structure, lTomo plan was developed successfully in reducing doses to the healthy tissues for early-stage left-sided breast cancer radiotherapy. An-Cheng Shiau, Chen-Hsi Hsieh, Hui-Ju Tien, Hsin-Pei Yeh, Chi-Ta Lin, Pei-Wei Shueng, and Le-Jung Wu Copyright © 2014 An-Cheng Shiau et al. All rights reserved. Significance of Image Guidance to Clinical Outcomes for Localized Prostate Cancer Sun, 13 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/860639/ Purpose. To compare toxicity profiles and biochemical tumor control outcomes between patients treated with image-guided intensity-modulated radiotherapy (IG-IMRT) and non-IGRT intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer. Materials and Methods. Between 2009 and 2012, 65 patients with localized prostate cancer were treated with IG-IMRT. This group of patients was retrospectively compared with a similar cohort of 62 patients who were treated between 2004 and 2009 with IMRT to the same dose without image guidance. Results. The median follow-up time was 4.8 years. The rectal volume receiving ≥40 and ≥70 Gy was significantly lower in the IG-IMRT group. Grade 2 and higher acute and late GI and GU toxicity rates were lower in IG-IMRT group, but there was no statistical difference. No significant improvement in biochemical control at 5 years was observed in two groups. In a Cox regression analysis identifying predictors for PSA relapse-free survival, only preradiotherapy PSA was significantly associated with biochemical control; IG-IMRT was not a statistically significant indicator. Conclusions. The use of image guidance in the radiation of prostate cancer at our institute did not show significant reduction in the rates of GI and GU toxicity and did not improve the biochemical control compared with IMRT. Qiuzi Zhong, Hong Gao, Gaofeng Li, Xia Xiu, Qinhong Wu, Ming Li, and Yonggang Xu Copyright © 2014 Qiuzi Zhong et al. All rights reserved. The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment Thu, 10 Jul 2014 11:28:10 +0000 http://www.hindawi.com/journals/bmri/2014/751392/ Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics. Jiamin Zhou, Yi Xiang, Teizo Yoshimura, Keqiang Chen, Wanghua Gong, Jian Huang, Ye Zhou, Xiaohong Yao, Xiuwu Bian, and Ji Ming Wang Copyright © 2014 Jiamin Zhou et al. All rights reserved. Epigenetic Silencing of CXCR4 Promotes Loss of Cell Adhesion in Cervical Cancer Thu, 10 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/581403/ In the network of chemokine signaling pathways, recent reports have described the SDF-1α/CXCR4 axis and its role in cancer progression and metastasis. Interestingly, we found downregulation of CXCR4 at both transcript and protein level in cervical cancer cell lines and primary tumors. We also found CXCR4 promoter hypermethylation in cervical cancer cell lines and primary biopsy samples. DNA hypomethylating drug 5-AZA-2′-deoxycytidine and histone deacetylase inhibitor Trichostatin A treatments in cell lines reactivate both CXCR4 transcription and protein expression. Cell adhesion assay demonstrated that autocrine SDF-1α promotes the loss of cell adhesion while paracrine SDF-1α predominantly protects the normal cervical cells from loss of cell adhesion. Cervical cancer cell line C-33A having increased expression of CXCR4 after TSA treatment showed increased cell adhesion by paracrine source of SDF-1α in comparison to untreated C-33A. These findings demonstrate the first evidence that epigenetic silencing of CXCR4 makes the cells inefficient to respond to the paracrine source of SDF-1α leading to loss of cell adhesion, one of the key events in metastases and progression of the disease. Our results provide novel insight of SDF-1α/CXCR4 signaling in tumor microenvironment which may be promising to further delineate molecular mechanism of cervical carcinogenesis. Suresh Singh Yadav, Shyam Babu Prasad, Mitali Das, Soni Kumari, Lakshmi Kant Pandey, Sunita Singh, Satyajit Pradhan, and Gopeshwar Narayan Copyright © 2014 Suresh Singh Yadav et al. All rights reserved. Clinical Study of Nasopharyngeal Carcinoma Treated by Helical Tomotherapy in China: 5-Year Outcomes Wed, 09 Jul 2014 11:07:19 +0000 http://www.hindawi.com/journals/bmri/2014/980767/ Background. To evaluate the outcomes of nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT). Methods. Between September 2007 and August 2012, 190 newly diagnosed NPC patients were treated with HT. Thirty-one patients were treated with radiation therapy as single modality, 129 with additional cisplatin-based chemotherapy with or without anti-EGFR monoclonal antibody therapy, and 30 with concurrent anti-EGFR monoclonal antibody therapy. Results. Acute radiation related side effects were mainly grade 1 or 2. Grade 3 and greater toxicities were rarely noted. The median followup was 32 (3–38) months. The local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were 96.1%, 98.2%, 92.0%, and 86.3%, respectively, at 3 years. Cox multivariate regression analysis showed that age and T stage were independent predictors for 3-year OS. Conclusions. Helical tomotherapy for NPC patients achieved excellent 3-year locoregional control, distant metastasis-free survival, and overall survival, with relatively minor acute and late toxicities. Age and T stage were the main prognosis factors. Lei Du, Xin-Xin Zhang, Lin Ma, Lin-Chun Feng, Fang Li, Gui-Xia Zhou, Bao-Lin Qu, Shou-Ping Xu, Chuan-Bin Xie, and Jack Yang Copyright © 2014 Lei Du et al. All rights reserved. Cisplatin-Based Chemotherapy versus Cetuximab in Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Cancer Treatment Sun, 06 Jul 2014 07:36:52 +0000 http://www.hindawi.com/journals/bmri/2014/904341/ Background and Purpose. This study aimed to analyze survival, clinical responses, compliance, and adverse effects in locally advanced head and neck cancer (LAHNC) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy (SD-CCRT) or cetuximab with concurrent radiation therapy (BioRT). Materials and Methods. We retrospectively evaluated 170 LAHNC patients diagnosed between January 1, 2009, and July 31, 2012: 116 received CCRT and 54 received BioRT. Results. Complete response rates were similar in the SD-CCRT and BioRT groups (63.8% versus 59.3%; ), and locoregional relapse rates were 18.1% and 13.0%, respectively (). The 3-year relapse-free survival rate was 65.8% in the SD-CCRT group and 65.5% in the BioRT group, respectively (). The 3-year overall survival rate was 78.5% in the SD-CCRT group and 70.9% in the BioRT group, respectively (). Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group. Mucositis frequency was similar. Conclusions. Primary SD-CCRT and BioRT both showed good clinical response and survival. Hematologic toxicities were more frequent, but tolerable, in the SD-CCRT group. Both groups showed good compliance. Ming-Hung Hu, Ling-Wei Wang, Hsueh-Ju Lu, Pen-Yuan Chu, Shyh-Kuan Tai, Tsung-Lun Lee, Ming-Huang Chen, Muh-Hwa Yang, and Peter Mu-Hsin Chang Copyright © 2014 Ming-Hung Hu et al. All rights reserved. Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α Thu, 03 Jul 2014 08:36:59 +0000 http://www.hindawi.com/journals/bmri/2014/934691/ Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer. Mee-Ran Shin, Hwa-Jeong Lee, Soo-Kyung Kang, Q-Schick Auh, Young-Man Lee, Youn-Chul Kim, and Eun-Cheol Kim Copyright © 2014 Mee-Ran Shin et al. All rights reserved. Effects of Single or Combined Treatments with Radiation and Chemotherapy on Survival and Danger Signals Expression in Glioblastoma Cell Lines Tue, 01 Jul 2014 11:41:21 +0000 http://www.hindawi.com/journals/bmri/2014/453497/ The success of chemo- and radiotherapy in glioblastoma multiforme, the most common and lethal primary brain tumour, could rely on the induction of immunogenic tumour cell death and on the induction of anticancer immune response. In this study we investigated cell survival to single treatments or combination of X-rays and temozolomide in glioblastoma cell lines (T98G and U251MG) and we attempted to identify danger signals (HMGB1 and HSP70) released by dying cells in the microenvironment that could activate antitumour immunity contributing to the therapeutic efficacy of conventional treatments. Our data suggest that HSP70 translocates from cytoplasm to extracellular environment after an increase in radiation dose and HMGB1 translocates from the nucleus to the cytoplasm and subsequently is released into the extracellular space, confirming a role of these proteins as signals released after radiation-induced damage in glioblastoma cells. We also could state that TMZ had limited effectiveness in activating HMGB1 and HSP70 signalling and, instead, an adjuvant effect was observed in some combined treatments, depending on schedule, cell line, and timing. A big challenge in tumour therapy is, therefore, to identify the most beneficial combination and chronology of multiple treatment options to contribute to the improvement of the therapeutic outcome. Francesca Pasi, Alessandro Paolini, Rosanna Nano, Riccardo Di Liberto, and Enrica Capelli Copyright © 2014 Francesca Pasi et al. All rights reserved. Metabolic Effects of Hypoxia in Colorectal Cancer by 13C NMR Isotopomer Analysis Tue, 01 Jul 2014 09:16:39 +0000 http://www.hindawi.com/journals/bmri/2014/759791/ 13C NMR isotopomer analysis was used to characterize intermediary metabolism in three colorectal cancer cell lines (WiDr, LS1034, and C2BBe1) and determine the “metabolic remodeling” that occurs under hypoxia. Under normoxia, the three colorectal cancer cell lines present high rates of lactate production and can be seen as “Warburg” like cancer cells independently of substrate availability, since such profile was dominant at both high and low glucose media contents. The LS1034 was the less glycolytic of the three cell lines and was the most affected by the event of hypoxia, raising abruptly glucose consumption and lactate production. The other two colorectal cell lines, WiDr and C2BBe1, adapted better to hypoxia and were able to maintain their oxidative fluxes even at the very low levels of oxygen. These differential metabolic behaviors of the three colorectal cell lines show how important an adequate knowledge of the “metabolic remodeling” that follows a given cancer treatment is towards the correct (re)design of therapeutic strategies against cancer. Ana M. Abrantes, Ludgero C. Tavares, Salomé Pires, João Casalta-Lopes, Cândida Mendes, Marta Simões, Manuela M. Grazina, Rui A. Carvalho, and Maria Filomena Botelho Copyright © 2014 Ana M. Abrantes et al. All rights reserved. The Sirtuin 3 Expression Profile Is Associated with Pathological and Clinical Outcomes in Colon Cancer Patients Tue, 01 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/871263/ Aim. To investigate the correlation between Sirtuin 3 (SIRT3) expression and the clinical outcome of patients with colon cancer. Methods. The tumor specimens from 127 patients with colon cancer were obtained for SIRT3 immunohistochemical staining. Patients were followed up. In in vitro study, SIRT3 gene was inhibited to observe the effects of SIRT3 on the biological behavior of cultured colon cells. Results. The SIRT3 expression level was found to be significantly associated with the lymph node metastasis () and tumor stages (). The colon cancer-specific survival was 64.6% among patients with high SIRT3 expressions and 88.6% among patients with low SIRT3 expressions (log-rank ). The overall survival was 80.2% among patients with low SIRT3 expressions and 55.9% among patients with high SIRT3 expressions (log-rank ). In vitro study showed that silencing of SIRT3 gene inhibited the proliferation, invasion, and cells migration but increased the apoptosis in the cultured colon cell lines. Conclusion. This study provides evidence supporting that SIRT3 is closely associated with the clinical outcomes of colon cancer. SIRT3 may be considered as a marker for colon cancer. Chunyuan Liu, Zonghai Huang, Hong Jiang, and Fujun Shi Copyright © 2014 Chunyuan Liu et al. All rights reserved. Targeting the Neddylation Pathway to Suppress the Growth of Prostate Cancer Cells: Therapeutic Implication for the Men’s Cancer Sun, 29 Jun 2014 08:04:17 +0000 http://www.hindawi.com/journals/bmri/2014/974309/ The neddylation pathway has been recognized as an attractive anticancer target in several malignancies, and its selective inhibitor, MLN4924, has recently advanced to clinical development. However, the anticancer effect of this compound against prostate cancer has not been well investigated. In this study, we demonstrated that the neddylation pathway was functional and targetable in prostate cancer cells. Specific inhibition of this pathway with MLN4924 suppressed the proliferation and clonogenic survival of prostate cancer cells. Mechanistically, MLN4924 treatment inhibited cullin neddylation, inactivated Cullin-RING E3 ligases (CRLs), and led to accumulation of tumor-suppressive CRLs substrates, including cell cycle inhibitors (p21, p27, and WEE1), NF-κB signaling inhibitor IκBα, and DNA replication licensing proteins (CDT1 and ORC1). As a result, MLN4924 triggered DNA damage, G2 phase cell cycle arrest, and apoptosis. Taken together, our results demonstrate the effectiveness of targeting the neddylation pathway with MLN4924 in suppressing the growth of prostate cancer cells, implicating a potentially new therapeutic approach for the men’s cancer. Xiaofang Wang, Lihui Li, Yupei Liang, Chunjie Li, Hu Zhao, Dingwei Ye, Menghong Sun, Lak Shin Jeong, Yan Feng, Shen Fu, Lijun Jia, and Xiaomao Guo Copyright © 2014 Xiaofang Wang et al. All rights reserved. Dissecting the Role of Bone Marrow Stromal Cells on Bone Metastases Thu, 26 Jun 2014 12:02:11 +0000 http://www.hindawi.com/journals/bmri/2014/875305/ Tumor-induced bone disease is a dynamic process that involves interactions with many cell types. Once metastatic cancer cells reach the bone, they are in contact with many different cell types that are present in the cell-rich bone marrow. These cells include the immune cells, myeloid cells, fibroblasts, osteoblasts, osteoclasts, and mesenchymal stem cells. Each of these cell populations can influence the behavior or gene expression of both the tumor cells and the bone microenvironment. Additionally, the tumor itself can alter the behavior of these bone marrow cells which further alters both the microenvironment and the tumor cells. While many groups focus on studying these interactions, much remains unknown. A better understanding of the interactions between the tumor cells and the bone microenvironment will improve our knowledge on how tumors establish in bone and may lead to improvements in diagnosing and treating bone metastases. This review details our current knowledge on the interactions between tumor cells that reside in bone and their microenvironment. Denise Buenrostro, Serk In Park, and Julie A. Sterling Copyright © 2014 Denise Buenrostro et al. All rights reserved. Dosimetric Coverage of the External Anal Sphincter by 3-Dimensional Conformal Fields in Rectal Cancer Patients Receiving Neoadjuvant Chemoradiation: Implications for the Concept of Sphincter-Preserving Radiation Therapy Wed, 25 Jun 2014 10:55:06 +0000 http://www.hindawi.com/journals/bmri/2014/578243/ Background. We evaluated the anatomic location of the external anal sphincter (EAS) to pelvic bony landmarks related to 3-dimensional conformal radiotherapy (3DRT) and studied the dosimetric coverage of the EAS in patients undergoing neoadjuvant chemoradiation for rectal cancer. Methods. Sixty-four consecutive rectal cancer patients treated with neoadjuvant chemoradiation were included. All patients were treated in a prone position on a bellyboard by 3DRT. The inferior border of the RT fields was at least 3–5 cm inferior to the gross tumorous volume (GTV) or at the inferior border of the obturator foramen (IBOF), whichever was more inferior. The EAS was contoured and dose distributions were determined using dose-volume histograms. Results. In 53 out of 64 cases (82.8%), the EAS was completely inferior to the IBOF. In the remaining 11 cases, the EAS was either overlapping the IBOF (10 cases; 15.6%) or completely superior to the IBOF (1 case; 1.7%). The average mean dose delivered to the EAS was 2795 cGy. Lower mean doses were delivered to the EAS when the center of the EAS was located more distant from the GTV. Conclusions. Meticulous planning to define the inferior border of the RT field is recommended to avoid irradiating the EAS. Yi-Jen Chen, Michelle B. Chen, Alan J. Liu, Julian Sanchez, Peter Tsai, and An Liu Copyright © 2014 Yi-Jen Chen et al. All rights reserved. NTPDase5/PCPH as a New Target in Highly Aggressive Tumors: A Systematic Review Mon, 23 Jun 2014 11:30:59 +0000 http://www.hindawi.com/journals/bmri/2014/123010/ The protooncogene PCPH was recently identified as being the ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5). This protooncogene is converted into an oncogene by a single base pair deletion, resulting in frame change and producing a premature stop codon, leading to a mutated protein (mt-PCPH) with only 27 kDa, which is much smaller than the original 47 kDa protein. Overexpression of the PCPH as well as the mutated PCPH increases the cellular resistance to stress and apoptosis. This is intriguing considering that the active form, that is, the oncogene, is the mutated PCPH. Several studies analyzed the expression of NTPDase5/mt-PCPH in a wide range of tumor cells and evaluated its role and mechanisms in cancer and other pathogenic processes. The main point of this review is to integrate the findings and proposed theories about the role played by NTPDase5/mt-PCPH in cancer progression, considering that these proteins have been suggested as potential early diagnostic tools and therapy targets. Paula Andreghetto Bracco, Ana Paula Santin Bertoni, and Márcia Rosângela Wink Copyright © 2014 Paula Andreghetto Bracco et al. All rights reserved. Postmastectomy Radiotherapy for Locally Advanced Breast Cancer Receiving Neoadjuvant Chemotherapy Sun, 22 Jun 2014 13:02:36 +0000 http://www.hindawi.com/journals/bmri/2014/719175/ Neoadjuvant chemotherapy (NAC) is widely used in locally advanced breast cancer (BC) treatment. The role of postmastectomy radiotherapy (PMRT) after NAC is strongly debated. The aim of our analysis was to identify major prognostic factors in a single-center series, with emphasis on PMRT. From 1997 to 2011, 170 patients were treated with NAC and mastectomy at our center; 98 cases (57.6%) underwent PMRT and 72 cases (42.4%) did not receive radiation. At a median follow-up period of 7.7 years (range 2–16) for the whole cohort, median time to locoregional recurrence (LRR) was 3.3 years (range 0.7–12.4). The 5-year and 10-year actuarial LRR rate were 14.5% and 15.9%, respectively. At the multivariate analysis the factors that significantly correlated with survival outcome were ≥4 positive nodes (HR 5.0, 1.51–16.52; ), extracapsular extension (HR 2.18, 1.37–3.46; ), and estrogen receptor positive disease (HR 0.57, 0.36–0.90; ). Concerning LRR according to use of radiation, PMRT reduced LRR for patient with clinical T3 staged disease (). Our experience confirmed the impact of pathological nodal involvement on survival outcome. PMRT was found to improve local control in patients presenting with clinical T3 tumors, regardless of the response to chemotherapy. Icro Meattini, Sara Cecchini, Vanessa Di Cataldo, Calogero Saieva, Giulio Francolini, Vieri Scotti, Pierluigi Bonomo, Monica Mangoni, Daniela Greto, Jacopo Nori, Lorenzo Orzalesi, Donato Casella, Roberta Simoncini, Massimiliano Fambrini, Simonetta Bianchi, and Lorenzo Livi Copyright © 2014 Icro Meattini et al. All rights reserved. Acoustic Radiation Force Impulse Imaging: A New Tool for the Diagnosis of Papillary Thyroid Microcarcinoma Sun, 22 Jun 2014 11:32:36 +0000 http://www.hindawi.com/journals/bmri/2014/416969/ Purpose. To evaluate the diagnostic performance of ARFI imaging in differentiating between benign and malignant thyroid nodules <1 cm. Materials and Methods. 173 pathologically proven thyroid nodules (77 benign, 96 malignant) in 157 patients were included in this study. Receiver-operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance of conventional ultrasound (US) and ARFI imaging in papillary thyroid microcarcinoma (PTMC). The independent risk factors for predicting PTMC were evaluated. Results. The mean SWV value of benign and malignant thyroid nodules were 2.57 ± 0.79 m/s (range: 0.90–4.92 m/s) and 3.88 ± 2.24 m/s (range: 1.49–9.00 m/s) (). Az for VTI elastography score was higher than that for hypoechoic, absence of halo sign, and type III vascularity (). The optimal cut-offs for VTI elastography score and SWV were score 4 and 3.10 m/s. Gender, hypoechoic, taller than wide, VTI elastography score ≥ 4, and SWV > 3.10 m/s had been found to be independent risk factors for predicting PTMC. Conclusion. ARFI elastography can provide elasticity information of PTMC quantitatively (VTQ) and directly reflects the overall elastic properties (VTI). Gender, hypoechogenicity, taller than wide, VTI elastography score ≥ 4, and SWV > 3.10 m/s are independent risk factors for predicting PTMC. ARFI elastography seems to be a new tool for the diagnosis of PTMC. Yi-Feng Zhang, Chang Liu, Hui-Xiong Xu, Jun-Mei Xu, Jing Zhang, Le-Hang Guo, Shu-Guang Zheng, Lin-Na Liu, and Xiao-Hong Xu Copyright © 2014 Yi-Feng Zhang et al. All rights reserved. Long Non-Coding RNA Deregulation in Tongue Squamous Cell Carcinoma Sun, 22 Jun 2014 06:29:35 +0000 http://www.hindawi.com/journals/bmri/2014/405860/ Background. The deregulated tumorigenic long non-coding RNA (lncRNA) has been reported in several malignancies. However, there is still no comprehensive study on tongue squamous cell carcinoma (SCC). Methods. Functional reannotation for the human lncRNA was carried out by ncFANs. Real-time quantitative PCR was used to validate the identified lncRNAs. Results. Using the functional annotation algorithm from ncFANs, 8 differentially expressed lncRNAs were identified. Lnc-PPP2R4-5, lnc-SPRR2D-1, lnc-MAN1A2-1, lnc-FAM46A-1, lnc-MBL2-4:1, and lnc-MBL2-4:3 were upregulated in the microdissected tongue SCC tissues. In comparison, lnc-AL355149.1-1 and lnc-STXBP5-1 showed significant downregulation. High level of lnc-MBL2-4:3 was significantly associated with the node positive tongue SCC patients. Further, patients with advanced T-stage demonstrated a further reduction of lnc-AL355149.1-1 in the tumor tissues. Treatment of tongue SCC cells with 5-fluorouracil and paclitaxel can reserve the expression patterns observed in the tongue SCC tissues. Further, changes of lnc-MBL2-4:3 and lnc-AL355149.1-1 expression levels were noticed in the cisplatin-resistant tongue SCC cells. Conclusions. Our results demonstrated that functional reannotation allows us to identify novel lncRNAs using the existing gene expression array dataset. The association of lncRNA with the T-stage and nodal status of tongue SCC patients suggested that lncRNA deregulation was involved in the pathogenesis of tongue SCC. Wei Gao, Jimmy Yu-Wai Chan, and Thian-Sze Wong Copyright © 2014 Wei Gao et al. All rights reserved. Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis Mon, 16 Jun 2014 09:19:47 +0000 http://www.hindawi.com/journals/bmri/2014/364207/ Background. The prognostic significance of COX2 for survival of patients with oral cancer remains controversial. Thus, the meta-analysis was performed in order to identify COX2 expression impact on prognosis of oral cancer. Method. Relevant literatures were searched using the following electronic databases without any language restrictions: Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and CBM. Version 12.0 STATA software (Stata Corporation, College Station, Texas, USA) was used for the current meta-analysis. Odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence interval (95% CI) were also calculated to clarify the correlation between COX2 expression and prognosis of oral cancer. Results. Final analysis of 979 oral cancer patients from 12 clinical cohort studies was performed. The meta-analysis results show that COX2 expression in cancer tissues was significantly higher than those in normal and benign tissues (all P < 0.05). Combined HR of COX2 suggests that positive COX2 expression has a shorter overall survival (OS) than those of negative COX2 expression (P < 0.05). Conclusion. The meta-analysis study shows that elevated COX2 expression may be associated with the pathogenesis of oral cancer and with a worse prognosis in oral cancer patients. Zhi-Ming Wang, Jie Liu, Hong-Bo Liu, Ming Ye, Yu-Fei Zhang, and Dong-Sheng Yang Copyright © 2014 Zhi-Ming Wang et al. All rights reserved. Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis? Thu, 12 Jun 2014 07:19:45 +0000 http://www.hindawi.com/journals/bmri/2014/934038/ The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for), and the principles of biological organization that would help in integrating and understanding experimental data. Mariano Bizzarri and Alessandra Cucina Copyright © 2014 Mariano Bizzarri and Alessandra Cucina. All rights reserved. A RXR Ligand 6-OH-11-O-Hydroxyphenanthrene with Antitumour Properties Enhances (−)-Epigallocatechin-3-gallate Activity in Three Human Breast Carcinoma Cell Lines Wed, 11 Jun 2014 14:24:32 +0000 http://www.hindawi.com/journals/bmri/2014/853086/ (−)-Epigallocatechin-3-gallate (EGCG) and chemotherapeutic agents cotreatment can improve cytotoxicity against cancer cells. We showed that EGCG and the rexinoid 6-OH-11-O-hydroxyphenanthrene (IIF), given together, were cytotoxic toward MCF-7, MCF-7TAM, and MDA-MB-231, three breast carcinoma cell lines showing different molecular characteristics. Cell growth arrest and apoptosis were greater after EGCG and IIF cotreatment than after individual administration. Cytotoxicity was related to upregulation of 67-kDa laminin receptor (LR67), one of the principal molecular targets of EGCG, and activation of the nuclear retinoic X receptors (RXRs) pathway. Furthermore, the transcription factor Forkhead box O3 (Foxo3a), a protein able to trigger apoptosis through upregulation of genes necessary for cell death, was activated. EGCG and IIF cotreatment produced a significant nuclear import of Foxo3a from the cytoplasm in MCF-7, MCF-7TAM, and MDA-MB-231 cells. In MCF-7TAM cells only, Foxo3a nuclear localization was associated with p473AKT downregulation. For the first time we showed that when EGCG and IIF, two harmless molecules, were given together, they might increase cytotoxicity in three breast carcinoma cell lines, two of them being representative of poorly responsive breast carcinoma types. Fulvia Farabegoli, Marzia Govoni, Carmen Ciavarella, Marina Orlandi, and Alessio Papi Copyright © 2014 Fulvia Farabegoli et al. All rights reserved. Immunological Dysregulation in Multiple Myeloma Microenvironment Wed, 11 Jun 2014 11:36:49 +0000 http://www.hindawi.com/journals/bmri/2014/198539/ Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target. Alessandra Romano, Concetta Conticello, Maide Cavalli, Calogero Vetro, Alessia La Fauci, Nunziatina Laura Parrinello, and Francesco Di Raimondo Copyright © 2014 Alessandra Romano et al. All rights reserved. The Role of 3 Tesla Diffusion-Weighted Imaging in the Differential Diagnosis of Benign versus Malignant Cervical Lymph Nodes in Patients with Head and Neck Squamous Cell Carcinoma Mon, 09 Jun 2014 08:56:12 +0000 http://www.hindawi.com/journals/bmri/2014/532095/ Objective. The aim of this study was to validate the role of diffusion-weighted imaging (DWI) at 3 Tesla in the differential diagnosis between benign and malignant laterocervical lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC). Materials and Methods. Before undergoing surgery, 80 patients, with biopsy proven HNSCC, underwent a magnetic resonance exam. Sensitivity (Se) and specificity (Spe) of conventional criteria and DWI in detecting laterocervical lymph node metastases were calculated. Histological results from neck dissection were used as standard of reference. Results. In the 239 histologically proven metastatic lymphadenopathies, the mean apparent diffusion coefficient (ADC) value was 0.903 × 10−3 mm2/sec. In the 412 pathologically confirmed benign lymph nodes, an average ADC value of 1.650 × 10−3 mm2/sec was found. For differentiating between benign versus metastatic lymph nodes, DWI showed Se of 97% and Spe of 93%, whereas morphological criteria displayed Se of 61% and Spe of 98%. DWI showed an area under the ROC curve (AUC) of 0.964, while morphological criteria displayed an AUC of 0.715. Conclusions. In a DWI negative neck for malignant lymph nodes, the planned dissection could be converted to a wait-and-scan policy, whereas DWI positive neck would support the decision to perform a neck dissection. Flavio Barchetti, Nicola Pranno, Guglielmo Giraldi, Alessandro Sartori, Silvia Gigli, Giovanni Barchetti, Luigi Lo Mele, and Luigi Tonino Marsella Copyright © 2014 Flavio Barchetti et al. All rights reserved. Microenvironment, Oncoantigens, and Antitumor Vaccination: Lessons Learned from BALB-neuT Mice Tue, 03 Jun 2014 12:15:22 +0000 http://www.hindawi.com/journals/bmri/2014/534969/ The tyrosine kinase human epidermal growth factor receptor 2 (HER2) gene is amplified in approximately 20% of human breast cancers and is associated with an aggressive clinical course and the early development of metastasis. Its crucial role in tumor growth and progression makes HER2 a prototypic oncoantigen, the targeting of which may be critical for the development of effective anticancer therapies. The setup of anti-HER2 targeting strategies has revolutionized the clinical outcome of HER2+ breast cancer. However, their initial success has been overshadowed by the onset of pharmacological resistance that renders them ineffective. Since the tumor microenvironment (TME) plays a crucial role in drug resistance, the design of more effective anticancer therapies should depend on the targeting of both cancer cells and their TME as a whole. In this review, starting from the successful know-how obtained with a HER2+ mouse model of mammary carcinogenesis, the BALB-neuT mice, we discuss the role of TME in mammary tumor development. Indeed, a deeper knowledge of antigens critical for cancer outbreak and progression and of the mechanisms that regulate the interplay between cancer and stromal cell populations could advise promising ways for the development of the best anticancer strategy. Laura Conti, Roberto Ruiu, Giuseppina Barutello, Marco Macagno, Silvio Bandini, Federica Cavallo, and Stefania Lanzardo Copyright © 2014 Laura Conti et al. All rights reserved. Promoter Region Hypermethylation and mRNA Expression of MGMT and p16 Genes in Tissue and Blood Samples of Human Premalignant Oral Lesions and Oral Squamous Cell Carcinoma Mon, 02 Jun 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/248419/ Promoter methylation and relative gene expression of O6-methyguanine-DNA-methyltransferase (MGMT) and p16 genes were examined in tissue and blood samples of patients with premalignant oral lesions (PMOLs) and oral squamous cell carcinoma (OSCC). Methylation-specific PCR and reverse transcriptase PCR were performed in 146 tissue and blood samples from controls and patients with PMOLs and OSCC. In PMOL group, significant promoter methylation of MGMT and p16 genes was observed in 59% () and 57% () of tissue samples, respectively, and 39% () and 33% () of blood samples, respectively. Promoter methylation of both genes was more frequent in patients with OSCC, that is, 76% () and 82% () in tissue and 57% () and 70% () in blood, respectively. Significant downregulation of MGMT and p16 mRNA expression was observed in both tissue and blood samples from patients with PMOLs and OSCC. Hypermethylation-induced transcriptional silencing of MGMT and p16 genes in both precancer and cancer suggests important role of these changes in progression of premalignant state to malignancy. Results support use of blood as potential surrogate to tissue samples for screening or diagnosing PMOLs and early OSCC. Vikram Bhatia, Madhu Mati Goel, Annu Makker, Shikha Tewari, Alka Yadu, Priyanka Shilpi, Sandeep Kumar, S. P. Agarwal, and Sudhir K. Goel Copyright © 2014 Vikram Bhatia et al. All rights reserved. CXC and CC Chemokines as Angiogenic Modulators in Nonhaematological Tumors Thu, 29 May 2014 08:43:38 +0000 http://www.hindawi.com/journals/bmri/2014/768758/ Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors. Matteo Santoni, Sergio Bracarda, Massimo Nabissi, Francesco Massari, Alessandro Conti, Emilio Bria, Giampaolo Tortora, Giorgio Santoni, and Stefano Cascinu Copyright © 2014 Matteo Santoni et al. All rights reserved. A Novel Technique for Prealignment in Multimodality Medical Image Registration Thu, 22 May 2014 13:33:27 +0000 http://www.hindawi.com/journals/bmri/2014/726852/ Image pair is often aligned initially based on a rigid or affine transformation before a deformable registration method is applied in medical image registration. Inappropriate initial registration may compromise the registration speed or impede the convergence of the optimization algorithm. In this work, a novel technique was proposed for prealignment in both monomodality and multimodality image registration based on statistical correlation of gradient information. A simple and robust algorithm was proposed to determine the rotational differences between two images based on orientation histogram matching accumulated from local orientation of each pixel without any feature extraction. Experimental results showed that it was effective to acquire the orientation angle between two unregistered images with advantages over the existed method based on edge-map in multimodalities. Applying the orientation detection into the registration of CT/MR, T1/T2 MRI, and monomadality images with respect to rigid and nonrigid deformation improved the chances of finding the global optimization of the registration and reduced the search space of optimization. Wu Zhou, Lijuan Zhang, Yaoqin Xie, and Changhong Liang Copyright © 2014 Wu Zhou et al. All rights reserved. Validation of Planning Target Volume Margins by Analyzing Intrafractional Localization Errors for 14 Prostate Cancer Patients Based on Three-Dimensional Cross-Correlation between the Prostate Images of Planning CT and Intrafraction Cone-Beam CT during Volumetric Modulated Arc Therapy Thu, 22 May 2014 09:40:04 +0000 http://www.hindawi.com/journals/bmri/2014/960928/ Time-averaged intreatment prostate localization errors were calculated, for the first time, by three-dimensional prostate image cross-correlation between planning CT and intrafraction kilovoltage cone-beam CT (CBCT) during volumetric modulated arc therapy (VMAT). The intrafraction CBCT volume was reconstructed by an inhouse software after acquiring cine-mode projection images during VMAT delivery. Subsequently, the margin between a clinical target volume and a planning target volume (PTV) was obtained by applying the van Herk and variant formulas using the calculated localization errors. The resulting PTV margins were approximately 2 mm in lateral direction and 4 mm in craniocaudal and anteroposterior directions, which are consistent with the margin prescription employed in our facility. Kenshiro Shiraishi, Masahiko Futaguchi, Akihiro Haga, Akira Sakumi, Katsutake Sasaki, Kentaro Yamamoto, Hiroshi Igaki, Kuni Ohtomo, Kiyoshi Yoda, and Keiichi Nakagawa Copyright © 2014 Kenshiro Shiraishi et al. All rights reserved. Real-Time Elastography of the Prostate Thu, 22 May 2014 09:21:12 +0000 http://www.hindawi.com/journals/bmri/2014/180804/ Palpation of organs is one of the oldest clinical examination techniques, for instance, if you think of the palpation of the breast or the digital rectal examination of the prostate, where hard palpable regions are suspicious for cancer. This is the basic principle of real-time elastography, an ultrasound technique, which is able to visualise tissue elasticity. Since prostate cancer features an increased stiffness due to the higher cell and vessel density than the normal surrounding tissue, real-time elastography has been used for several years for prostate cancer detection. This review introduces the different techniques of ultrasound elastography and furthermore summarises its limitations and potentials. D. Junker, T. De Zordo, M. Quentin, M. Ladurner, J. Bektic, W. Horniger, W. Jaschke, and F. Aigner Copyright © 2014 D. Junker et al. All rights reserved. Exosome in Tumour Microenvironment: Overview of the Crosstalk between Normal and Cancer Cells Wed, 21 May 2014 07:49:41 +0000 http://www.hindawi.com/journals/bmri/2014/179486/ Cancer development is a multistep process in which exosomes play important roles. Exosomes are small vesicles formed in vesicular bodies in the endosomal network. The major role of exosomes seems to be the transport of bioactive molecules between cells. Depending on the cell of origin, exosomes are implicated in the regulation of several cellular events, with phenotypic consequences in recipient cells. Cancer derived exosomes (CCEs) are important players in the formation of the tumour microenvironment by (i) enabling the escape of tumour cells to immunological system and help initiating the inflammatory response; (ii) acting in the differentiation of fibroblasts and mesenchymal cells into myofibroblasts; (iii) triggering the angiogenic process; and (iv) enhancing the metastatic evolution of the tumour by promoting epithelial to mesenchymal transformation of tumour cells and by preparing the tumour niche in the new anatomical location. Since the finding that exosomes content resembles that of the cell of origin, they may be regarded as suitable biomarkers for cancer diagnosis, allowing for diagnosis and prognosis via a minimal invasive procedure. Exosome involvement in cancer may open new avenues regarding therapeutics, such as vectors for targeted drug delivery. Catarina Roma-Rodrigues, Alexandra R. Fernandes, and Pedro Viana Baptista Copyright © 2014 Catarina Roma-Rodrigues et al. All rights reserved. Use Dose Bricks Concept to Implement Nasopharyngeal Carcinoma Treatment Planning Wed, 21 May 2014 07:39:02 +0000 http://www.hindawi.com/journals/bmri/2014/720876/ Purpose. A “dose bricks” concept has been used to implement nasopharyngeal carcinoma treatment plan; this method specializes particularly in the case with bell shape nasopharyngeal carcinoma case. Materials and Methods. Five noncoplanar fields were used to accomplish the dose bricks technique treatment plan. These five fields include (a) right superior anterior oblique (RSAO), (b) left superior anterior oblique (LSAO), (c) right anterior oblique (RAO), (d) left anterior oblique (LAO), and (e) superior inferior vertex (SIV). Nondivergence collimator central axis planes were used to create different abutting field edge while normal organs were blocked by multileaf collimators in this technique. Results. The resulting 92% isodose curves encompassed the CTV, while maximum dose was about 115%. Approximately 50% volume of parotid glands obtained 10–15% of total dose and 50% volume of brain obtained less than 20% of total dose. Spinal cord receives only 5% from the scatter dose. Conclusions. Compared with IMRT, the expenditure of planning time and costing, “dose bricks” may after all be accepted as an optional implementation in nasopharyngeal carcinoma conformal treatment plan; furthermore, this method also fits the need of other nonhead and neck lesions if organ sparing and noncoplanar technique can be executed. Jia-Ming Wu, Tsan-Jung Yu, Shyh-An Yeh, Pei-Ju Chao, Chih-Jou Huang, and Tsair-Fwu Lee Copyright © 2014 Jia-Ming Wu et al. All rights reserved. Evaluation of Prognostic Significance of Circulating Tumor Cells Detection in Rectal Cancer Patients Treated with Preoperative Radiotherapy: Prospectively Collected Material Data Wed, 21 May 2014 07:33:02 +0000 http://www.hindawi.com/journals/bmri/2014/712827/ The aim of this study was to evaluate the prognostic value of circulating tumor cells (CTC) in nonmetastatic rectal cancer patients treated with short-term preoperative radiotherapy. In this single-center trial, 162 patients with rectal cancer after preoperative short-term radiotherapy ( Gy) were recruited from January, 2008 to September, 2011. Clearance of CTC was determined in 91 patients enrolled in the molecular analysis. CTC presence was evaluated with real-time reverse transcription polymerase chain reaction assay (qPCR) based on the expression of three tumor genetic markers: carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), and/or cancer stem cells marker CD133 (CEA/CK20/CD133). We found that CTC detection 7 days after surgery was of prognostic significance for the local recurrence (P value = 0.006). CTC detected preoperatively and 24 hours after resection had no prognostic value in cancer recurrence; however, there was a significant relationship between CTC prevalence 24 hours after surgery and lymph node metastasis (pN1-2). We also confirmed a significant clearance of CTC in peripheral blood (PB) 24 hours after surgery. Preoperative sampling is not significant for prognosis in rectal cancer patients treated with short-term radiotherapy. Detection of CTC in PB 7 days after surgery is an independent factor predicting local recurrence in this group of patients. Dominika Nesteruk, Andrzej Rutkowski, Stanisław Fabisiewicz, Jacek Pawlak, Janusz A. Siedlecki, and Anna Fabisiewicz Copyright © 2014 Dominika Nesteruk et al. All rights reserved. Prolonged Nitric Oxide Exposure Enhances Anoikis Resistance and Migration through Epithelial-Mesenchymal Transition and Caveolin-1 Upregulation Tue, 20 May 2014 07:43:26 +0000 http://www.hindawi.com/journals/bmri/2014/941359/ Nitric oxide (NO) in tumor microenvironment may have a significant impact on metastatic behaviors of cancer. Noncytotoxic doses of NO enhanced anoikis resistance and migration in lung cancer H23 cells via an increase in lamellipodia, epithelial-mesenchymal transition (EMT) markers including vimentin and snail, and caveolin-1 (Cav-1). However, the induction of EMT was found in Cav-1-knock down cells treated with NO, suggesting that EMT was through Cav-1-independent pathway. These effects of NO were consistently observed in other lung cancer cells including H292 and H460 cells. These findings highlight the novel role of NO on EMT and metastatic behaviors of cancer cells. Pithi Chanvorachote, Varisa Pongrakhananon, and Preedakorn Chunhacha Copyright © 2014 Pithi Chanvorachote et al. All rights reserved. Development and Characterization of New Monoclonal Antibodies against Human Recombinant CA XII Tue, 20 May 2014 06:57:38 +0000 http://www.hindawi.com/journals/bmri/2014/309307/ Carbonic anhydrases (CAs) are enzymes that catalyse the reversible hydration of CO2 to bicarbonate. CA XII is considered a potential biomarker of tumor cells and a promising target for specific therapies. The aim of the current study was to develop new monoclonal antibodies (MAbs) against human recombinant CA XII and evaluate their diagnostic potential. An extracellular catalytic domain of human CA XII was expressed in E. coli and used as an immunogen. Seven stable hybridoma cell lines producing high-affinity IgG antibodies against human CA XII were generated. The majority of MAbs were highly specific to CA XII and did not cross-react with human recombinant CA I, CA II, CA VII, and CA XIII. In order to demonstrate the diagnostic value of the MAbs, they were employed for the immunohistochemistry analysis of CA XII expression in tissues. Two MAbs (15A4 and 4A6) demonstrated a strong and specific immunostaining of CA XII in human tissue specimens. Flow cytometry analysis of 5 human tumor cell lines with the MAb 15A4 revealed its immunoreactivity with cellular CA XII. In conclusion, the MAbs raised against recombinant catalytic domain of CA XII recognize cellular CA XII and represent a promising diagnostic tool for the immunodetection of CA XII-expressing cells. Dovile Dekaminaviciute, Rita Lasickiene, Seppo Parkkila, Vaida Jogaite, Jurgita Matuliene, Daumantas Matulis, and Aurelija Zvirbliene Copyright © 2014 Dovile Dekaminaviciute et al. All rights reserved. Role of MicroRNA-1 in Human Cancer and Its Therapeutic Potentials Sun, 18 May 2014 10:43:43 +0000 http://www.hindawi.com/journals/bmri/2014/428371/ While the mechanisms of human cancer development are not fully understood, evidence of microRNA (miRNA, miR) dysregulation has been reported in many human diseases, including cancer. miRs are small noncoding RNA molecules that regulate posttranscriptional gene expression by binding to complementary sequences in the specific region of gene mRNAs, resulting in downregulation of gene expression. Not only are certain miRs consistently dysregulated across many cancers, but they also play critical roles in many aspects of cell growth, proliferation, metastasis, apoptosis, and drug resistance. Recent studies from our group and others revealed that miR-1 is frequently downregulated in various types of cancer. Through targeting multiple oncogenes and oncogenic pathways, miR-1 has been demonstrated to be a tumor suppressor gene that represses cancer cell proliferation and metastasis and promotes apoptosis by ectopic expression. In this review, we highlight recent findings on the aberrant expression and functional significance of miR-1 in human cancers and emphasize its significant values for therapeutic potentials. Chao Han, Zujiang Yu, Zhenfeng Duan, and Quancheng Kan Copyright © 2014 Chao Han et al. All rights reserved. Expression of LacdiNAc Groups on N-Glycans among Human Tumors Is Complex Sun, 18 May 2014 10:28:51 +0000 http://www.hindawi.com/journals/bmri/2014/981627/ Aberrant glycosylation of proteins and lipids is one of the characteristic features of malignantly transformed cells. The GalNAcβ1 → 4GlcNAc (LacdiNAc or LDN) group at the nonreducing termini of both N- and O-glycans is not generally found in mammalian cells. We previously showed that the expression level of the LacdiNAc group in N-glycans decreases dramatically during the progression of human breast cancer. In contrast, the enhanced expression of the LacdiNAc group has been shown to be associated with the progression of human prostate, ovarian, and pancreatic cancers. Therefore, the expression of the disaccharide group appears to be dependent on types of tumors. The mechanism of formation of the LacdiNAc group in human tumors and cancer cells has been studied, and two β4-N-acetylgalacto-saminyltransferases (β4GalNAcTs), β4GalNAcT3 and β4GalNAcT4, have been shown to be involved in the biosynthesis of this disaccharide group in a tissue-dependent manner. Transfection of the β4GalNAcT3 gene brought about significant changes in the malignant phenotypes of human neuroblastoma, indicating that this disaccharide group is important for suppressing the tumor growth. Kiyoko Hirano, Akio Matsuda, Takashi Shirai, and Kiyoshi Furukawa Copyright © 2014 Kiyoko Hirano et al. All rights reserved. Expression of Serum Exosomal MicroRNA-21 in Human Hepatocellular Carcinoma Sun, 18 May 2014 08:42:37 +0000 http://www.hindawi.com/journals/bmri/2014/864894/ New strategies for the diagnosis of hepatocellular carcinoma (HCC) are urgently needed. There is an increasing interest in using microRNAs (miRNAs) as biomarkers in diseases. In this study, we examined the expression of miR-21 in serum exosomes from patients with HCC or chronic hepatitis B (CHB) and investigated the potential clinical significance of miR-21. Quantitative RT-PCR indicated that the concentration of miR-21 was significantly higher in exosomes than in exosome-depleted supernatants or the whole serum. Further, the expression level of serum exosomal miR-21 was significantly higher in patients with HCC than those with CHB or healthy volunteers (, , resp.). High level of miR-21 expression correlated with cirrhosis () and advanced tumor stage (). Although serum level of miR-21 was higher in patients with HCC than in patients with CHB and healthy volunteers, the sensitivity of detection is much lower than using exosomal miR-21. These findings indicate that miR-21 is enriched in serum exosomes which provides increased sensitivity of detection than whole serum. Exosomal miR-21 may serve as a potential biomarker for HCC diagnosis. Hongwei Wang, Lijuan Hou, Aihui Li, Yuxiu Duan, Haili Gao, and Xinwen Song Copyright © 2014 Hongwei Wang et al. All rights reserved. C-Kit Expression, Angiogenesis, and Grading in Canine Mast Cell Tumour: A Unique Model to Study C-Kit Driven Human Malignancies Mon, 12 May 2014 13:59:34 +0000 http://www.hindawi.com/journals/bmri/2014/730246/ Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans. Rosa Patruno, Ilaria Marech, Nicola Zizzo, Michele Ammendola, Patrizia Nardulli, Claudia Gadaleta, Marcello Introna, Gennaro Capriuolo, Rosa Angela Rubini, Domenico Ribatti, Cosmo Damiano Gadaleta, and Girolamo Ranieri Copyright © 2014 Rosa Patruno et al. All rights reserved. Experience of 1166 Thyroidectomy without Use of Prophylactic Antibiotic Mon, 12 May 2014 13:12:03 +0000 http://www.hindawi.com/journals/bmri/2014/758432/ Background. Although the procedure requires a small surgical incision and a short duration, incision infection rate is very low in thyroidectomy; however, doctors still have misgivings about infection events. Aim. We retrospectively analyzed the prevention of incision infection without perioperative use of antibacterial medications following thyroidectomy. Materials and Methods. 1166 patients of thyroidectomy were not administered perioperative antibiotics. Unilateral total lobectomy or partial thyroidectomy was performed in 68.0% patients with single-side nodular goiter or thyroid adenoma. Bilateral partial thyroidectomy was performed in 25.5% patients with nodular goiter or Graves’ disease. The mean time of operation was 80.6 ± 4.87 (range: 25–390) min. Results. Resuturing was performed in two patients of secondary hemorrhage from residual thyroid following bilateral partial thyroidectomy. Temporally recurrent nerve paralysis was reported following right-side total lobectomy and left-side subtotal lobectomy in a nodular goiter patient. One case had suppurative infection in neck incision 5 days after bilateral partial thyroidectomy. Conclusions. Thyroidectomy, which is a clean incision, involves a small incision, short duration, and minor hemorrhage. If the operation is performed under strict conditions of sterility and hemostasis, antibacterial medications may not be required to prevent incision infection, which reduces cost and discourages the excessive use of antibiotics. Qiang Lu, Shu-Qin Xie, Si-Yuan Chen, Li-Ju Chen, and Qian Qin Copyright © 2014 Qiang Lu et al. All rights reserved. Radiosensitization Effect of Nedaplatin on Nasopharyngeal Carcinoma Cells in Different Status of Epstein-Barr Virus Infection Mon, 12 May 2014 09:27:30 +0000 http://www.hindawi.com/journals/bmri/2014/713674/ This study aims to evaluate the radiosensitization effect of nedaplatin on nasopharyngeal carcinoma (NPC) cell lines with different Epstein-Barr virus (EBV) status. Human NPC cell lines CNE-2 (EBV-negative) and C666 (EBV-positive) were treated with 0–100 μg/mL nedaplatin, and inhibitory effects on cell viability and IC50 were calculated by MTS assay. We assessed changes in radiosensitivity of cells by MTS and colony formation assays, and detected the apoptosis index and changes in cell cycle by flow cytometry. MTS assay showed that nedaplatin caused significant cytotoxicity in CNE-2 and C666 cells in a time- and dose-dependent manner. After 24 h, nedaplatin inhibited growth of CNE-2 and C666 cells with IC50 values of 34.32 and 63.69 μg/mL, respectively. Compared with radiation alone, nedaplatin enhanced the radiation effect on both cell lines. Nedaplatin markedly increased apoptosis and cell cycle arrest in G2/M phase. Nedaplatin radiosensitized human NPC cells CNE-2 and C666, with a significantly greater effect on the former. The mechanisms of radiosensitization include induction of apoptosis and enhancement of cell cycle arrest in G2/M phase. Li Yin, Jing Wu, Jianfeng Wu, Jinjun Ye, Xuesong Jiang, Meng Chen, Dejun Wang, Xue Wang, Dan Zong, Jiajia Gu, Junying Zhang, Jianzhong Wu, Lin Xu, Xia He, and Wenjie Guo Copyright © 2014 Li Yin et al. All rights reserved. Human Serum Albumin Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN38) for Cancer Treatment Wed, 07 May 2014 08:31:06 +0000 http://www.hindawi.com/journals/bmri/2014/963507/ SN38 (7-ethyl-10-hydroxy-comptothecin) is a potent metabolite of irinotecan, which has been approved for treatment of metastatic colorectal cancer. Considering the notable potency of SN38, it has been introduced as an anticancer candidate. In this study, human serum albumin (HSA) conjugates of SN38 were formulated to overcome the solubility problem beside improving the active form stability and tumor tissue targeting. In this target, two different molar ratios of conjugates (SN38 : HSA 15 : 1 and 60 : 1) were prepared by derivatization of 20-hydroxyl group of SN38 with glycine, followed by addition of succinyl group to glycine through which HSA was covalently attached. The conjugates with particle size of about 100 nm revealed enhanced water solubility and were relatively stable in neutral and acidic solutions. For SN38-HSA-15 and SN38-HSA-60 IC50 values were compared with irinotecan in HT-29 human colon cancer cells. Furthermore, biodistribution studies of SN38-HSA conjugate resulted in proper blood concentration level within 4 h. Moreover, blood cytotoxicity assay revealed no toxicity effect on liver and spleen. Collectively, our present investigation offers a water-soluble form of SN38 attached to HSA and suggests using favorable properties as a promising anticancer agent for further preclinical and clinical investigations. Nima Sepehri, Hasti Rouhani, Ahmad Reza Ghanbarpour, Mehdi Gharghabi, Faranak Tavassolian, Mohsen Amini, Seyed Nasser Ostad, Mohammad Hossein Ghahremani, and Rassoul Dinarvand Copyright © 2014 Nima Sepehri et al. All rights reserved. Helical Tomotherapy Combined with Capecitabine in the Preoperative Treatment of Locally Advanced Rectal Cancer Tue, 06 May 2014 08:18:09 +0000 http://www.hindawi.com/journals/bmri/2014/352083/ The aim of this study was to evaluate the efficacy of helical tomotherapy plus capecitabine as a preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Thirty-six LARC patients receiving preoperative CRT were analyzed. Radiotherapy (RT) consisted of 45 Gy to the regional lymph nodes and simultaneous-integrated boost (SIB) 50.4 Gy to the tumor, 5 days/week for 5 weeks. Chemotherapy consisted of capecitabine 850 mg/m2, twice daily, during the RT days. Patients underwent surgery 6–8 weeks after completion of CRT. Information was collected for patient characteristics, treatment response, and acute and late toxicities. Grade 3/4 (G3+) toxicities occurred in 11.1% of patients (4/36). Sphincter preservation rate was 85.2% (23/27). Five patients (14.3%) achieved pathological complete response. Tumor, nodal, and ypT0-2N0 downstaging were noted in 60% (21/35), 69.6% (16/23), and 57.1% (20/35). Tumor regression grade 2~4 was achieved in 28 patients (80%). After a median follow-up time of 35 months, the most common G3+ late morbidity was ileus and fistula (5.7%, 2/35). The study showed that capecitabine plus helical tomotherapy with an SIB is feasible in treatment of LARC. The treatment modality can achieve a very encouraging sphincter preservation rate and a favorable ypT0-2N0 downstaging rate without excessive toxicity. Ming-Yii Huang, Chin-Fan Chen, Chun-Ming Huang, Hsiang-Lin Tsai, Yung-Sung Yeh, Cheng-Jen Ma, Chan-Han Wu, Chien-Yu Lu, Chee-Yin Chai, Chih-Jen Huang, and Jaw-Yuan Wang Copyright © 2014 Ming-Yii Huang et al. All rights reserved. FOXP3 Transcription Factor: A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer Wed, 30 Apr 2014 12:02:27 +0000 http://www.hindawi.com/journals/bmri/2014/341654/ Triple negative breast cancer (TNBC) is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2). FOXP3 (forkhead transcription factor 3) is a marker of regulatory T cells (Tregs), whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548) and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction). Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06) in relation to TNBC susceptibility. Most of the patients (83%) showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (). In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples. Leandra Fiori Lopes, Roberta Losi Guembarovski, Alda Losi Guembarovski, Marina Okuyama Kishima, Clodoaldo Zago Campos, Julie Massayo Maeda Oda, Carolina Batista Ariza, Karen Brajão de Oliveira, Sueli Donizete Borelli, and Maria Angelica Ehara Watanabe Copyright © 2014 Leandra Fiori Lopes et al. All rights reserved. Association of Tissue mRNA and Serum Antigen Levels of Members of the Urokinase-Type Plasminogen Activator System with Clinical and Prognostic Parameters in Prostate Cancer Tue, 29 Apr 2014 13:24:41 +0000 http://www.hindawi.com/journals/bmri/2014/972587/ The objective was to determine the mRNA expression and protein levels of uPA system components in tissue specimens and serum samples, respectively, from prostate cancer (PCa) patients and to assess their association with clinicopathological parameters and overall survival (OS). The mRNA expression levels of uPA, its receptor (uPAR), and its inhibitor type 1 (PAI-1) were analyzed in corresponding malignant and adjacent nonmalignant tissue specimens from 132 PCa patients by quantitative PCR. Preoperative serum samples from 81 PCa patients were analyzed for antigen levels of uPA system members by ELISA. RNA levels of uPA system components displayed significant correlations with each other in the tumor tissues. A significantly decreased uPA mRNA expression in PCa compared to the corresponding nonmalignant tissue was detected. High uPA mRNA level was significantly associated with a high Gleason score. Elevated concentration of soluble uPAR (suPAR) in serum was significantly associated with a poor OS of PCa patients (). PCa patients with high suPAR levels have a significantly higher risk of death (multivariate Cox’s regression analysis; , ). The association of high suPAR levels with poor survival of PCa patients suggests a prognostic impact of suPAR levels in serum of cancer patients. Omar Al-Janabi, Helge Taubert, Andrea Lohse-Fischer, Michael Fröhner, Sven Wach, Robert Stöhr, Bastian Keck, Max Burger, Wolf Wieland, Kati Erdmann, Manfred P. Wirth, Bernd Wullich, Gustavo Baretton, Viktor Magdolen, Matthias Kotzsch, and Susanne Füssel Copyright © 2014 Omar Al-Janabi et al. All rights reserved. Inflammation-Based Scores: A New Method for Patient-Targeted Strategies and Improved Perioperative Outcome in Cancer Patients Sun, 27 Apr 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/142425/ Systemic inflammatory response (SIR) has actually been shown as an important prognostic factor associated with lower postoperative survival in several types of cancer. Thus, the challenge for physicians is to find specific, low-cost, and highlyreliable inflammatory markers, clearly correlated with prognosis and able to preoperatively stratify patient’s risk. Inflammation is a promising target to improve perioperative outcome, and data show that anti-inflammation techniques have a great potential in the perioperative period of cancer surgery. Inflammation scores could be useful to stratify patients with a potential better response to anti-inflammation strategies. Furthermore, inflammation scores could prevent failure of clinical trials by a better definition of patients to be included in such trials; inflammation scoring could clarify the real role of different drugs and techniques on outcome after cancer surgery, defining if different therapies are required for different patients. The role of this review is to focus on the currently available scores, in order to clarify their rationale and to analyze the actual evidence and limits, providing physicians with an updated overview of the possible inflammation-based prognostic scores for cancer patients undergoing surgery. Dario Bugada, Massimo Allegri, Patricia Lavand'homme, Marc De Kock, and Guido Fanelli Copyright © 2014 Dario Bugada et al. All rights reserved. Oxidative Stress Indicators in Patients with Prostate Disorders in Enugu, South-East Nigeria Thu, 24 Apr 2014 13:47:34 +0000 http://www.hindawi.com/journals/bmri/2014/313015/ Depletion of cellular antioxidants can result from free radical formation due to normal endogenous reactions and the ingestion of exogenous substances and environmental factors. The levels of reactive oxygen species-(ROS-) scavenging enzymes such as SOD and glutathione peroxidase have been shown to be significantly altered in malignant cells and in primary cancer tissues. The aim of this study was to determine the antioxidant status of patients with prostate disorders in South-East Nigeria to ascertain the possible role of depletion of antioxidants in prostatic degeneration. 104 subjects made up of 40 PCa patients, 32 with BPH, and 32 controls participated in this study. The levels of superoxide dismutase, glutathione peroxidase, vitamin C, and vitamin E were estimated using standard procedures. The results show that both the BPH and PCa patients had a significant decrease () in GPX, SOD, vitamin C, and vitamin E levels compared to the control subjects. However, there was also a significant decrease () in SOD and vitamin C levels in PCa patients when compared with the BPH group. This indicates that patients with BPH and prostate cancer have decreased antioxidant status and may benefit from micronutrient supplementation. Romanda Duru, Obioma Njoku, and Ignatius Maduka Copyright © 2014 Romanda Duru et al. All rights reserved. IDH1/IDH2 but Not TP53 Mutations Predict Prognosis in Bulgarian Glioblastoma Patients Thu, 24 Apr 2014 12:53:22 +0000 http://www.hindawi.com/journals/bmri/2014/654727/ Mutations in genes encoding isocitrate dehydrogenase isoforms 1 (IDH1) and 2 (IDH2) have been associated with good prognosis for patients with brain neoplasias and have been commonly found together with mutated TP53 gene. To determine the prevalence of IDH1, IDH2, and TP53 mutations and their impact on overall survival 106 glioblastoma patients were analysed. IDH1 mutations were detected in 13 and IDH2 mutation in one patient. Two homozygous samples with R132H mutation in IDH1 gene and a novel aberration K129R in IDH2 gene were found. Sixty-four percent of IDH1/IDH2 mutated tumours harboured also a mutation in TP53 gene. Genetic aberrations in TP53 were present in 37 patients. Statistical analysis of the impact of the studied factors on the overall survival showed that the mutations in IDH1/IDH2, but not the ones in TP53, were associated with longer survival. Also, the impact of age on prognosis was confirmed. This is the first comprehensive study on glioblastomas in Bulgaria. Our results suggest that IDH1/IDH2 but not TP53 mutations together with other prognostic factors such as age might be applied in clinical practice for prediction of outcome in patients with glioblastomas. Gergana Stancheva, Teodora Goranova, Maria Laleva, Margarita Kamenova, Atanaska Mitkova, Nikolay Velinov, George Poptodorov, Vanio Mitev, Radka Kaneva, and Nikolay Gabrovsky Copyright © 2014 Gergana Stancheva et al. All rights reserved. Leczyme: A New Candidate Drug for Cancer Therapy Wed, 23 Apr 2014 13:40:28 +0000 http://www.hindawi.com/journals/bmri/2014/421415/ Sialic acid-binding lectin (SBL), isolated from oocytes of Rana catesbeiana, is leczyme and has both lectin and ribonuclease (RNase) activities. A remarkable antitumor effect of SBL has also been reported. SBL agglutinates various kinds of tumor cells but not normal cells. SBL agglutination activity is not affected by mono- or oligosaccharides. However, SBL-induced agglutination and antitumor effects are inhibited by sialomucin but not asialomucin. In addition, SBL has very little effect on sialidase-treated cells. SBL causes cancer-selective induction of apoptosis by multiple signaling pathways, which target RNA. Synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL) and interferon-γ (IFN-γ), have been reported. Thus, SBL may be a novel candidate molecule for anticancer drug development. Sialoglycoconjugates on the tumor cell surface may be associated with lectin activity and antitumor effects of SBL. We review the properties of SBL, particularly its lectin, RNase, and antitumor activities, and comprehensively examine the potential application of SBL for clinical purposes. Takeo Tatsuta, Shigeki Sugawara, Kohta Takahashi, Yukiko Ogawa, Masahiro Hosono, and Kazuo Nitta Copyright © 2014 Takeo Tatsuta et al. All rights reserved. Hyperglycemia, a Neglected Factor during Cancer Progression Thu, 17 Apr 2014 07:50:39 +0000 http://www.hindawi.com/journals/bmri/2014/461917/ Recent evidence from large cohort studies suggests that there exists a higher cancer incidence in people with type 2 diabetes (DM2). However, to date, the potential reasons for this association remain unclear. Hyperglycemia, the most important feature of diabetes, may be responsible for the excess glucose supply for these glucose-hungry cells, and it contributes to apoptosis resistance, oncogenesis, and tumor cell resistance to chemotherapy. Considering associations between diabetes and malignancies, the effect of hyperglycemia on cancer progression in cancer patients with abnormal blood glucose should not be neglected. In this paper, we describe the role that hyperglycemia plays in cancer progression and treatment and illustrate that hyperglycemia may contribute to a more malignant phenotype of cancer cells and lead to drug resistance. Therefore, controlling hyperglycemia may have important therapeutic implications in cancer patients. Wanxing Duan, Xin Shen, Jianjun Lei, Qinhong Xu, Yongtian Yu, Rong Li, Erxi Wu, and Qingyong Ma Copyright © 2014 Wanxing Duan et al. All rights reserved. The Molecular Mechanisms of Tanshinone IIA on the Apoptosis and Arrest of Human Esophageal Carcinoma Cells Tue, 15 Apr 2014 13:14:36 +0000 http://www.hindawi.com/journals/bmri/2014/582730/ Objective. To explore the possible mechanisms of Tanshinone IIA (TanIIA) on esophageal carcinoma cell lines. Methods. Two human esophageal carcinoma cell lines (EC-1 cells and ECa-109 cells) were treated with different concentrations of TanIIA. Cell proliferation was measured by CCK-8, colony-forming efficiency was calculated, cell cycle and apoptosis were measured, and changes in cell cycle- and apoptosis-related gene expression were measured by Western blotting. Results. The CCK-8 and colony formation assay indicated that TanIIA inhibited the cell proliferation of human esophageal cancer cells (IC50 below 1 μg/mL) at 48 h. Hoechst 33258 and flow cytometry showed that TanIIA induced apoptosis in both esophageal cancer cell lines. Flow cytometry showed that TanIIA arrested cell cycle in S phase and G2/M phase. Western blotting analysis showed that Akt1 and its phosphorylation were inhibited, the Bax/Bcl-2 ratio increased, and both caspase-9 and caspase-3 were activated after treatment with 1.3 μg/mL TanIIA at 48 h. Meanwhile, p53 and p21 protein levels increased, whereas cyclin B1, CDC2, and CDC2 phosphorylation were inhibited. Conclusion. TanIIA inhibits the growth of esophageal cancer cells and induces apoptosis in a time-dependent and concentration-dependent manner, possibly by affecting cell cycle- and apoptosis-related signaling pathways. Jiang-Feng Wang, Jian-Guo Feng, Jing Han, Bei-Bei Zhang, and Wei-Min Mao Copyright © 2014 Jiang-Feng Wang et al. All rights reserved. Differential Expression of Long Noncoding RNA in Primary and Recurrent Nasopharyngeal Carcinoma Mon, 14 Apr 2014 17:26:29 +0000 http://www.hindawi.com/journals/bmri/2014/404567/ Background. Recent studies suggested that non-protein-coding genes are implicated in the tumorigenic process of nasopharyngeal carcinoma (NPC). In the present study, we aimed to identify the differentially expressed long noncoding RNA (lncRNA) using data available in the public domain. Methods. Microarray data set GSE12452 was reannotated with ncFANs. Real-time quantitative PCR was used to quantify and validate the identified lncRNAs in NPC. Results. In primary NPC, upregulation of lnc-C22orf32-1, lnc-AL355149.1-1, and lnc-ZNF674-1 was observed. High levels of lnc-C22orf32-1 and lnc-AL355149.1-1 were significantly associated with the male patients. In addition, increased expression of lnc-C22orf32-1 and lnc-ZNF674-1 was associated with advanced tumor stages. Recurrent NPC displayed a distinctive lncRNA expression pattern. lnc-BCL2L11-3 was significantly increased in the recurrent NPC tissues. In addition, significant reduction of lnc-AL355149.1-1 and lnc-ZNF674-1 was observed in the recurrent NPC tissues. Conclusions. Our results demonstrated that it is feasible to identify the differentially expressed lncRNA in the microarray dataset by functional reannotation. The association of lncRNA with gender and tumor size implicated that lncRNA possibly plays a part in the pathogenesis of primary NPC. Further, the distinctive lncRNA identified in the recurrent NPC may reveal a distinctive development mechanism underlying tumor recurrence. Wei Gao, Jimmy Yu-Wai Chan, and Thian-Sze Wong Copyright © 2014 Wei Gao et al. All rights reserved. Extracts from Glioma Tissues following Cryoablation Have Proapoptosis, Antiproliferation, and Anti-Invasion Effects on Glioma Cells Thu, 10 Apr 2014 09:37:39 +0000 http://www.hindawi.com/journals/bmri/2014/236939/ Objective. This study is to investigate the in vivo apoptotic processes in glioma tissues following cryoablation and the effects of glioma tissue extracts on GL261 glioma cells in vitro. Methods. TUNEL and flow cytometry analysis were performed to detect the apoptotic processes in the glioma tissues following cryoablation and in the GL261 cells treated with cryoablated tumor extracts. The scratch assay, the transwell assay, and Western blot analysis were carried out to evaluate the effects of cryoablated tumor extracts on the migration, invasion, and proliferation of tumor cells. Results. Our in vivo results indicated that the rapid-onset apoptosis was induced via the intrinsic pathway and the delayed apoptosis was triggered through the extrinsic pathway. The in vitro results showed that extracts from glioma tissues following cryoablation induced apoptosis via extrinsic pathways in GL261 glioma cells. Furthermore, cryoablated tumor extracts significantly inhibited the migration and proliferation of these cells, which would be related to the inhibition of ERK1/2 pathway and the activation of P38 pathway. Conclusion. Glioma cells surviving in cryoablation undergo intrinsic or extrinsic apoptosis. Augmenting the induction of apoptosis or enhancing the cryosensitization of tumor cells by coupling cryoablation with specific chemotherapy effectively increases the efficiency of this therapeutic treatment. Tianzhu Liu, Xin Wang, Zhilin Yin, Jun Pan, Hongbo Guo, and Shizhong Zhang Copyright © 2014 Tianzhu Liu et al. All rights reserved. Early Preinvasive Lesions in Ovarian Cancer Tue, 08 Apr 2014 08:58:00 +0000 http://www.hindawi.com/journals/bmri/2014/639252/ Faced with the catastrophic prognosis for ovarian cancer due to the fact that it is most often diagnosed late at the peritoneal carcinomatosis stage, screening and early detection could probably reduce the mortality rate. A better understanding of the molecular characteristics of the different ovarian cancer subtypes and their specific molecular signatures is indispensable prior to development of new screening strategies. We discuss here the early natural history of ovarian cancer and its origins. Gautier Chene, Gery Lamblin, Karine Le Bail-Carval, Philippe Chabert, Naoual Bakrin, and Georges Mellier Copyright © 2014 Gautier Chene et al. All rights reserved. Silencing miR-21 Sensitizes Non-Small Cell Lung Cancer A549 Cells to Ionizing Radiation through Inhibition of PI3K/Akt Mon, 07 Apr 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/617868/ We investigated the role of microRNA-21 (miR-21) in radiotherapy resistance of non-small cell lung cancers (NSCLC) and the underlying molecular mechanism. A549 cells were transfected with anti-miR-21 or the negative control oligonucleotides and real-time PCR was applied to detect miR-21 expression level. After ionizing radiation (IR), the survival fractions, proliferation, apoptosis, and expression of phosphorylated-Akt of A549 cells were determined by clonogenic survival analysis, MTT assay, flow cytometry, and Western blotting. Downregulation of miR-21 in radioresistant NSCLC A549 cells inhibited the colony-forming ability and proliferation of A549 cells after IR. Moreover, silencing miR-21 enhanced apoptosis of A549 cells induced by IR accompanied by decreased phosphorylated-Akt protein level. However, PI3K activator IGF-1 reversed suppression of phosphorylated-Akt protein level and promotion of apoptosis of A549 cells after IR caused by miR-21 knockdown. Silencing miR-21 in radioresistant NSCLC A549 cells sensitized them to IR by inhibiting cell proliferation and enhancing cell apoptosis through inhibition of PI3K/Akt signaling pathway. This might help in sensitization of NSCLC to radiotherapy. Yongfu Ma, Hui Xia, Yang Liu, and Min Li Copyright © 2014 Yongfu Ma et al. All rights reserved. Dose Distributions of an 192Ir Brachytherapy Source in Different Media Mon, 07 Apr 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/946213/ This study used MCNPX code to investigate the brachytherapy 192Ir dose distributions in water, bone, and lung tissue and performed radiophotoluminescent glass dosimeter measurements to verify the obtained MCNPX results. The results showed that the dose-rate constant, radial dose function, and anisotropy function in water were highly consistent with data in the literature. However, the lung dose near the source would be overestimated by up to 12%, if the lung tissue is assumed to be water, and, hence, if a tumor is located in the lung, the tumor dose will be overestimated, if the material density is not taken into consideration. In contrast, the lung dose far from the source would be underestimated by up to 30%. Radial dose functions were found to depend not only on the phantom size but also on the material density. The phantom size affects the radial dose function in bone more than those in the other tissues. On the other hand, the anisotropy function in lung tissue was not dependent on the radial distance. Our simulation results could represent valid clinical reference data and be used to improve the accuracy of the doses delivered during brachytherapy applied to patients with lung cancer. C. H. Wu, Y. J. Liao, Y. W. Hsueh Liu, S. K. Hung, M. S. Lee, and S. M. Hsu Copyright © 2014 C. H. Wu et al. All rights reserved. Cancer Diagnostic and Predictive Biomarkers Thu, 03 Apr 2014 11:39:11 +0000 http://www.hindawi.com/journals/bmri/2014/980163/ Franco M. Buonaguro, David Pauza, Maria Lina Tornesello, Pierre Hainaut, Renato Franco, and Francesco M. Marincola Copyright © 2014 Franco M. Buonaguro et al. All rights reserved. Extracellular Matrix Proteins Expression Profiling in Chemoresistant Variants of the A2780 Ovarian Cancer Cell Line Thu, 03 Apr 2014 11:30:03 +0000 http://www.hindawi.com/journals/bmri/2014/365867/ Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel-resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly—over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis. Radosław Januchowski, Piotr Zawierucha, Marcin Ruciński, Michał Nowicki, and Maciej Zabel Copyright © 2014 Radosław Januchowski et al. All rights reserved. Cancer Monitoring Methods Thu, 03 Apr 2014 07:06:09 +0000 http://www.hindawi.com/journals/bmri/2014/981495/ Aleksandra Nikolic, Oronza Antonietta Botrugno, Jelena Urosevic, and Natasa Tosic Copyright © 2014 Aleksandra Nikolic et al. All rights reserved. Diagnostic Value of Virtual Touch Tissue Quantification for Breast Lesions with Different Size Wed, 02 Apr 2014 13:37:47 +0000 http://www.hindawi.com/journals/bmri/2014/142504/ Purpose. To evaluate diagnostic value of the virtual touch tissue quantification (VTTQ) for breast lesions with different sizes. Materials and Methods. Patients with 206 breast lesions were categorized into three groups according to lesion size (<10 mm, 10–20 mm, and >20 mm). Breast lesions were examined by conventional ultrasound and VTTQ, and shear wave velocity (SWV) of each lesion and adjacent normal breast tissue were measured. Diagnoses were confirmed by pathological examination after surgery. The receiver-operating characteristic curve (ROC) analyses were performed to evaluate the diagnostic value of SWV, and the area under curves (AUC) was compared among groups. Results. SWV of malignant lesions was much higher than that of benign lesions, whereas the difference was not obvious for lesions <10 mm (). There was statistical significant difference of AUC between lesions <10 mm and 10–20 mm (), as well as lesions <10 mm and >20 mm (). The sensitivity of lesions <10 mm was 33.33%, which was relatively low compared to other groups. Conclusion. According to our results, VTTQ is a promising method for breast lesions >10 mm, and further studies were warranted to improve sensitivity of VTTQ for breast lesions <10 mm. Minghua Yao, Jian Wu, Liling Zou, Guang Xu, Juan Xie, Rong Wu, and Huixiong Xu Copyright © 2014 Minghua Yao et al. All rights reserved. Evaluation of Virtual Touch Tissue Imaging Quantification, a New Shear Wave Velocity Imaging Method, for Breast Lesion Assessment by Ultrasound Mon, 31 Mar 2014 12:13:32 +0000 http://www.hindawi.com/journals/bmri/2014/960262/ Objectives. To evaluate virtual touch tissue imaging quantification (VTIQ) as a new elastography method concerning its intra- and interexaminer reliability and its ability to differentiate benign from malignant breast lesions in comparison to and in combination with ultrasound (US) B-mode breast imaging reporting and data system (BI-RADS) assessment. Materials and Methods. US and VTIQ were performed by two examiners in 103 women with 104 lesions. Intra- and interexaminer reliability of VTIQ was assessed. The area under the receiver operating curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BIRADS, VTIQ, and combined data were compared. Results. Fifty-four of 104 lesions were malignant. Intraexaminer reliability was consistent, and interexaminer agreement showed a strong positive correlation (). The mean VTIQ values in malignant lesions were significantly higher than those in benign (7.73 m/s ± 1.02 versus 4.46 m/s ± 1.87; ). The combination of US-BIRADS with the optimal cut-off for clinical decision making of 5.18 m/s yielded a sensitivity of 98%, specificity of 82%, PPV of 86%, and NPV of 98%. The combination of BIRADS and VTIQ led to improved test validity. Conclusion. VTIQ is highly reliable and reproducible. There is a significant difference regarding the mean maximum velocity of benign and malignant lesions. Adding VTIQ to BIRADS assessment improves the specificity. Michael Golatta, Mirjam Schweitzer-Martin, Aba Harcos, Sarah Schott, Christina Gomez, Anne Stieber, Geraldine Rauch, Christoph Domschke, Joachim Rom, Florian Schütz, Christof Sohn, and Jörg Heil Copyright © 2014 Michael Golatta et al. All rights reserved. Cytokines, Fatigue, and Cutaneous Erythema in Early Stage Breast Cancer Patients Receiving Adjuvant Radiation Therapy Mon, 31 Mar 2014 08:08:14 +0000 http://www.hindawi.com/journals/bmri/2014/523568/ We investigated the hypothesis that patients developing high-grade erythema of the breast skin during radiation treatment could be more likely to present increased levels of proinflammatory cytokines which may lead, in turn, to associated fatigue. Forty women with early stage breast cancer who received adjuvant radiotherapy were enrolled from 2007 to 2010. Fatigue symptoms, erythema, and cytokine levels (IL-1β, IL-2, IL6, IL-8, TNF-α, and MCP-1) were registered at baseline, during treatment, and after radiotherapy completion. Seven (17.5%) patients presented fatigue without associated depression/anxiety. Grade ≥2 erythema was observed in 5 of these 7 patients. IL-1β, IL-2, IL-6, and TNF-α were statistically increased 4 weeks after radiotherapy (). After the Heckman two-step analysis, a statistically significant influence of skin erythema on proinflammatory markers increase (P = 0.00001) was recorded; in the second step, these blood markers showed a significant impact on fatigue (P = 0.026). A seeming increase of fatigue, erythema, and proinflammatory markers was observed between the fourth and the fifth week of treatment followed by a decrease after RT. There were no significant effects of hormone therapy, breast volume, and anemia on fatigue. Our study seems to suggest that fatigue is related to high-grade breast skin erythema during radiotherapy through the increase of cytokines levels. Vitaliana De Sanctis, Linda Agolli, Vincenzo Visco, Flavia Monaco, Roberta Muni, Alessandra Spagnoli, Barbara Campanella, Maurizio Valeriani, Giuseppe Minniti, Mattia F. Osti, Claudio Amanti, Patrizia Pellegrini, Serena Brunetti, Anna Costantini, Marco Alfò, Maria Rosaria Torrisi, Paolo Marchetti, and Riccardo Maurizi Enrici Copyright © 2014 Vitaliana De Sanctis et al. All rights reserved. Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCN Mon, 24 Mar 2014 06:29:34 +0000 http://www.hindawi.com/journals/bmri/2014/474905/ Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures. M. Distler, D. Aust, J. Weitz, C. Pilarsky, and Robert Grützmann Copyright © 2014 M. Distler et al. All rights reserved. BMP-4 Genetic Variants and Protein Expression Are Associated with Platinum-Based Chemotherapy Response and Prognosis in NSCLC Wed, 19 Mar 2014 13:52:23 +0000 http://www.hindawi.com/journals/bmri/2014/801640/ To explore the role of genetic polymorphisms of bone morphogenic proteins 4 (BMP-4) in the response to platinum-based chemotherapy and the clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC), 938 patients with stage III (A+B) or IV NSCLC were enrolled in this study. We found that the variant genotypes of 6007C > T polymorphisms significantly associated with the chemotherapy response. The 6007CC genotype carriers had a higher chance to be responder to chemotherapy (adjusted odd ratio = 2.77; 95% CI: 1.83–4.18; adjusted < 0.001). The 6007C > T polymorphisms and BMP-4 expression also affect the prognosis of NSCLC. Patients with high BMP-4 expression had a significantly higher chance to be resistant to chemotherapy than those with low BMP-4 expression (OR = 2.81; 95% CI: 1.23–6.44; ). The hazard ratio (HR) for 6007TT was 2.37 times higher than 6007CC (). In summary, the 6007C > T polymorphism of BMP-4 gene and BMP-4 tissue expression may be used as potential predictor for the chemotherapy response and prognosis of advanced NSCLC. Sun Xian, Lang Jilu, Tian Zhennan, Zhou Yang, Hu Yang, Geng Jingshu, and Fu Songbin Copyright © 2014 Sun Xian et al. All rights reserved. EZH2 Silencing with RNA Interference Induces G2/M Arrest in Human Lung Cancer Cells In Vitro Tue, 18 Mar 2014 11:28:40 +0000 http://www.hindawi.com/journals/bmri/2014/348728/ Nonsmall-cell lung cancer has a high mortality rate and poor prognosis. In the present study, we silenced EZH2 and explored the consequent cell cycle changes. The expression of cell-cycle-related proteins, including p53, p21, Cdc2, and cyclin B1, was detected with western blotting, and the cell cycle distribution was determined with flow cytometry. Inhibition of EZH2 expression changed the cell cycle distribution, in particular inducing G2/M arrest. Expression of Cdc2 and cyclin B1 was significantly decreased in A549 and HTB-56 cells after EZH2-siRNA treatment. In addition, p53 expression was increased by 21% and 18%, and p21 expression was increased by 31% and 23%, in A549 and HTB-56 cells, respectively, in the presence of EZH2-siRNA. This study clearly demonstrates that modulation of EZH2 expression with siRNA affects the cell cycle and the expression levels of p53 and p21, thereby changing cyclin B1 and Cdc2 expression and inducing G2/M arrest. These results may explain the observed antitumor activity of EZH2 silencing. Such explorations of the molecular mechanism of EZH2 will help us develop novel approaches to the diagnosis, treatment, and prevention of nonsmall-cell lung cancer. Hui Xia, Wen Zhang, Yingjie Li, Nannan Guo, and Changhai Yu Copyright © 2014 Hui Xia et al. All rights reserved. The Role of Hypoxia-Inducible Factor-1α, Glucose Transporter-1, (GLUT-1) and Carbon Anhydrase IX in Endometrial Cancer Patients Wed, 12 Mar 2014 10:22:09 +0000 http://www.hindawi.com/journals/bmri/2014/616850/ Hypoxia-inducible factor-1 (HIF-1), glucose transporter-1 (GLUT-1), and carbon anhydrase IX (CAIX) are important molecules that allow adaptation to hypoxic environments. The aim of our study was to investigate the correlation between HIF-1, GLUT-1, and CAIX protein level with the clinicopathological features of endometrial cancer patients. Materials and Methods. 92 endometrial cancer patients, aged 37–84, were enrolled to our study. In all patients clinical stage, histologic grade, myometrial invasion, lymph node, and distant metastases were determined. Moreover, the survival time was assessed. Immunohistochemical analyses were performed on archive formalin fixed paraffin embedded tissue sections. Results. High significant differences were reported between HIF-1 expression and the histologic subtype of cancer. Higher HIF-1 expression was associated with the higher risk of recurrence . The results of GLUT-1 and CAIX expression did not reveal any significant differences between the proteins expression in the primary tumor and the clinicopathological features. Conclusion. The important role of HIF-1 in the group of patients with the high risk of recurrence and the negative histologic subtype of the tumor suggest that the expression of this factor might be useful in the panel of accessory pathomorphological tests and could be helpful in establishing more accurate prognosis in endometrial cancer patients. Pawel Sadlecki, Magdalena Bodnar, Marek Grabiec, Andrzej Marszalek, Pawel Walentowicz, Alina Sokup, Jolanta Zegarska, and Małgorzata Walentowicz-Sadlecka Copyright © 2014 Pawel Sadlecki et al. All rights reserved. Liquiritigenin Induces Tumor Cell Death through Mitogen-Activated Protein Kinase- (MPAKs-) Mediated Pathway in Hepatocellular Carcinoma Cells Tue, 11 Mar 2014 06:58:11 +0000 http://www.hindawi.com/journals/bmri/2014/965316/ Liquiritigenin (LQ), separated from Glycyrrhiza radix, possesses anti-inflammatory, antihyperlipidemic, and antiallergic effects. Our present study aims to investigate the antihepatocellular carcinoma effects of LQ both in cell and animal models. LQ strikingly reduced cell viability, enhanced apoptotic rate, induced lactate dehydrogenase over-release, and increased intracellular reactive oxygen species (ROS) level and caspase 3 activity in both PLC/PRL/5 and HepG2 cells. The expression of cleaved PARP, the hall-marker of apoptosis, was enhanced by LQ. LQ treatment resulted in a reduction of the expressions of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and an increase of the phosphorylation of c-Jun N-terminal kinases (JNK) and P38. LQ-mediated cell viability reduction, mitochondrial dysfunction, apoptosis related protein abnormal expressions, and JNK and P38 activation were partially abolished by N-Acetyl-L-cysteine (a ROS inhibitor) pretreatment. Moreover, LQ suppressed the activation of extracellular signaling-regulated kinase (ERKs) and reduced the translocation of phosphor-ERKs from cytoplasm to nucleus. This antitumor activity was further confirmed in PLC/PRL/5-xenografted mice model. All these data indicate that the antihepatocellular carcinoma effects of LQ are related to its modulation of the activations of mitogen-activated protein kinase (MAPKs). The study provides experimental evidence supporting LQ as a potential therapeutic agent for hepatocellular carcinoma treatment. Di Wang, Jiahui Lu, Yan Liu, Qingfan Meng, Jing Xie, Zhenzuo Wang, and Lesheng Teng Copyright © 2014 Di Wang et al. All rights reserved. Evidence for the Existence of Triple-Negative Variants in the MCF-7 Breast Cancer Cell Population Tue, 04 Mar 2014 12:54:06 +0000 http://www.hindawi.com/journals/bmri/2014/836769/ The MCF-7 line, derived in 1973 from a malignant pleural effusion, is one of the most commonly used culture models for human breast cancer. Despite its long history, MCF-7 is a surprisingly heterogeneous line. We previously showed that if MCF-7 cells were cultured for a prolonged period either in the absence of estrogen or in the presence of the antiestrogen tamoxifen, sub-lines were selected that differed from the parental line in ploidy, mean cell volume, signaling pathway usage, and drug sensitivity. This suggests a process of selection of preexisting variants rather than of adaptation of the parental line. All the sublines were estrogen receptor (ER) positive, raising the question of whether MCF-7 also contains ER negative variants. Here, we have looked for such variants by culturing for a prolonged period in the presence of fulvestrant, an estrogen antagonist that has no estrogen agonist activity. Three sublines were developed, each of which was ER negative, progesterone receptor (PR) negative and expressed only a low level of HER2. Each of the variants differed from the original MCF-7 line in ploidy, modal cell volume, and signaling pathway usage. Control experiments in which cells were cultured for a prolonged period in the absence of estrogen selected for variants that were ER and PR positive. The properties of the triple-negative MCF-7 were compared with those of an existing triple-negative cell line, MDA-MB-231, and human epidermal growth factor receptor 2 (HER2)+ SKBr3, as well as from those of the “immortalized” breast epithelial line MCF10A. The results suggest that new variants or phenotypes of MCF-7 might be generated continuously in culture, and by implication this might apply to breast cancer development and even normal breast epithelial development in vivo. Euphemia Leung, Ji Eun Kim, Marjan Askarian-Amiri, Graeme J. Finlay, and Bruce C. Baguley Copyright © 2014 Euphemia Leung et al. All rights reserved. Impact of Immunogenetic IL28B Polymorphism on Natural Outcome of HCV Infection Wed, 26 Feb 2014 11:49:25 +0000 http://www.hindawi.com/journals/bmri/2014/710642/ With the aim of investigating whether interleukin 28B gene (IL28B) rs1297860 polymorphism is associated with different hepatitis C (HCV) infection statuses, we compared IL28B allelic distribution in an Italian case series of 1050 patients with chronic infection and different outcomes, 47 individuals who spontaneously cleared HCV, and 178 blood donors. Furthermore, we compared IL28B variants among 3882 Caucasian patients with chronic infection, 397 with spontaneous clearance, and 1366 blood donors reported in PubMed. Overall data confirmed a relation between IL28B C allele and HCV spontaneous clearance. Furthermore, we found that IL28B T allele had a weak relation with chronic HCV progression to hepatocellular carcinoma. Study findings are in accordance with the hepatocellular carcinogenic model where IL28B TT genotype, by promoting a persistent chronic hepatitis which leads to both hepatocyte injury and chronic inflammation, could facilitate HCC development. Conversely, patients with lymphoproliferative disorders had not any significantly different IL28B rs1297860 allelic distribution than those with chronic HCV, but, like all chronic HCV-related diseases, they showed a lower CC frequency than patients who spontaneously cleared HCV. Study results confirmed the model of persistent HCV infection as a risk factor for the pathogenesis of both liver and lymphoproliferative disorders. Valli De Re, Laura Gragnani, Elisa Fognani, Alessia Piluso, Francesco Izzo, Alessandra Mangia, Marina Crovatto, Graziella Gava, Pietro Casarin, Domenico Sansonno, Vito Racanelli, Salvatore De Vita, Pietro Pioltelli, Laura Caggiari, Mariangela De Zorzi, Massimiliano Berretta, Andrea Gini, Antonella Zucchetto, Franco Maria Buonaguro, Paolo De Paoli, and Anna Linda Zignego Copyright © 2014 Valli De Re et al. All rights reserved. ELFN1-AS1: A Novel Primate Gene with Possible MicroRNA Function Expressed Predominantly in Human Tumors Mon, 24 Feb 2014 17:18:19 +0000 http://www.hindawi.com/journals/bmri/2014/398097/ Human gene LOC100505644 uncharacterized LOC100505644 [Homo sapiens] (Entrez Gene ID 100505644) is abundantly expressed in tumors but weakly expressed in few normal tissues. Till now the function of this gene remains unknown. Here we identified the chromosomal borders of the transcribed region and the major splice form of the LOC100505644-specific transcript. We characterised the major regulatory motifs of the gene and its splice sites. Analysis of the secondary structure of the major transcript variant revealed a hairpin-like structure characteristic for precursor microRNAs. Comparative genomic analysis of the locus showed that it originated in primates de novo. Taken together, our data indicate that human gene LOC100505644 encodes some non-protein coding RNA, likely a microRNA. It was assigned a gene symbol ELFN1-AS1 (ELFN1 antisense RNA 1 (non-protein coding)). This gene combines features of evolutionary novelty and predominant expression in tumors. Dmitrii E. Polev, Iuliia K. Karnaukhova, Larisa L. Krukovskaya, and Andrei P. Kozlov Copyright © 2014 Dmitrii E. Polev et al. All rights reserved. Aberrant Glycosylation as Biomarker for Cancer: Focus on CD43 Thu, 13 Feb 2014 11:41:46 +0000 http://www.hindawi.com/journals/bmri/2014/742831/ Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms. Franca Maria Tuccillo, Annamaria de Laurentiis, Camillo Palmieri, Giuseppe Fiume, Patrizia Bonelli, Antonella Borrelli, Pierfrancesco Tassone, Iris Scala, Franco Maria Buonaguro, Ileana Quinto, and Giuseppe Scala Copyright © 2014 Franca Maria Tuccillo et al. All rights reserved. Technical Advancement of Radiation Therapy Tue, 11 Feb 2014 09:36:04 +0000 http://www.hindawi.com/journals/bmri/2014/797412/ Tsair-Fwu Lee, Jack Yang, Eng-Yen Huang, Chung-Chi Lee, Maria F. Chan, and An Liu Copyright © 2014 Tsair-Fwu Lee et al. All rights reserved. The Low Chamber Pancreatic Cancer Cells Had Stem-Like Characteristics in Modified Transwell System: Is It a Novel Method to Identify and Enrich Cancer Stem-Like Cells? Mon, 10 Feb 2014 11:49:44 +0000 http://www.hindawi.com/journals/bmri/2014/760303/ Cancer stem cells (CSCs) or cancer-initiating cells (CICs) play an important role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. It is important to construct an effective method to identify and isolate CSCs for biotherapy of cancer. During the past years, many researchers had paid more attention to it; however, this method was still on seeking. Therefore, compared to the former methods that were used to isolate the cancer stem cell, in the present study, we tried to use modified transwell system to isolate and enrich CSCs from human pancreatic cancer cell lines (Panc-1). Our results clearly showed that the lower chamber cells in modified transwell system were easily forming spheres; furthermore, these spheres expressed high levels of stem cell markers (CD133/CD44/CD24/Oct-4/ESA) and exhibited chemoresistance, underwent epithelial-to-mesenchymal transition (EMT), and possessed the properties of self-renewal in vitro and tumorigenicity in vivo. Therefore, we speculated that modified transwell assay system, as a rapid and effective method, can be used to isolate and enrich CSCs. Dongqing Wang, Haitao Zhu, Yanfang Liu, Qing Liu, Xiaodong Xie, Yuepeng Zhou, Lirong Zhang, Yan Zhu, Zhijian Zhang, and Zhaoliang Su Copyright © 2014 Dongqing Wang et al. All rights reserved. Role of ROBO4 Signalling in Developmental and Pathological Angiogenesis Thu, 06 Feb 2014 06:01:17 +0000 http://www.hindawi.com/journals/bmri/2014/683025/ Transmembrane roundabout receptor family members (ROBO1–ROBO4) principally orchestrate the neuronal guidance mechanism of the nervous system. Secreted glycoprotein SLITs are the most appreciated ligands for ROBOs. Recently identified ROBO4 is the key mediator of SLIT-ROBO mediated developmental and pathological angiogenesis. Although SLIT2 has been shown to interact with ROBO4 as ligand, it remains an open question whether this protein is the physiologic partner of ROBO4. The purpose of this review is to summarise how reliable SLIT2 as ligand for ROBO4 is, if not what the other possible mechanisms demonstrated till date for ROBO4 mediated developmental and pathological angiogenesis are. We conclude that ROBO4 is expressed specially in vascular endothelial cells and maintains the vascular integrity via either SLIT2 dependent or SLIT2 independent manner. On the contrary, it promotes the pathological angiogenesis by involving different signalling arm(s)/unknown ligand(s). This review explores the interactions SLIT2/ROBO1, SLIT2/ROBO1–ROBO4, ROBO1/ROBO4, and ROBO4/UNC5B which can be promising and potential therapeutic targets for developmental angiogenesis defects and pathological angiogenesis. Finally we have reviewed the ROBO4 signalling pathways and made an effort to elaborate the insight of this signalling as therapeutic target of pathological angiogenesis. Suresh Singh Yadav and Gopeshwar Narayan Copyright © 2014 Suresh Singh Yadav and Gopeshwar Narayan. All rights reserved. CDK/CCN and CDKI Alterations for Cancer Prognosis and Therapeutic Predictivity Wed, 29 Jan 2014 09:38:14 +0000 http://www.hindawi.com/journals/bmri/2014/361020/ The regulation of cell growth and division occurs in an accurate sequential manner. It is dictated by the accumulation of cyclins (CCNs) and cyclin-dependent kinases (CDKs) complexes and degradation of CCNs. In human tumors, instead, the cell cycle is deregulated, causing absence of differentiation and aberrant cell growth. Oncogenic alterations of CCNs, CDKs, and CDKIs have been reported in more than 90% of human cancers, and the most frequent are those related to the G1 phase. Several molecular mechanisms, including gene overexpression, chromosomal translocations, point mutations, insertions and deletions, missense and frame shift mutation, splicing, or methylation, may be responsible for these alterations. The cell cycle regulators are involved in tumor progression given their association with cancers characterized by higher incidence of relapses and chemotherapy resistance. In the last decade anticancer drug researches focused on new compounds, able to target molecules related to changes in genes associated with tumor status. Recently, the studies have focused on the restoration of cell cycle control modulating molecular targets involved in cancer-cell alterations. This paper aims to correlate alterations of cell cycle regulators with human cancers and therapeutic responsivity. Patrizia Bonelli, Franca Maria Tuccillo, Antonella Borrelli, Antonietta Schiattarella, and Franco Maria Buonaguro Copyright © 2014 Patrizia Bonelli et al. All rights reserved. Induction of Apoptosis in Human Multiple Myeloma Cell Lines by Ebselen via Enhancing the Endogenous Reactive Oxygen Species Production Mon, 27 Jan 2014 08:31:40 +0000 http://www.hindawi.com/journals/bmri/2014/696107/ Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway. Liang Zhang, Liwei Zhou, Jia Du, Mengxia Li, Chengyuan Qian, Yi Cheng, Yang Peng, Jiayin Xie, and Dong Wang Copyright © 2014 Liang Zhang et al. All rights reserved. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer Wed, 22 Jan 2014 07:25:20 +0000 http://www.hindawi.com/journals/bmri/2014/925845/ As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer. Zhiwen Xiao, Guopei Luo, Chen Liu, Chuntao Wu, Liang Liu, Zuqiang Liu, Quanxing Ni, Jiang Long, and Xianjun Yu Copyright © 2014 Zhiwen Xiao et al. All rights reserved. The Preoperative Maximum Standardized Uptake Value Measured by 18F-FDG PET/CT as an Independent Prognostic Factor of Overall Survival in Endometrial Cancer Patients Mon, 20 Jan 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/234813/ Purpose. The aim of this study was to determine if the preoperative maximum standardized uptake value (SUVmax) measured by 18F-FDG PET/CT in the primary tumor has prognostic value in the group of patients with endometrial cancer. Patients, Materials, and Methods. A total of one hundred one consecutive endometrial cancer patients, age range 40–82 years (mean 62 years) and FIGO I–IV stage, who underwent 18-FDG-PET/CT within two weeks prior radical surgery, were enrolled to the study. The maximum SUV was measured and compared with the clinicopathologic features of surgical specimens. The relationship between SUVmax and overall survival was analyzed. Results. The mean preoperative SUVmax was 14.34; range (3.90–33.80) and was significantly lower for FIGO I than for higher stages (), as well as for grade 1 than for grade 2 and 3 (), deep myometrial invasion () and for high risk group (). The analysis of survival ROC curve revealed SUVmax cut-off value of 17.7 to predict high risk of recurrence. Endometrial cancer patients with SUVmax higher than 17.7 characterized by lower overall survival. Conclusion. The preoperative SUVmax measured by 18F-FDG PET/CT is considered as an important indicator reflecting tumor aggressiveness which may predict poor prognosis. High value of SUVmax would be useful for making noninvasive diagnoses and deciding the appropriate therapeutic strategy for patients with endometrial cancer. Malgorzata Walentowicz-Sadlecka, Bogdan Malkowski, Pawel Walentowicz, Pawel Sadlecki, Andrzej Marszalek, Tomasz Pietrzak, and Marek Grabiec Copyright © 2014 Malgorzata Walentowicz-Sadlecka et al. All rights reserved. Magnetic Resonance-Guided Laser Induced Thermal Therapy for Glioblastoma Multiforme: A Review Thu, 16 Jan 2014 13:52:45 +0000 http://www.hindawi.com/journals/bmri/2014/761312/ Magnetic resonance-guided laser induced thermotherapy (MRgLITT) has become an increasingly relevant therapy for tumor ablation due to its minimally invasive approach and broad applicability across many tissue types. The current state of the art applies laser irradiation via cooled optical fiber applicators in order to generate ablative heat and necrosis in tumor tissue. Magnetic resonance temperature imaging (MRTI) is used concurrently with this therapy to plan treatments and visualize tumor necrosis. Though application in neurosurgery remains in its infancy, MRgLITT has been found to be a promising therapy for many types of brain tumors. This review examines the current use of MRgLITT with regard to the special clinical challenge of glioblastoma multiforme and examines the potential applications of next-generation nanotherapy specific to the treatment of glioblastoma. Sarah E. Norred and Jacqueline Anne Johnson Copyright © 2014 Sarah E. Norred and Jacqueline Anne Johnson. All rights reserved. Oncogenic Processes Thu, 16 Jan 2014 13:20:53 +0000 http://www.hindawi.com/journals/bmri/2014/879013/ Rita de Cassia Stocco, Franco Peppino Roperto, Lubna Nasir, and Marcelo Palma Sircili Copyright © 2014 Rita de Cassia Stocco et al. All rights reserved. Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells? Wed, 15 Jan 2014 16:15:43 +0000 http://www.hindawi.com/journals/bmri/2014/859871/ There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics. Emanuela Paldino, Valentina Tesori, Patrizia Casalbore, Antonio Gasbarrini, and Maria Ausiliatrice Puglisi Copyright © 2014 Emanuela Paldino et al. All rights reserved. State of the Art in the Studies on Crotamine, a Cell Penetrating Peptide from South American Rattlesnake Wed, 15 Jan 2014 16:11:55 +0000 http://www.hindawi.com/journals/bmri/2014/675985/ Animal venoms comprise a naturally selected cocktail of bioactive peptides/proteins and other molecules, each of which playing a defined role thanks to the highly specific interactions with diverse molecular targets found in the prey. Research focused on isolation, structural, and functional characterizations of novel natural biologics (bioactive peptides/proteins from natural sources) has a long way to go through from the basic science to clinical applications. Herein, we overview the structural and functional characteristics of the myoneurotoxin crotamine, firstly isolated from the South American rattlesnake venom. Crotamine is the first venom peptide classified as a natural cell penetrating and antimicrobial peptide (CPP and AMP) with a more pronounced antifungal activity. In contrast to other known natural CPPs and AMPs, crotamine demonstrates a wide spectrum of biological activities with potential biotechnological and therapeutic values. More recent studies have demonstrated the selective in vitro anticancer activity of crotamine. In vivo, using a murine melanoma model, it was shown that crotamine delays tumor implantation, inhibits tumor cells proliferation, and also increases the survival of mice engrafted with subcutaneous melanoma. The structural and functional properties and also the possible biotechnological applications of minimized molecules derived from crotamine are also discussed. Irina Kerkis, Mirian A. F. Hayashi, Alvaro R. B. Prieto da Silva, Alexandre Pereira, Paulo Luiz De Sá Júnior, Andre J. Zaharenko, Gandhi Rádis-Baptista, Alexandre Kerkis, and Tetsuo Yamane Copyright © 2014 Irina Kerkis et al. All rights reserved. Investigating the Feasibility of Rapid MRI for Image-Guided Motion Management in Lung Cancer Radiotherapy Sun, 12 Jan 2014 16:58:04 +0000 http://www.hindawi.com/journals/bmri/2014/485067/ Cycle-to-cycle variations in respiratory motion can cause significant geometric and dosimetric errors in the administration of lung cancer radiation therapy. A common limitation of the current strategies for motion management is that they assume a constant, reproducible respiratory cycle. In this work, we investigate the feasibility of using rapid MRI for providing long-term imaging of the thorax in order to better capture cycle-to-cycle variations. Two nonsmall-cell lung cancer patients were imaged (free-breathing, no extrinsic contrast, and 1.5 T scanner). A balanced steady-state-free-precession (b-SSFP) sequence was used to acquire cine-2D and cine-3D (4D) images. In the case of Patient 1 (right midlobe lesion, ~40 mm diameter), tumor motion was well correlated with diaphragmatic motion. In the case of Patient 2, (left upper-lobe lesion, ~60 mm diameter), tumor motion was poorly correlated with diaphragmatic motion. Furthermore, the motion of the tumor centroid was poorly correlated with the motion of individual points on the tumor boundary, indicating significant rotation and/or deformation. These studies indicate that image quality and acquisition speed of cine-2D MRI were adequate for motion monitoring. However, significant improvements are required to achieve comparable speeds for truly 4D MRI. Despite several challenges, rapid MRI offers a feasible and attractive tool for noninvasive, long-term motion monitoring. Amit Sawant, Paul Keall, Kim Butts Pauly, Marcus Alley, Shreyas Vasanawala, Billy W. Loo Jr., Jacob Hinkle, and Sarang Joshi Copyright © 2014 Amit Sawant et al. All rights reserved. Isocitrate Dehydrogenase-1 Mutations as Prognostic Biomarker in Glioblastoma Multiforme Patients in West Bohemia Thu, 09 Jan 2014 10:01:24 +0000 http://www.hindawi.com/journals/bmri/2014/735659/ Introduction. Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults. Recent whole-genome studies revealed novel GBM prognostic biomarkers such as mutations in metabolic enzyme IDH—isocitrate dehydrogenases (IDH1 and IDH2). The distinctive mutation IDH1 R132H was uncovered to be a strong prognostic biomarker for glioma patients. We investigated the prognostic role of IDH1 R132H mutation in GBM patients in West Bohemia. Methods. The IDH1 R132H mutation was assessed by the RT-PCR in the tumor samples from 45 GBM patients treated in the Faculty Hospital in Pilsen and was correlated with the progression free and overall survival. Results. The IDH1 R132H mutation was identified in 20 from 44 GBM tumor samples (45.4%). The majority of mutated tumors were secondary GBMs (16 in 18, 89.9%). Low frequency of IDH1 mutations was observed in primary GBMs (4 in 26, 15.3%). Patients with IDH R132H mutation had longer PFS, 136 versus 51 days (, Wilcoxon), and OS, 270 versus 130 days (, Wilcoxon test). Summary. The prognostic value of IDH1 R132H mutation in GBM patients was verified. Patients with mutation had significantly longer PFS and OS than patients with wild-type IDH1 and suffered more likely from secondary GBMs. J. Polivka, J. Polivka Jr., V. Rohan, M. Pesta, T. Repik, P. Pitule, and O. Topolcan Copyright © 2014 J. Polivka et al. All rights reserved. Beta-Catenin and Epithelial Tumors: A Study Based on 374 Oropharyngeal Cancers Wed, 08 Jan 2014 07:52:48 +0000 http://www.hindawi.com/journals/bmri/2014/948264/ Introduction. Although altered regulation of the Wnt pathway via beta-catenin is a frequent event in several human cancers, its potential implications in oral/oropharyngeal squamous cell carcinomas (OSCC/OPSCC) are largely unexplored. Work purpose was to define association between beta-catenin expression and clinical-pathological parameters in 374 OSCCs/OP-SCCs by immunohistochemistry (IHC). Materials and Methods. Association between IHC detected patterns of protein expression and clinical-pathological parameters was assessed by statistical analysis and survival rates by Kaplan-Meier curves. Beta-catenin expression was also investigated in OSCC cell lines by Real-Time PCR. An additional analysis of the DNA content was performed on 22 representative OSCCs/OPSCCs by DNA-image-cytometric analysis. Results and Discussion. All carcinomas exhibited significant alterations of beta-catenin expression (). Beta-catenin protein was mainly detected in the cytoplasm of cancerous cells and only focal nuclear positivity was observed. Higher cytoplasmic expression correlated significantly with poor histological differentiation, advanced stage, and worst patient outcome (). By Real-Time PCR significant increase of beta-catenin mRNA was detected in OSCC cell lines and in 45% of surgical specimens. DNA ploidy study demonstrated high levels of aneuploidy in beta-catenin overexpressing carcinomas. Conclusions. This is the largest study reporting significant association between beta-catenin expression and clinical-pathological factors in patients with OSCCs/OPSCCs. Angela Santoro, Giuseppe Pannone, Silvana Papagerakis, H. Stan McGuff, Barbara Cafarelli, Silvia Lepore, Salvatore De Maria, Corrado Rubini, Marilena Mattoni, Stefania Staibano, Ernesto Mezza, Gaetano De Rosa, Gabriella Aquino, Simona Losito, Carla Loreto, Salvatore Crimi, Pantaleo Bufo, and Lorenzo Lo Muzio Copyright © 2014 Angela Santoro et al. All rights reserved. The Functional Role of MnSOD as a Biomarker of Human Diseases and Therapeutic Potential of a New Isoform of a Human Recombinant MnSOD Mon, 06 Jan 2014 07:05:58 +0000 http://www.hindawi.com/journals/bmri/2014/476789/ Reactive oxygen species (ROS) are generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. This work describes the role of the manganese superoxide dismutase (MnSOD) as a biomarker of different human diseases and proposes a new therapeutic application for the prevention of cancer and its treatment. The paper also describes how a new form of human MnSOD was discovered, its initial application, and its clinical potentials. The MnSOD isolated from a human liposarcoma cell line (LSA) was able to kill cancer cells expressing estrogen receptors, but it did not have cytotoxic effects on normal cells. Together with its oncotoxic activity, the recombinant MnSOD (rMnSOD) exerts a radioprotective effect on normal cells irradiated with X-rays. The rMnSOD is characterized by the presence of a leader peptide, which allows the protein to enter cells: this unique property can be used in the radiodiagnosis of cancer or chemotherapy, conjugating radioactive substances or chemotherapic drugs to the leader peptide of the MnSOD. Compared to traditional chemotherapic agents, the drugs conjugated with the leader peptide of MnSOD can selectively reach and enter cancer cells, thus reducing the side effects of traditional treatments. Antonella Borrelli, Antonietta Schiattarella, Patrizia Bonelli, Franca Maria Tuccillo, Franco Maria Buonaguro, and Aldo Mancini Copyright © 2014 Antonella Borrelli et al. All rights reserved. New Molecules and Old Drugs as Emerging Approaches to Selectively Target Human Glioblastoma Cancer Stem Cells Thu, 02 Jan 2014 11:25:01 +0000 http://www.hindawi.com/journals/bmri/2014/126586/ Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM), the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed. Roberto Würth, Federica Barbieri, and Tullio Florio Copyright © 2014 Roberto Würth et al. All rights reserved. Deregulation of the miRNAs Expression in Cervical Cancer: Human Papillomavirus Implications Tue, 31 Dec 2013 12:58:38 +0000 http://www.hindawi.com/journals/bmri/2013/407052/ MicroRNAs (miRNAs) are a class of small non coding RNAs of 18–25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC. Yazmín Gómez-Gómez, Jorge Organista-Nava, and Patricio Gariglio Copyright © 2013 Yazmín Gómez-Gómez et al. All rights reserved. Radiobiology of Radiosurgery for the Central Nervous System Sun, 29 Dec 2013 15:37:24 +0000 http://www.hindawi.com/journals/bmri/2013/362761/ According to Leksell radiosurgery is defined as “the delivery of a single, high dose of irradiation to a small and critically located intracranial volume through the intact skull.” Before its birth in the early 60s and its introduction in clinical therapeutic protocols in late the 80s dose application in radiation therapy of the brain for benign and malignant lesions was based on the administration of cumulative dose into a variable number of fractions. The rationale of dose fractionation is to lessen the risk of injury of normal tissue surrounding the target volume. Radiobiological studies of cell culture lines of malignant tumors and clinical experience with patients treated with conventional fractionated radiotherapy helped establishing this radiobiological principle. Radiosurgery provides a single high dose of radiation which translates into a specific toxic radiobiological response. Radiobiological investigations to study the effect of high dose focused radiation on the central nervous system began in late the 50s. It is well known currently that radiobiological principles applied for dose fractionation are not reproducible when single high dose of ionizing radiation is delivered. A review of the literature about radiobiology of radiosurgery for the central nervous system is presented. Antonio Santacroce, Marcel A. Kamp, Wilfried Budach, and Daniel Hänggi Copyright © 2013 Antonio Santacroce et al. All rights reserved. Stat3 Upregulates Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4 Expression in Osteosarcoma Cells Wed, 25 Dec 2013 11:00:51 +0000 http://www.hindawi.com/journals/bmri/2013/310691/ The activation of signal transducer and activator of transcription 3 (Stat3) signaling is the common hallmark in various human cancers including osteosarcoma. In the present study, according to PCR-based microarrays using cDNA prepared from interleukin-6 (IL-6) treated osteosarcoma cells, we found that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) was a transcriptional target of Stat3. Overexpression of Stat3 promoted LGR4 expression, while its deficiency using small interfering RNA (siRNA) reduced LGR4 expression. Furthermore, we identified a Stat3 binding motif located at −556 to −549 bp in the LGR4 promoter that is able to interact with Stat3. Thus, our results suggest a previously unknown Stat3-LGR4 molecular network, which may control osteosarcoma development and progression. Jia Liu, Wei Wei, Chang-An Guo, Ning Han, Jian-feng Pan, Teng Fei, and Zuo-qin Yan Copyright © 2013 Jia Liu et al. All rights reserved. Expression Analysis of SPARC/Osteonectin in Oral Squamous Cell Carcinoma Patients: From Saliva to Surgical Specimen Mon, 16 Dec 2013 11:50:23 +0000 http://www.hindawi.com/journals/bmri/2013/736438/ Oral squamous cell carcinoma (OSCC) remains a significant cause of morbidity and mortality, with approximately 540,000 new cases annually worldwide. The molecular mechanisms related to the pathogenesis of this disease are still poorly understood. The discovery of a molecular marker that allows the early detection of this cancer, which can be easily identified in biological samples, such as saliva, without intervening in advanced stages, is a challenge. Numerous studies have identified a panel of molecular markers differently expressed in OSCC and normal oral mucosa. In particular, it was found an aberrant expression of matricellular glycoprotein SPARC. SPARC is involved in normal tissue remodeling, regulating the deposition of extracellular matrix, but also in neoplastic transformation. In fact, aberrant SPARC expression was detected both in stromal cells associated with cancer and in tumor cells. The aim of our study was the evaluation of SPARC on a retrospective series of 119 OSCC cases and the validation of the obtained data on a prospective series of 27 patients with OSCC, of whom we have previously collected saliva, and smeared material. The obtained results were correlated with each other and with clinical pathological parameters at our disposal. The study demonstrated a prognostic value of SPARC, especially with regard to its expression in the stroma surrounding OSCC (P < 0.05). Gabriella Aquino, Rocco Sabatino, Monica Cantile, Corrado Aversa, Franco Ionna, Gerardo Botti, Elvira La Mantia, Francesca Collina, Gabriella Malzone, Giuseppe Pannone, Nunzia Simona Losito, Renato Franco, and Francesco Longo Copyright © 2013 Gabriella Aquino et al. All rights reserved. Preoperative Chemoradiotherapy in Elderly Patients with Locally Advanced Rectal Cancer Thu, 12 Dec 2013 11:57:48 +0000 http://www.hindawi.com/journals/bmri/2013/610786/ Purpose. To evaluate the treatment tolerance and clinical outcomes in patients aged 70 and older with locally advanced rectal carcinoma treated with multimodality approach. Methods and Materials. We retrospectively analysed 20 consecutive elderly patients, with histologically proven rectal adenocarcinoma, staged T3-4, and/or node-positive tumour, who received chemoradiotherapy and proceeded to surgical approach. Performance status score and adult comorbidity evaluation-27 score were calculated, and their influence on treatment tolerance and clinical outcomes was analysed. Results. All patients completed programmed chemoradiotherapy treatment. Gastrointestinal toxicity was the most common acute side effects: proctitis in 70% of patients and diarrhoea in 55%, classified as Grade 3 in 3 patients only. Radiation dermatitis was reported in 7 patients (35%) and it was graded G3 in one patient. There was no haematological toxicity. Eighteen patients out of 20 underwent surgery. Sphincter preservation was assured in 13 patients. Comorbidity index was related to higher severe acute toxicity () but no influenced treatment outcomes. Conclusion. Treatment tolerance with combined modality is good in elderly patients. Due to age, no dose reduction for radiation therapy and chemotherapy should be considered. Francesca De Felice, Daniela Musio, Luciano Izzo, Federico Pugliese, Paolo Izzo, Antonio Bolognese, and Vincenzo Tombolini Copyright © 2013 Francesca De Felice et al. All rights reserved. Viral and Cellular Biomarkers in the Diagnosis of Cervical Intraepithelial Neoplasia and Cancer Mon, 09 Dec 2013 17:38:52 +0000 http://www.hindawi.com/journals/bmri/2013/519619/ Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of the cervix persistently infected with one of about 13 human papillomavirus (HPV) genotypes. The majority of HPV infections induces low grade squamous epithelial lesions that in more than 90% of cases spontaneously regress and in about 10% eventually progress to high grade lesions and even less frequently evolve to invasive cancer. Tumor progression is characterized by (1) increased expression of E6 and E7 genes of high risk HPVs, known to bind to and inactivate p53 and pRb oncosuppressors, respectively; (2) integration of viral DNA into host genome, with disruption of E2 viral genes and host chromosomal loci; and (3) molecular alterations of key regulators of cell cycle. Molecular markers with high sensitivity and specificity in differentiating viral infections associated with cellular abnormalities with high risk of progression are strongly needed for cervical cancer screening and triage. This review will focus on the analysis of clinical validated or candidate biomarkers, such as HPV DNA, HPV E6/E7 mRNA, HPV proteins, p16(INK4a) and Ki67, TOP2A and MCM2 cellular factors, and DNA methylation profiles, which will likely improve the identification of premalignant lesions that have a high risk to evolve into invasive cervical cancer. Maria Lina Tornesello, Luigi Buonaguro, Paolo Giorgi-Rossi, and Franco M. Buonaguro Copyright © 2013 Maria Lina Tornesello et al. All rights reserved. The Function of miRNA in Hepatic Cancer Stem Cell Sun, 08 Dec 2013 08:28:33 +0000 http://www.hindawi.com/journals/bmri/2013/358902/ Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and ranks third in the leading causes of cancer patient’s death. Cancer stem cells (HSCs), also known as tumor-initiating cells, have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, chemotherapy drug resistance, tumor metastasis, and progression. In spite of their clinical importance, the detailed mechanism about how HSCs are intricately regulated in the molecular level remains elusive. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, has been demonstrated to serve as a vital player in modulating a number of biological activities ranging from embryogenesis to programmed cell death as well as the maintenance of HSCs. In this review, we synthesize these latest findings of miRNA regulation of HSCs and try to elucidate their mechanistic roles in orchestrating cellular equilibrium. This recent progress underlies the functional role of miRNA in cellular transformation of liver cancer, which has largely extended our knowledge how HSCs are controlled by miRNA network, and in the development of novel miRNA-based anticancer therapies specifically targeting HSCs in the coming future. Wei Qi, Weicheng Liang, Huiqing Jiang, and Mary Miuyee Waye Copyright © 2013 Wei Qi et al. All rights reserved. Proteomic Analysis of PTCH1+/− Fibroblast Lysate and Conditioned Culture Media Isolated from the Skin of Healthy Subjects and Nevoid Basal Cell Carcinoma Syndrome Patients Wed, 04 Dec 2013 13:55:47 +0000 http://www.hindawi.com/journals/bmri/2013/794028/ Background. The pathogenesis underlying the increased predisposition to the development of basal cell carcinomas (BCCs) in the context of Gorlin-Goltz syndrome is linked to molecular mechanisms that differ from sporadic BCCs. Patients with Gorlin syndrome tend to develop multiple BCCs at an early age and present with tumors of non-sun-exposed skin. The aim of this study was to compare the proteomic profile of cultured fibroblast and fibroblast conditioned culture media of PTCH1+ and nonmutated fibroblasts. Results. Proteomic analysis was performed using Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry in PTCH1+ fibroblast conditioned media isolated from not affected sun-protected skin areas of Gorlin patients and from healthy subjects. 12 protein cluster peaks, >5 kDa, had significant differences in their peak intensities between PTCH1+ and PTCH1− subject groups. We detected a strongly MMP1 overexpression in PTCH1+ fibroblasts obtained from NBCCS patients with respect to healthy donors. Conclusion. Protein profiles in the fibroblast conditioned media revealed statistically significant differences between two different types (missense versus nonsense) of PTCH1 mutations. These differences could be useful as signatures to identify PTCH1 gene carriers at high risk for the development of NBCCS-associated malignancies and to develop novel experimental molecular tailored therapies based on these druggable targets. Giovanni Ponti, Giorgia Bertazzoni, Lorenza Pastorino, Emanuela Monari, Aurora Cuoghi, Stefania Bergamini, Elisa Bellei, Luisa Benassi, Paola Azzoni, Tiziana Petrachi, Cristina Magnoni, Giovanni Pellacani, Pietro Loschi, Annamaria Pollio, Alexander Michael Witkowski, and Aldo Tomasi Copyright © 2013 Giovanni Ponti et al. All rights reserved. Contour Propagation Using Feature-Based Deformable Registration for Lung Cancer Mon, 02 Dec 2013 11:15:11 +0000 http://www.hindawi.com/journals/bmri/2013/701514/ Accurate target delineation of CT image is a critical step in radiotherapy treatment planning. This paper describes a novel strategy for automatic contour propagation, based on deformable registration, for CT images of lung cancer. The proposed strategy starts with a manual-delineated contour in one slice of a 3D CT image. By means of feature-based deformable registration, the initial contour in other slices of the image can be propagated automatically, and then refined by active contour approach. Three algorithms are employed in the strategy: the Speeded-Up Robust Features (SURF), Thin-Plate Spline (TPS), and an adapted active contour (Snake), used to refine and modify the initial contours. Five pulmonary cancer cases with about 400 slices and 1000 contours have been used to verify the proposed strategy. Experiments demonstrate that the proposed strategy can improve the segmentation performance in the pulmonary CT images. Jaccard similarity (JS) mean is about 0.88 and the maximum of Hausdorff distance (HD) is about 90%. In addition, delineation time has been considerably reduced. The proposed feature-based deformable registration method in the automatic contour propagation improves the delineation efficiency significantly. Yuhan Yang, Shoujun Zhou, Peng Shang, En Qi, Shibin Wu, and Yaoqin Xie Copyright © 2013 Yuhan Yang et al. All rights reserved. Detection of EGFR Mutations by TaqMan Mutation Detection Assays Powered by Competitive Allele-Specific TaqMan PCR Technology Sun, 01 Dec 2013 16:06:49 +0000 http://www.hindawi.com/journals/bmri/2013/385087/ Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are predictive of response to treatment with tyrosine kinase inhibitors. Competitive Allele-Specific TaqMan PCR (castPCR) is a highly sensitive and specific technology. EGFR mutations were assessed by TaqMan Mutation Detection Assays (TMDA) based on castPCR technology in 64 tumor samples: a training set of 30 NSCLC and 6 colorectal carcinoma (CRC) samples and a validation set of 28 NSCLC cases. The sensitivity and specificity of this method were compared with routine diagnostic techniques including direct sequencing and the EGFR Therascreen RGQ kit. Analysis of the training set allowed the identification of the threshold value for data analysis (0.2); the maximum cycle threshold (); and the cut-off ΔCt value (7) for the EGFR TMDA. By using these parameters, castPCR technology identified both training and validation set EGFR mutations with similar frequency as compared with the Therascreen kit. Sequencing detected rare mutations that are not identified by either castPCR or Therascreen, but in samples with low tumor cell content it failed to detect common mutations that were revealed by real-time PCR based methods. In conclusion, our data suggest that castPCR is highly sensitive and specific to detect EGFR mutations in NSCLC clinical samples. Cristin Roma, Claudia Esposito, Anna Maria Rachiglio, Raffaella Pasquale, Alessia Iannaccone, Nicoletta Chicchinelli, Renato Franco, Rita Mancini, Salvatore Pisconti, Antonella De Luca, Gerardo Botti, Alessandro Morabito, and Nicola Normanno Copyright © 2013 Cristin Roma et al. All rights reserved. Molecular Markers for Prostate Cancer in Formalin-Fixed Paraffin-Embedded Tissues Mon, 25 Nov 2013 09:14:08 +0000 http://www.hindawi.com/journals/bmri/2013/283635/ Prostate cancer (PCa) is the most frequently diagnosed type of cancer in developed countries. The decisive method of diagnosis is based on the results of biopsies, morphologically evaluated to determine the presence or absence of cancer. Although this approach leads to a confident diagnosis in most cases, it can be improved by using the molecular markers present in the tissue. Both miRNAs and proteins are considered excellent candidates for biomarkers in formalin-fixed paraffin-embedded (FFPE) tissues, due to their stability over long periods of time. In the last few years, a concerted effort has been made to develop the necessary tools for their reliable measurement in these types of samples. Furthermore, the use of these kinds of markers may also help in establishing tumor grade and aggressiveness, as well as predicting the possible outcomes in each particular case for the different treatments available. This would aid clinicians in the decision-making process. In this review, we attempt to summarize and discuss the potential use of microRNA and protein profiles in FFPE tissue samples as markers to better predict PCa diagnosis, progression, and response to therapy. Tamara Sequeiros, Marta García, Melania Montes, Mireia Oliván, Marina Rigau, Eva Colás, Inés de Torres, Juan Morote, Jaume Reventós, and Andreas Doll Copyright © 2013 Tamara Sequeiros et al. All rights reserved. Chromogenic In Situ Hybridization and p16/Ki67 Dual Staining on Formalin-Fixed Paraffin-Embedded Cervical Specimens: Correlation with HPV-DNA Test, E6/E7 mRNA Test, and Potential Clinical Applications Sun, 24 Nov 2013 11:07:38 +0000 http://www.hindawi.com/journals/bmri/2013/453606/ Although HPV-DNA test and E6/E7 mRNA analyses remain the current standard for the confirmation of human papillomavirus (HPV) infections in cytological specimens, no universally adopted techniques exist for the detection of HPV in formalin-fixed paraffin-embedded samples. Particularly, in routine laboratories, molecular assays are still time-consuming and would require a high level of expertise. In this study, we investigated the possible use of a novel HPV tyramide-based chromogenic in situ hybridization (CISH) technology to locate HPV on tissue specimens. Then, we evaluate the potential usefulness of /Ki-67 double stain on histological samples, to identify cervical cells expressing HPV E6/E7 oncogenes. In our series, CISH showed a clear signal in 95.2% of the specimens and reached a sensitivity of 86.5%. CISH positivity always matched with HPV-DNA positivity, while 100% of cases with punctated signal joined with cervical intraepithelial neoplasia grade 2 or worse (CIN2+). p16/Ki67 immunohistochemistry gave an interpretable result in 100% of the cases. The use of dual stain significantly increased the agreement between pathologists, which reached 100%. Concordance between dual stain and E6/E7 mRNA test was 89%. In our series, both CISH and /Ki67 dual stain demonstrated high grade of performances. In particular, CISH would help to distinguish episomal from integrated HPV, in order to allow conclusions regarding the prognosis of the lesion, while /Ki67 dual stain approach would confer a high level of standardization to the diagnostic procedure. Roberta Zappacosta, Antonella Colasante, Patrizia Viola, Tommaso D’Antuono, Giuseppe Lattanzio, Serena Capanna, Daniela Maria Pia Gatta, and Sandra Rosini Copyright © 2013 Roberta Zappacosta et al. All rights reserved. Plasma Levels of Soluble HLA-E and HLA-F at Diagnosis May Predict Overall Survival of Neuroblastoma Patients Thu, 21 Nov 2013 15:42:35 +0000 http://www.hindawi.com/journals/bmri/2013/956878/ The purpose of this study was to identify the plasma/serum biomarkers that are able to predict overall survival (OS) of neuroblastoma (NB) patients. Concentration of soluble (s) biomarkers was evaluated in plasma (sHLA-E, sHLA-F, chromogranin, and B7H3) or serum (calprotectin) samples from NB patients or healthy children. The levels of biomarkers that were significantly higher in NB patients were then analyzed considering localized or metastatic subsets. Finally, biomarkers that were significantly different in these two subsets were correlated with patient’s outcome. With the exception of B7H3, levels of all molecules were significantly higher in NB patients than those in controls. However, only chromogranin, sHLA-E, and sHLA-F levels were different between patients with metastatic and localized tumors. sHLA-E and -F levels correlated with each other but not chromogranin. Chromogranin levels correlated with different event-free survival (EFS), whereas sHLA-E and -F levels also correlated with different OS. Association with OS was also detected considering only patients with metastatic disease. In conclusion, low levels of sHLA-E and -F significantly associated with worse EFS/OS in the whole cohort of NB patients and in patients with metastatic NB. Thus, these molecules deserve to be tested in prospective studies to evaluate their predictive power for high-risk NB patients. Fabio Morandi, Giuliana Cangemi, Sebastiano Barco, Loredana Amoroso, Maria Giuliano, Anna Rita Gigliotti, Vito Pistoia, and Maria Valeria Corrias Copyright © 2013 Fabio Morandi et al. All rights reserved. What Would Be the Most Appropriate Ratio in the Setting of Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancer Wed, 20 Nov 2013 08:58:21 +0000 http://www.hindawi.com/journals/bmri/2013/391021/ We hypothesize that the correlation between the radiation dose expressed as the biologically effective dose (BED) and the clinical endpoints will correlate better as the value of the ratio is increased to >10 Gy, which theoretically minimizes the overestimation of the dose potency associated with the linear quadratic (LQ) formula in the setting of stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). A search was conducted in the PubMed electronic databases in August 2011. In the studies analyzed, increasing the ratio is associated with an increase in the strength of the correlation between isocenter BED and local control, especially in the studies with median followup of ≥24 months, for which Spearman’s correlation coefficients of 0.74–0.76 were achieved for of 20 Gy, 30 Gy, and 50 Gy ( 0.007–0.008). A trend toward statistical significance was observed for the correlation of isocenter BED and the 2-year overall survival when an of 20 Gy was used approached statistical significance (). Our results suggest that an  Gy may be more appropriate for the prediction of dose response in the setting of lung SBRT. Alexander Chi, Sijin Wen, Zhongxing Liao, Jack Fowler, Jiahong Xu, Nam P. Nguyen, James S. Welsh, and Ritsuko Komaki Copyright © 2013 Alexander Chi et al. All rights reserved. P-Glycoprotein-Activity Measurements in Multidrug Resistant Cell Lines: Single-Cell versus Single-Well Population Fluorescence Methods Sun, 17 Nov 2013 08:47:09 +0000 http://www.hindawi.com/journals/bmri/2013/676845/ Background. P-gp expression has been linked to the efflux of chemotherapeutic drugs in human cancers leading to multidrug resistance. Fluorescence techniques have been widely applied to measure the P-gp activity. In this paper, there is a comparison between the advantages of two fluorescence approaches of commonly available and affordable instruments: the microplate reader (MPR) and the flow cytometer to detect the P-gp efflux activity using calcein-AM. Results. The selectivity, sensibility, and reproducibility of the two methods have been defined. Our results showed that the MPR is more powerful for the detection of small inhibition, whereas the flow cytometry method is more reliable at higher concentrations of the inhibitors. We showed that to determine precisely the inhibition efficacy the flow cytometry is better; hence, to get the correct Emax and EC50 values, we cannot only rely on the MPR. Conclusion. Both techniques can potentially be used extensively in the pharmaceutical industry for high-throughput drug screening and in biology laboratories for academic research, monitoring the P-gp efflux in specific assays. Jennifer Pasquier, Damien Rioult, Nadine Abu-Kaoud, Sabine Marie, Arash Rafii, Bella S. Guerrouahen, and Frank Le Foll Copyright © 2013 Jennifer Pasquier et al. All rights reserved. CYP19 Genetic Polymorphism Haplotype AASA Is Associated with a Poor Prognosis in Premenopausal Women with Lymph Node-Negative, Hormone Receptor-Positive Breast Cancer Thu, 14 Nov 2013 14:35:00 +0000 http://www.hindawi.com/journals/bmri/2013/562197/ Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C), rs1065779 (A/C), CYP19 (TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes of CCLA (41.1%), AASA (17.1%), CASA (11.9%), CCLC (8.9%), CCSA (7.5%), AASC (8.9%), and others (4.6%). In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3; ), DFS (aHR, 2.5; ), and OS (aHR, 2.9; ) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; ), DFS (HR, 3.2; ), and OS (HR, 6.4; ). However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; ) and OS (aHR, 4.4; ). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women. Sung-Hsin Kuo, Shi-Yi Yang, Huang-Chun Lien, Chiao Lo, Ching-Hung Lin, Yen-Sen Lu, Ann-Lii Cheng, King-Jeng Chang, and Chiun-Sheng Huang Copyright © 2013 Sung-Hsin Kuo et al. All rights reserved. Immune Modulation and Stereotactic Radiation: Improving Local and Abscopal Responses Thu, 14 Nov 2013 11:44:24 +0000 http://www.hindawi.com/journals/bmri/2013/658126/ New and innovative treatment strategies for cancer patients in the fields of immunotherapy and radiotherapy are rapidly developing in parallel. Among the most promising preclinical treatment approaches is combining immunotherapy with radiotherapy where early data suggest synergistic effects in several tumor model systems. These studies demonstrate that radiation combined with immunotherapy can result in superior efficacy for local tumor control. More alluring is the emergence of data suggesting an equally profound systemic response also known as “abscopal” effects with the combination of radiation and certain immunotherapies. Studies addressing optimal radiation dose, fractionation, and modality to be used in combination with immunotherapy still require further exploration. However, recent anecdotal clinical reports combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic sustained clinical responses, both local and abscopal. Technologic advances in clinical radiation therapy has made it possible to deliver hypofractionated regimens anywhere in the body using stereotactic radiation techniques, facilitating further clinical investigations. Thus, stereotactic radiation in combination with immunotherapy agents represents an exciting and potentially fruitful new space for improving cancer therapeutic responses. Jing Zeng, Timothy J. Harris, Michael Lim, Charles G. Drake, and Phuoc T. Tran Copyright © 2013 Jing Zeng et al. All rights reserved. The Synergistic Effects of Low Dose Fluorouracil and TRAIL on TRAIL-Resistant Human Gastric Adenocarcinoma AGS Cells Wed, 13 Nov 2013 08:50:57 +0000 http://www.hindawi.com/journals/bmri/2013/293874/ The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member which has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. However, many cancer cells remain resistant to TRAIL. In this study, we had investigated the synergistic effects of low dose fluorouracil (5-Fu) and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells and explored the potential mechanisms. Cell viability was analyzed by sulforhodamine B (SRB) assay and the synergistic effects were evaluated by Jin’s formula and confirmed by both morphological changes under inverted microscope and flow cytometry. The expression of TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAIL-R4 (DcR2), procaspase-3, procaspase-8, and procaspase-9 was detected by western blotting. Our results showed that there were significant synergistic effects of low dose 5-Fu and TRAIL on TRAIL-resistant AGS cells, and this effect was supposed to be mediated by decreasing DcR2 expression and increasing DR5 expression. The extrinsic and intrinsic apoptosis pathways were both activated. The data suggest that combined treatment of low dose 5-Fu and TRAIL can be an effective therapeutic approach for gastric adenocarcinoma. Hong Zhu, Min Huang, Daoling Ren, Jianping He, Fen Zhao, Cheng Yi, and Ying Huang Copyright © 2013 Hong Zhu et al. All rights reserved. Clinical Evaluation of CyberKnife in the Treatment of Vestibular Schwannomas Sun, 10 Nov 2013 10:48:42 +0000 http://www.hindawi.com/journals/bmri/2013/297093/ Objective. This study assessed the posttreatment tumor control and auditory function of vestibular schwannoma (VS) patients after CyberKnife (CK) and analyzed the possible prognostic factors of hearing loss. Methods. We retrospectively studied 117 VS patients, with Gardner-Robertson (GR) classification grades I to IV, who underwent CK between 2006 and 2012. Data including radiosurgery treatment parameters, pre- and postoperative tumor size, and auditory function were collected and examined. Results. With CK, 117 patients had excellent tumor control rates (99.1%), with a mean imaging followup of 61.1 months. Excluding 52 patients (GR III-IV pretreatment), 53 (81.5%) of the remaining 65 patients (initial GR I-II) maintained GR I or II hearing after CK, with a mean audiometric followup of 64.5 months. Twelve patients experienced hearing degradation (91.6% were GR II pretreatment); they appeared to have significantly larger tumor sizes, significantly smaller cochlear sizes, and higher prescribed cochlear doses, compared to the patients with preserved hearing. Conclusion. Our data showed that CK treatment provided an excellent tumor control rate and a comparable hearing preservation rate in VS patients. Patients with pretreatment GR II hearing levels, larger tumor volumes, smaller cochlear sizes, and higher prescribed cochlear doses may have poor hearing prognoses. Jo-Ting Tsai, Jia-Wei Lin, Chien-Min Lin, Yuan-Hao Chen, Hsin-I Ma, Yee-Min Jen, Yi-Hsun Chen, and Da-Tong Ju Copyright © 2013 Jo-Ting Tsai et al. All rights reserved. Tyrosine Phosphorylation Modulates the Vascular Responses of Mesenteric Arteries from Human Colorectal Tumors Sun, 10 Nov 2013 10:07:14 +0000 http://www.hindawi.com/journals/bmri/2013/545983/ The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may modulate their vascular response. To do this, mesenteric arteries supplying blood flow to colorectal tumors or to normal intestine were obtained during surgery and prepared for isometric tension recording in an organ bath. Increasing tyrosine phosphorylation with the phosphatase inhibitor, sodium orthovanadate produced arterial contraction which was lower in tumoral than in control arteries, whereas it reduced the contraction to noradrenaline in tumoral but not in control arteries and reduced the relaxation to bradykinin in control but not in tumoral arteries. Protein expression of VEGF-A and of the VEGF receptor FLT1 was similar in control and tumoral arteries, but expression of the VEGF receptor KDR was increased in tumoral compared with control arteries. This suggests that tyrosine phosphorylation may produce inhibition of the contraction in tumoral mesenteric arteries, which may increase blood flow to the tumor when tyrosine phosphorylation is increased by stimulation of VEGF receptors. Eduardo Ferrero, María Dolores Mauricio, Miriam Granado, Oscar García-Villar, Martín Aldasoro, José María Vila, Manuel Hidalgo, Jorge Luis Ferrero, Nuria Fernández, Luis Monge, and Ángel Luis García-Villalón Copyright © 2013 Eduardo Ferrero et al. All rights reserved. Gamma Knife Surgery as Monotherapy with Clinically Relevant Doses Prolongs Survival in a Human GBM Xenograft Model Sun, 10 Nov 2013 09:13:06 +0000 http://www.hindawi.com/journals/bmri/2013/139674/ Object. Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (). Conclusion. GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild. Bente Sandvei Skeie, Jian Wang, Ernest Dodoo, Jan Ingeman Heggdal, Janne Grønli, Linda Sleire, Sidsel Bragstad, Jeremy C. Ganz, Martha Chekenya, Sverre Mørk, Paal-Henning Pedersen, and Per Øyvind Enger Copyright © 2013 Bente Sandvei Skeie et al. All rights reserved. Indomethacin-Enhanced Anticancer Effect of Arsenic Trioxide in A549 Cell Line: Involvement of Apoptosis and Phospho-ERK and p38 MAPK Pathways Sun, 10 Nov 2013 09:03:49 +0000 http://www.hindawi.com/journals/bmri/2013/237543/ Background. Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationale for combination therapy in successful treatment of lung cancer. Concurrent use of cyclooxygenase (COX) inhibitors with arsenic trioxide (ATO) might be a possible treatment option. Methods. Cytotoxicity of ATO, dexamethasone (Dex), celecoxib (Cel), and Indomethacin (Indo) individually or in combination was determined at 24, 48, and 72 hrs in A549 lung cancer cells. The COX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations. Results. The IC50s of ATO and Indo were 68.7 μmol/L and 396.5 μmol/L, respectively. Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone. Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use. Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs. Conclusions. Combination therapy with ATO and Indo exerted a very potent in vitro cytotoxic effect against A549 lung cancer cells. Activation of ERK and p38 pathways might be the mechanism of higher cytotoxic effect of ATO-Indo combination. Ali Mandegary, Maryam Torshabi, Mohammad Seyedabadi, Bagher Amirheidari, Elham Sharif, and Mohammad Hossein Ghahremani Copyright © 2013 Ali Mandegary et al. All rights reserved. Usefulness of Traditional Serum Biomarkers for Management of Breast Cancer Patients Thu, 07 Nov 2013 14:07:10 +0000 http://www.hindawi.com/journals/bmri/2013/685641/ The measurement of serum tumor markers levels in breast cancer (BC) patients is an economic and noninvasive diagnostic assay frequently requested by clinical oncologists to get information about the presence or absence of disease as well as its evolution. Despite their wide use in clinical practice, there is still an intense debate between scientific organizations about the real usefulness for patient monitoring during followup as well as response to therapy evaluation in case of advanced BC. In this review, we want to highlight the current recommendations published by scientific organizations about the use of “established” BC serum markers (CEA, TPA, TPS, CIFRA-21, CA15-3, and s-HER2) in clinical oncology practice. Moreover, we will focus on recent papers evidencing the usefulness of tumor markers levels measurement as a guide for the prescription and diagnostic integration of molecular imaging exams such as those performed by hybrid 18-fluorofeoxyglucose-positron emission tomography with integrated computed tomography. This technology is nowadays able to detect early cancer lesions undetectable by conventional morphological imaging investigation and most likely responsible for increasing of serum tumor markers levels. Peppino Mirabelli and Mariarosaria Incoronato Copyright © 2013 Peppino Mirabelli and Mariarosaria Incoronato. All rights reserved. A Comprehensive Focus on Global Spectrum of BRCA1 and BRCA2 Mutations in Breast Cancer Thu, 07 Nov 2013 09:15:14 +0000 http://www.hindawi.com/journals/bmri/2013/928562/ Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs. Fatemeh Karami and Parvin Mehdipour Copyright © 2013 Fatemeh Karami and Parvin Mehdipour. All rights reserved. A Combination of Radiosurgery and Soluble Tissue Factor Enhances Vascular Targeting for Experimental Glioblastoma Wed, 06 Nov 2013 14:46:30 +0000 http://www.hindawi.com/journals/bmri/2013/390714/ Radiosurgery for glioblastoma is limited to the development of resistance, allowing tumor cells to survive and initiate tumor recurrence. Based on our previous work that coadministration of tissue factor and lipopolysaccharide following radiosurgery selectively induced thrombosis in cerebral arteriovenous malformations, achieving thrombosis of 69% of the capillaries and 39% of medium sized vessels, we hypothesized that a rapid and selective shutdown of the capillaries in glioblastoma vasculature would decrease the delivery of oxygen and nutrients, reducing tumor growth, preventing intracranial hypertension, and improving life expectancy. Glioblastoma was formed by implantation of GL261 cells into C57Bl/6 mouse brain. Mice were intravenously injected tissue factor, lipopolysaccharide, a combination of both, or placebo 24 hours after radiosurgery. Control mice received both agents after sham irradiation. Coadministration of tissue factor and lipopolysaccharide led to the formation of thrombi in up to 87 ± 8% of the capillaries and 46 ± 4% of medium sized vessels within glioblastoma. The survival rate of mice in this group was 80% versus no survivor in placebo controls 30 days after irradiation. Animal body weight increased with time in this group (, ). Thus, radiosurgery enhanced treatment with tissue factor, and lipopolysaccharide selectively induces thrombosis in glioblastoma vasculature, improving life expectancy. Jian Tu, Zhiqiang Hu, and Zhongbin Chen Copyright © 2013 Jian Tu et al. All rights reserved. Effectiveness and Safety of Intensive Triplet Chemotherapy Plus Bevacizumab, FIr-B/FOx, in Young-Elderly Metastatic Colorectal Cancer Patients Wed, 06 Nov 2013 09:12:37 +0000 http://www.hindawi.com/journals/bmri/2013/143273/ Four-drug regimens, such as FIr-B/FOx schedule, can improve efficacy of first-line treatment of metastatic colorectal cancer (MCRC) patients. The present study specifically evaluates feasibility of FIr-B/FOx first-line intensive regimen in fit young-elderly MCRC patients, representing approximately 40% of overall MCRC patients. Activity, efficacy, and safety were equivalent to overall MCRC patients, not significantly different according to KRAS genotype. Clinical outcome was significantly prolonged in liver-limited compared to other/multiple metastatic disease. Safety evaluation of the individual young-elderly patient showed that limiting toxicity syndromes (LTS) in multiple sites were significantly increased, compared to LTS in single site, with respect to non-elderly patients. Gemma Bruera, Katia Cannita, Aldo Victor Giordano, Roberto Vicentini, Corrado Ficorella, and Enrico Ricevuto Copyright © 2013 Gemma Bruera et al. All rights reserved. Persistence or Clearance of Human Papillomavirus Infections in Women in Ouro Preto, Brazil Tue, 05 Nov 2013 15:04:03 +0000 http://www.hindawi.com/journals/bmri/2013/578276/ Persistent high-risk (HR) human papillomavirus (HPV) infection is necessary for development of precursor lesions and cervical cancer. We investigate persistence and clearance of HPV infections and cofactors in unvaccinated women. Cervical samples of 569 women (18–75 years), received for routine evaluation in the Health Department of Ouro Preto, Brazil, were collected and subjected to PCR (MY09/11 or GP5+/6+ primers), followed by RFLP or sequencing. All women were interviewed to collect sociodemographic and behavioral information. Viral infection persistence or clearance was reevaluated after 24 months and was observed in 59.6% and 40.4% of women, respectively. HPVs 16, 33, 59, 66, 69, and 83 (HR) were the most persistent types whereas HPVs 31, 45, and 58 were less persistent. Clearance or persistence did not differ between groups infected by HPVs 18, 53, and 67. In low-risk (LR) types, HPV 6 infected samples were associated with clearance, while HPV 11, 61, 72, or 81 infected samples were persistent in the follow-up. No statistically significant association was detected between persistent HPV infections and sociodemographic and behavioral characteristics analyzed. To study persistence or clearance in HPV infection allows the identification of risk groups, cofactors, and strategies for prevention of cervical cancer. P. M. Miranda, N. N. T. Silva, B. C. V. Pitol, I. D. C. G. Silva, J. L. Lima-Filho, R. F. Carvalho, R. C. Stocco, W. Beçak, and A. A. Lima Copyright © 2013 P. M. Miranda et al. All rights reserved. Side Population Cells as Prototype of Chemoresistant, Tumor-Initiating Cells Mon, 04 Nov 2013 13:12:52 +0000 http://www.hindawi.com/journals/bmri/2013/517237/ Classically, isolation of CSCs from tumors exploits the detection of cell surface markers associated with normal stem cells. Invariable expression of these cell surface markers in almost all proliferating tumor cells that albeit impart specific functionality, the universality, and clinical credibility of CSC phenotype based on markers is still dubious. Side Population (SP) cells, as defined by Hoechst dye exclusion in flow cytometry, have been identified in many solid tumors and cell lines and the SP phenotype can be considered as an enriched source of stem cells as well as an alternative source for the isolation of cancer stem cells especially when molecular markers for stem cells are unknown. SP cells may be responsible for the maintenance and propagation of tumors and the proportion of SP cells may be a predictor of patient outcome. Several of these markers used in cell sorting have emerged as prognostic markers of disease progression though it is seen that the development of new CSC-targeted strategies is often hindered by poor understanding of their regulatory networks and functions. This review intends to appraise the experimental progress towards enhanced isolation and drug screening based on property of acquired chemoresistance of cancer stem cells. Vinitha Richard, Madhumathy G. Nair, T. R. Santhosh Kumar, and M. Radhakrishna Pillai Copyright © 2013 Vinitha Richard et al. All rights reserved. Demethylation of Cancer/Testis Antigens and CpG ODN Stimulation Enhance Dendritic Cell and Cytotoxic T Lymphocyte Function in a Mouse Mammary Model Mon, 04 Nov 2013 09:17:43 +0000 http://www.hindawi.com/journals/bmri/2013/196894/ Background. Cancer/testis antigens (CTAs) are ideal targets for cancer immunotherapy in virtue of their restricted expression profile in normal tissues. However, CTA-targeted immunotherapy has been rather disappointing clinical setting for CTAs are downregulated by cytosine-phosphate-guanosine (CpG) methylation in their promoter regions, so that tumor cells have low immunogenicity. Methods. We reinduced mouse CTA P1A through demethylation process and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/c (H-) mice with dendritic cells pulsed with a P1A-specific peptide and CpG oligodeoxynucleotide (ODN) immune adjuvant. Results. We found that demethylation and CpG ODN immune adjuvant stimulation facilitated DC maturation and enhanced the allogenic capacity of P1A-specific CTLs against target cells both in vitro and in vivo. Conclusions. Our results suggested that CTA induction and immune adjuvant stimulation is a feasible strategy in cancer immunotherapy. Jun-Zhong Sun, Lei Gao, Li Gao, Wei Wang, Nan Du, Juan Yang, Ling Wan, Fang Liu, Li-li Wang, and Li Yu Copyright © 2013 Jun-Zhong Sun et al. All rights reserved. PSF Knockdown Enhances Apoptosis via Downregulation of LC3B in Human Colon Cancer Cells Thu, 31 Oct 2013 11:05:05 +0000 http://www.hindawi.com/journals/bmri/2013/204973/ Our previous study demonstrated that PTB-associated splicing factor (PSF) is an important regulator of cell death and plays critical roles in the survival and growth of colon cancer cells. However, the molecular mechanism that activates these downstream signaling events remains unknown. To address this issue, we investigated the effects of PSF knockdown in two different colon cancer cell lines, DLD-1 and HT-29. We found that knockdown of PSF markedly decreased the autophagic molecule LC3B in DLD-1 cells but not in HT-29 cells. Furthermore, DLD-1 cells were more susceptible to PSF knockdown-induced cell growth inhibition and apoptosis than HT-29 cells. This susceptibility is probably a result of LC3B inhibition, given the known relationship between autophagy and apoptosis. C3B is associated with a number of physiological processes, including cell growth and apoptotic cell death. Our results suggest that autophagy is inhibited by PSF knockdown and that apoptosis and cell growth inhibition may act together to mediate the PSF-LC3B signaling pathway. Furthermore, we found that the peroxisome proliferator-activated receptor gamma (PPARγ)-PSF complex induced LC3B downregulation in DLD-1 cells. The results of this study identify a new physiological role for the PSF-LC3B axis as a potential endogenous modulator of colon cancer treatment. Tamotsu Tsukahara, Yoshikazu Matsuda, and Hisao Haniu Copyright © 2013 Tamotsu Tsukahara et al. All rights reserved. Crocus sativus L. (Saffron) Stigma Aqueous Extract Induces Apoptosis in Alveolar Human Lung Cancer Cells through Caspase-Dependent Pathways Activation Tue, 29 Oct 2013 11:07:59 +0000 http://www.hindawi.com/journals/bmri/2013/417928/ Worldwide, lung cancer is the most common form of cancer. Saffron has been used in folk medicine for centuries. We investigated the potential of saffron to induce cytotoxic and apoptotic effects in lung cancer cells (A549). We also examined the caspase-dependent pathways activation of saffron-induced apoptosis against the A549 cells. A549 cells were incubated with different concentrations of saffron extract; then cell morphological changes, cell viability, and apoptosis were determined by the normal invertmicroscope, MTT assay, Annexin V and propidium iodide, and flow cytometric analysis, respectively. Activated caspases were detected by treatment of saffron in lung cancer cells using fluorescein-labeled inhibitors of polycaspases. The proliferation of the A549 cells were decreased after treatment with saffron in a dose- and time-dependent manner. The percentage of apoptotic cells increased with saffron concentrations. Saffron induced morphological changes, decreased percentage of viable cells, and induced apoptosis. Saffron could induce apoptosis in the A549 cells and activate caspase pathways. The levels of caspases involved in saffron-induced apoptosis in the A549 cells indicating caspase-dependent pathway were induced by saffron. The anticancer activity of the aqueous extract of saffron could be attributed partly to its inhibition of the cell proliferation and induction of apoptosis in cancer cells through caspase-dependent pathways activation. Saeed Samarghandian, Abasalt Borji, Seyed Kazem Farahmand, Reza Afshari, and Saeideh Davoodi Copyright © 2013 Saeed Samarghandian et al. All rights reserved. Carbohydrate 19.9 Antigen Serum Levels in Liver Disease Sun, 27 Oct 2013 09:58:23 +0000 http://www.hindawi.com/journals/bmri/2013/531640/ Background. Carbohydrate 19.9 antigen (CA19.9) has been used in the diagnosis and followup of gastrointestinal tumours. The aim of this prospective longitudinal study was the evaluation of CA19.9 levels in patients with chronic hepatitis and hepatic cirrhosis hepatitis C virus and B virus correlated. Materials and Methods. 180 patients were enrolled, 116 with HCV-related chronic liver disease (48% chronic hepatitis, 52% cirrhosis) and 64 with HBV-related chronic liver disease (86% chronic hepatitis, 14% cirrhosis). Patients with high levels of CA19.9 underwent abdominal ecography, gastroendoscopy, colonoscopy, and abdominal CT scan. Results. 51.7% of patients with HCV-related chronic liver disease and 48.4% of those with HBV-related chronic liver disease presented high levels of CA19.9. None was affected by pancreatic or intestinal neoplasia, cholestatic jaundice, or other diseases potentially able to induce Ca19.9 elevations. CA19.9 levels were elevated in 43.3% of HCV chronic hepatitis, in 56.3% of HCV cirrhosis, in 45.1% of HBV chronic hepatitis, and in 58% of HBV cirrhosis. Conclusions. CA19.9 commonly increases in the serum of patients with chronic viral hepatitis. Elevation of CA 19.9 is not specific for neoplastic disease and is related to the severity of fibrosis and to the viral aetiology of hepatitis. Gaetano Bertino, Annalisa Maria Ardiri, Giuseppe Stefano Calvagno, Giulia Malaguarnera, Donatella Interlandi, Marco Vacante, Nicoletta Bertino, Francesco Lucca, Roberto Madeddu, and Massimo Motta Copyright © 2013 Gaetano Bertino et al. All rights reserved. A Light-Field-Based Method to Adjust On-Axis Rounded Leaf End MLC Position to Predict Off-Axis MLC Penumbra Region Dosimetric Performance in a Radiation Therapy Planning System Thu, 24 Oct 2013 19:30:18 +0000 http://www.hindawi.com/journals/bmri/2013/461801/ Purpose. An analytical and experimental study of split shape dose calculation correction by adjusting the position of the on-axis round leaf end position is presented. We use on-axis corrected results to predict off-axis penumbra region dosimetric performance in an intensity-modulated radiation therapy treatment planning system. Materials and Methods. The precise light-field edge position () was derived from the on-axis 50% dose position created by using the nominal light field for geometric and mathematical manipulation. Leaf position () could be derived from by defining in the treatment planning system for monitor unit calculation. On-axis offset (correction) could be obtained from the position corresponding to 50% of the central axis dose minus the position. The off-axis 50% dose position can then be derived from the on-axis 50% dose position. Results. The monitor unit calculation of the split shape using the on-axis rounded leaf end MLC penumbra region could provide an under-or overdose of 7.5% per millimeter without an offset correction. When using the on-axis rounded leaf end offset correction to predict the off-axis dose, the difference between the off- and on-axis 50% dose position is within ±1.5 mm. Conclusions. It is possible to achieve a dose calculation within 0.5% error for an adjusted MLC leaf edge location in the treatment planning system with careful measurement and an accurate on-axis offset correction. Dose calculations located at an off-axis spilt shape region should be used carefully due to noncorrectable errors which were found to be up to 10%. Jia-Ming Wu, Tsair-Fwu Lee, Shyh-An Yeh, Kuan-Yin Hsiao, Hsin-Hsiung Chen, Pei-Ju Chao, and Yi-Ting Chen Copyright © 2013 Jia-Ming Wu et al. All rights reserved. Interactive Multigrid Refinement for Deformable Image Registration Tue, 22 Oct 2013 15:03:03 +0000 http://www.hindawi.com/journals/bmri/2013/532936/ Deformable image registration is the spatial mapping of corresponding locations between images and can be used for important applications in radiotherapy. Although numerous methods have attempted to register deformable medical images automatically, such as salient-feature-based registration (SFBR), free-form deformation (FFD), and demons, no automatic method for registration is perfect, and no generic automatic algorithm has shown to work properly for clinical applications due to the fact that the deformation field is often complex and cannot be estimated well by current automatic deformable registration methods. This paper focuses on how to revise registration results interactively for deformable image registration. We can manually revise the transformed image locally in a hierarchical multigrid manner to make the transformed image register well with the reference image. The proposed method is based on multilevel B-spline to interactively revise the deformable transformation in the overlapping region between the reference image and the transformed image. The resulting deformation controls the shape of the transformed image and produces a nice registration or improves the registration results of other registration methods. Experimental results in clinical medical images for adaptive radiotherapy demonstrated the effectiveness of the proposed method. Wu Zhou and Yaoqin Xie Copyright © 2013 Wu Zhou and Yaoqin Xie. All rights reserved. The Treatment Outcome and Radiation-Induced Toxicity for Patients with Head and Neck Carcinoma in the IMRT Era: A Systematic Review with Dosimetric and Clinical Parameters Tue, 22 Oct 2013 09:26:01 +0000 http://www.hindawi.com/journals/bmri/2013/401261/ A descriptive analysis was made in terms of the related radiation induced acute and late mucositis and xerostomia along with survival and tumor control rates (significance level at 0.016, bonferroni correction), for irradiation in head and neck carcinomas with either 2D Radiation Therapy (2DRT) and 3D conformal (3DCRT) or Intensity Modulated Radiation Therapy (IMRT). The mean score of grade II xerostomia for IMRT versus 2-3D RT was 0.31 ± 0.23 and 0.56 ± 0.23, respectively (Mann Whitney, ). The parotid-dose for IMRT versus 2-3D RT was 29.56 ± 5.45 and 50.73 ± 6.79, respectively (Mann Whitney, ). The reported mean parotid-gland doses were significantly correlated with late xerostomia (spearman test, rho = 0.5013, ). A trend was noted for the superiority of IMRT concerning the acute oral mucositis. The 3-year overall survival for either IMRT or 2-3DRT was 89.5% and 82.7%, respectively (, Kruskal-Wallis test). The mean 3-year locoregional control rate was 83.6% (range: 70–97%) and 74.4 (range: 61–82%), respectively (, Kruskal-Wallis). In conclusion, no significant differences in terms of locoregional control, overall survival and acute mucositis could be noted, while late xerostomia is definitely higher in 2-3D RT versus IMRT. Patients with head and neck carcinoma should be referred preferably to IMRT techniques. Vassilis Kouloulias, Stella Thalassinou, Kalliopi Platoni, Anna Zygogianni, John Kouvaris, Christos Antypas, Efstathios Efstathopoulos, and Kelekis Nikolaos Copyright © 2013 Vassilis Kouloulias et al. All rights reserved. Effect of Adjuvant Magnetic Fields in Radiotherapy on Non-Small-Cell Lung Cancer Cells In Vitro Thu, 10 Oct 2013 11:45:19 +0000 http://www.hindawi.com/journals/bmri/2013/657259/ Objectives. To explore sensitization and possible mechanisms of adjuvant magnetic fields (MFs) in radiotherapy (RT) of non-small-cell lung cancer. Methods. Human A549 lung adenocarcinoma cells were treated with MF, RT, and combined MF-RT. Colony-forming efficiency was calculated, cell cycle and apoptosis were measured, and changes in cell cycle- and apoptosis-related gene expression were measured by microarray. Results. A 0.5 T, 8 Hz stationary MF showed a duration-dependent inhibitory effect lasting for 1–4 hours. The MF-treated groups had significantly greater cell inhibition than did controls (). Surviving fractions and growth curves derived from colony-forming assay showed that the MF-only, RT-only, and MF-RT groups had inhibited cell growth; the MF-RT group showed a synergetic effect. Microarray of A549 cells exposed for 1 hour to MF showed that 19 cell cycle- and apoptosis-related genes had 2-fold upregulation and 40 genes had 2-fold downregulation. MF significantly arrested cells in G2 and M phases, apparently sensitizing the cells to RT. Conclusions. MF may inhibit A549 cells and can increase their sensitivity to RT, possibly by affecting cell cycle- and apoptosis-related signaling pathways. Jianguo Feng, Huaying Sheng, Chihong Zhu, Hao Jiang, and Shenglin Ma Copyright © 2013 Jianguo Feng et al. All rights reserved. The Cytotoxic Effect of Magainin II on the MDA-MB-231 and M14K Tumour Cell Lines Wed, 09 Oct 2013 17:39:36 +0000 http://www.hindawi.com/journals/bmri/2013/831709/ Many studies have highlighted the tumoricidal properties of some natural peptides known to have antimicrobial virtues. Also, the increasingly higher resistance to conventional antibiotics has become a global public health issue, and the need for new antibiotics has stimulated interest in finding and synthesizing new antimicrobial peptides, which may also be used as chemotherapeutic agents. Relying on the literature, the purpose of our in vitro research was to assess the tumoricidal potential of magainin II on a series of tumour cell lines, namely, MDA-MB-231 (breast adenocarcinoma) and M14K (human mesothelioma). The experimental results of our study revealed that the cytotoxic effects of magainin II depend on its concentration. Its efficiency is significant at 120 μM concentrations, and, although it is much lower, it persists even at 60 μM concentrations. The effects were insignificant at 30 μM concentrations. In our experimental research, the tumoricidal effect of magainin II was not significantly dependent on the type of tumour cell line used. Radu Anghel, Daniela Jitaru, Laurenţiu Bădescu, Magda Bădescu, and Manuela Ciocoiu Copyright © 2013 Radu Anghel et al. All rights reserved. Development of a Modelling to Correlate Site and Diameter of Brain Metastases with Hippocampal Sparing Using Volumetric Modulated Arc Therapy Wed, 09 Oct 2013 16:51:31 +0000 http://www.hindawi.com/journals/bmri/2013/568597/ Purpose. To correlate site and diameter of brain metastases with hippocampal sparing in patients treated by RapidArc (RA) technique on whole brain with simultaneously integrated boost (SIB). Methods and Materials. An RA plan was calculated for brain metastases of 1-2-3 cm of diameter. The whole brain dose was 32.25 Gy (15 fractions), and SIB doses to brain metastases were 63 Gy (2 and 3 cm) or 70.8 Gy (1 cm). Plans were optimized and evaluated for conformity, target coverage, prescription isodose to target volume, homogeneity index, and hippocampal sparing. Results. Fifteen brain lesions and RA plan were generated. Hippocampal volume was 4.09 cm3, and hippocampal avoidance volume was 17.50 cm3. Related to site of metastases, the mean hippocampal dose was 9.68 Gy2 for occipital lobe, 10.56 Gy2 for frontal lobe, 10.56 Gy2 for parietal lobe, 10.94 Gy2 for deep brain structures, and 40.44 Gy2 for temporal lobe. The mean hippocampal dose was 9.45 Gy2, 10.15 Gy2, and 11.70 Gy2 for diameter’s metastases of 1.2 and 3 cm, respectively, excluding results relative to temporal brain lesions. Conclusions. Location more than size of metastases can adversely influence the hippocampus sparing. Further investigation is necessary to meet definitive considerations. Silvia Chiesa, Mario Balducci, Luigi Azario, Simona Gaudino, Francesco Cellini, Gian Carlo Mattiucci, Cesare Colosimo, and Vincenzo Valentini Copyright © 2013 Silvia Chiesa et al. All rights reserved. Prognostic Value of Combined Aquaporin 3 and Aquaporin 5 Overexpression in Hepatocellular Carcinoma Wed, 09 Oct 2013 14:51:33 +0000 http://www.hindawi.com/journals/bmri/2013/206525/ Background. Aquaporin (AQP) 3 and AQP 5 are involved in tumorigenesis and tumor progression of several tumor types. Aim. To investigate expression patterns and clinical significance of AQP3 and AQP5 in hepatocellular carcinoma (HCC). Methods. Immunohistochemistry was performed to detect the expression of AQP3 and AQP5 in HCC tissues. Results. Immunohistochemistry analysis showed the increased expression of AQP3 and AQP5 protein levels in HCC tissues compared with their adjacent nonneoplastic tissues (both ). In addition, combined AQP3 and AQP5 protein expression was significantly associated with serum AFP (), tumor stage (), and tumor grade (). Moreover, HCC patients highly expressing both AQP3 and AQP5 proteins had worse 5-year disease-free survival and 5-year overall survival ( and 0.005, resp.). Furthermore, the Cox proportional hazards model showed that combined AQP3 and AQP5 protein expression was an independent poor prognostic factor for both 5-year disease-free survival () and 5-year overall survival () in HCC. Conclusion. Our data suggest for the first time that the aberrant expression of AQP3 and AQP5 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of AQP3 in combination with upregulation of AQP5 may be an unfavorable prognostic factor for HCC. Xiaodong Guo, Ting Sun, Mei Yang, Zhiyan Li, Zhiwei Li, and Yuejuan Gao Copyright © 2013 Xiaodong Guo et al. All rights reserved. Evaluation of Wall Correction Factor of INER's Air-Kerma Primary Standard Chamber and Dose Variation by Source Displacement for HDR 192Ir Brachytherapy Tue, 08 Oct 2013 14:37:53 +0000 http://www.hindawi.com/journals/bmri/2013/436979/ The aim of the present study was to estimate the wall effect of the self-made spherical graphite-walled cavity chamber with the Monte Carlo method for establishing the air-kerma primary standard of high-dose-rate (HDR) 192Ir brachytherapy sources at the Institute of Nuclear Energy Research (INER, Taiwan). The Monte Carlo method established in this paper was also employed to respectively simulate wall correction factors of the 192Ir air-kerma standard chambers used at the National Institute of Standards and Technology (NIST, USA) and the National Physical Laboratory (NPL, UK) for comparisons and verification. The chamber wall correction calculation results will be incorporated into INER's HDR 192Ir primary standard in the future. For the brachytherapy treatment in the esophagus or in the bronchi, the position of the isotope may have displacement in the cavity. Thus the delivered dose would differ from the prescribed dose in the treatment plan. We also tried assessing dose distribution due to the position displacement of HDR 192Ir brachytherapy source in a phantom with a central cavity by the Monte Carlo method. The calculated results could offer a clinical reference for the brachytherapy within the human organs with cavity. J. H. Lee, J. N. Wang, T. T. Huang, S. H. Su, B. J. Chang, C. H. Su, and S. M. Hsu Copyright © 2013 J. H. Lee et al. All rights reserved. Higher Incidence of Lung Adenocarcinomas Induced by DMBA in Connexin 43 Heterozygous Knockout Mice Thu, 03 Oct 2013 17:29:16 +0000 http://www.hindawi.com/journals/bmri/2013/618475/ Gap junctions are communicating junctions which are important for tissue homeostasis, and their disruption is involved in carcinogenic processes. This study aimed to verify the influence of deletion of one allele of the Connexin 43 gene on cancer incidence in different organs. The 7, 12-dimethylbenzanthracene (DMBA) carcinogenic model, using hebdomadary doses by gavage of 9 mg per animal, was used to induce tumors in Connexin 43 heterozygous or wild-type mice. The experiment began in the eighth week of the mice life, and all of them were euthanized when reaching inadequate physical condition, or at the end of 53 weeks. No statistical differences occurred for weight gain and cancer survival time () between heterozygous and wild-type mice. Cx43+/− mice presented significantly higher susceptibility to lung cancer () which was not evidenced for benign neoplasms (). In addition, incidence of ovarian neoplasms was 2.5-fold higher in Cx43+/− mice, although not statistically significant. Other organs showed a very similar cancer occurrence between Cx43 groups. The experiment strengthens the evidence of the relationship between Connexin 43 deficiency and carcinogenesis. Krishna Duro de Oliveira, Marcello Vannucci Tedardi, Bruno Cogliati, and Maria Lúcia Zaidan Dagli Copyright © 2013 Krishna Duro de Oliveira et al. All rights reserved. Endothelial Gene Expression and Molecular Changes in Response to Radiosurgery in In Vitro and In Vivo Models of Cerebral Arteriovenous Malformations Wed, 02 Oct 2013 08:50:23 +0000 http://www.hindawi.com/journals/bmri/2013/408253/ Radiosurgery for cerebral arteriovenous malformations (AVMs) is limited to 2-year latency. There is no early marker to monitor whether the lesion is responsive to radiosurgery. In this study, we examined endothelial gene expression and molecular changes in response to radiosurgery. Gene expression of E- and P-selectin, ICAM-1, PECAM-1, VCAM-1, tissue factor, and vWF in human cerebral microvascular endothelial cells was quantified by RT-qPCR at different radiation doses and time points. Soluble E- and P-selectin, ICAM-1, VCAM-1, and tissue factor in an animal model of AVMs were quantified by ELISA at different time after radiosurgery. We found that gene expression of E- and P-selectin, ICAM-1, PECAM-1, and VCAM-1 was upregulated by radiation in a dose-dependent manner (). Gene expression of E- and P-selectin and ICAM-1 was more sensitive to irradiation than that of PECAM-1 and VCAM-1. Radiosurgery induced gene expression of P-selectin, ICAM-1, PECAM-1, and VCAM-1 was linearly correlated with time (). Radiosurgery induced elevation of soluble E- and P-selectin, ICAM-1, VCAM-1, and tissue factor in a rat model of AVMs (). Thus, a combination of these molecules measured at different time points may serve as an early predictor of responsiveness of AVMs to radiosurgery. Jian Tu, Zhiqiang Hu, and Zhongbin Chen Copyright © 2013 Jian Tu et al. All rights reserved. Role of STAT3 in Cancer Metastasis and Translational Advances Wed, 02 Oct 2013 08:36:54 +0000 http://www.hindawi.com/journals/bmri/2013/421821/ Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. Mohammad Zahid Kamran, Prachi Patil, and Rajiv P. Gude Copyright © 2013 Mohammad Zahid Kamran et al. All rights reserved. Immune Monitoring in Cancer Vaccine Clinical Trials: Critical Issues of Functional Flow Cytometry-Based Assays Mon, 30 Sep 2013 14:34:57 +0000 http://www.hindawi.com/journals/bmri/2013/726239/ The development of immune monitoring assays is essential to determine the immune responses against tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs) and their possible correlation with clinical outcome in cancer patients receiving immunotherapies. Despite the wide range of techniques used, to date these assays have not shown consistent results among clinical trials and failed to define surrogate markers of clinical efficacy to antitumor vaccines. Multiparameter flow cytometry- (FCM-) based assays combining different phenotypic and functional markers have been developed in the past decade for informative and longitudinal analysis of polyfunctional T-cells. These technologies were designed to address the complexity and functional heterogeneity of cancer biology and cellular immunity and to define biomarkers predicting clinical response to anticancer treatment. So far, there is still a lack of standardization of some of these immunological tests. The aim of this review is to overview the latest technologies for immune monitoring and to highlight critical steps involved in some of the FCM-based cellular immune assays. In particular, our laboratory is focused on melanoma vaccine research and thus our main goal was the validation of a functional multiparameter test (FMT) combining different functional and lineage markers to be applied in clinical trials involving patients with melanoma. Iole Macchia, Francesca Urbani, and Enrico Proietti Copyright © 2013 Iole Macchia et al. All rights reserved. Stat3 Inhibits PTPN13 Expression in Squamous Cell Lung Carcinoma through Recruitment of HDAC5 Thu, 26 Sep 2013 15:27:38 +0000 http://www.hindawi.com/journals/bmri/2013/468963/ Proteins of the protein tyrosine phosphatase (PTP) family are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, and apoptosis. PTPN13 (also known as FAP1, PTPL1, PTPLE, PTPBAS, and PTP1E), a putative tumor suppressor, is frequently inactivated in lung carcinoma through the loss of either mRNA or protein expression. However, the molecular mechanisms underlying its dysregulation have not been fully explored. Interleukin-6 (IL-6) mediated Stat3 activation is viewed as crucial for multiple tumor growth and progression. Here, we demonstrate that PTPN13 is a direct transcriptional target of Stat3 in the squamous cell lung carcinoma. Our data show that IL-6 administration or transfection of a constitutively activated Stat3 in HCC-1588 and SK-MES-1 cells inhibits PTPN13 mRNA transcription. Using luciferase reporter and ChIP assays, we show that Stat3 binds to the promoter region of PTPN13 and promotes its activity through recruiting HDAC5. Thus, our results suggest a previously unknown Stat3-PTPN13 molecular network controlling squamous cell lung carcinoma development. Xiu-juan Han, Li Xue, Li Gong, Shao-jun Zhu, Li Yao, Shu-mei Wang, Miao Lan, Wei Zhang, and Yan-hong Li Copyright © 2013 Xiu-juan Han et al. All rights reserved. Helical Irradiation of the Total Skin with Dose Painting to Replace Total Skin Electron Beam Therapy for Therapy-Refractory Cutaneous CD4+ T-Cell Lymphoma Mon, 23 Sep 2013 14:46:48 +0000 http://www.hindawi.com/journals/bmri/2013/717589/ A 36-year-old woman was diagnosed with a therapy-refractory cutaneous CD4+ T-cell lymphoma, T3N0M0B0, and stage IIB. Helical irradiation of the total skin (HITS) and dose painting techniques, with 30 Gy in 40 fractions interrupted at 20 fractions with one week resting, 4 times per week were prescribed. The diving suit was dressed whole body to increase the superficial dose and using central core complete block (CCCB) technique for reducing the internal organ dose. The mean doses of critical organs of head, chest, and abdomen were 2.1 to 29.9 Gy, 2.9 to 8.1 Gy, and 3.6 to 15.7 Gy, respectively. The mean dose of lesions was 84.0 cGy. The dosage of left side pretreated area was decreased 57%. The tumor regressed progressively without further noduloplaques. During the HITS procedure, most toxicity was grade I except leukocytopenia with grade 3. No epitheliolysis, phlyctenules, tumor lysis syndrome, fever, vomiting, dyspnea, edema of the extremities, or diarrhea occurred during the treatment. HITS with dose painting techniques provides precise dosage delivery with impressive results, sparing critical organs, and offering limited transient and chronic sequelae for previously locally irradiated, therapy-refractory cutaneous T-cell lymphoma. Chen-Hsi Hsieh, Pei-Wei Shueng, Shih-Chiang Lin, Hui-Ju Tien, An-Cheng Shiau, Yueh-Hung Chou, Meng-Hao Wu, Jen-Yu Wang, Chi-Kuan Chen, and Yu-Jen Chen Copyright © 2013 Chen-Hsi Hsieh et al. All rights reserved. Stage-Stratified Analysis of Prognostic Significance of Bax-Interacting Factor-1 Expression in Resected Colorectal Cancer Mon, 23 Sep 2013 13:46:13 +0000 http://www.hindawi.com/journals/bmri/2013/329839/ Background/Aim. Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). Methods. We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. Results. Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285–0.739; ). Conclusion. Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC. Yoon Ho Ko, Young-Seok Cho, Hye Sung Won, Ho Jung An, Der Sheng Sun, Soon Uk Hong, Jin Hee Park, and Myung Ah Lee Copyright © 2013 Yoon Ho Ko et al. All rights reserved. Hypoxia and Human Genome Stability: Downregulation of BRCA2 Expression in Breast Cancer Cell Lines Sun, 22 Sep 2013 10:39:39 +0000 http://www.hindawi.com/journals/bmri/2013/746858/ Previously, it has been reported that hypoxia causes increased mutagenesis and alteration in DNA repair mechanisms. In 2005, an interesting study showed that hypoxia-induced decreases in BRCA1 expression and the consequent suppression of homologous recombination may lead to genetic instability. However, nothing is yet known about the involvement of BRCA2 in hypoxic conditions in breast cancer. Initially, a cell proliferation assay allowed us to hypothesize that hypoxia could negatively regulate the breast cancer cell growth in short term in vitro studies. Subsequently, we analyzed gene expression in breast cancer cell lines exposed to hypoxic condition by microarray analysis. Interestingly, genes involved in DNA damage repair pathways such as mismatch repair, nucleotide excision repair, nonhomologous end-joining and homologous recombination repair were downregulated. In particular, we focused on the BRCA2 downregulation which was confirmed at mRNA and protein level. In addition, breast cancer cells were treated with dimethyloxalylglycine (DMOG), a cell-permeable inhibitor of both proline and asparaginyl hydroxylases able to induce HIF-1α stabilization in normoxia, providing results comparable to those previously described. These findings may provide new insights into the mechanisms underlying genetic instability mediated by hypoxia and BRCA involvement in sporadic breast cancers. Daniele Fanale, Viviana Bazan, Stefano Caruso, Marta Castiglia, Giuseppe Bronte, Christian Rolfo, Giuseppe Cicero, and Antonio Russo Copyright © 2013 Daniele Fanale et al. All rights reserved. Efficacy and Safety of Docetaxel Plus Oxaliplatin and Capecitabine in the First Line Treatment of Advanced Gastric Adenocarcinoma Sun, 15 Sep 2013 13:35:40 +0000 http://www.hindawi.com/journals/bmri/2013/971096/ Objective. To evaluate the efficacy and safety of docetaxel plus oxaliplatin and capecitabine (DOX) in the first line treatment of advanced gastric adenocarcinoma. Methods. A total of 37 patients were enrolled into this study, and they received DOX regimen (docetaxel 75 mg/m2 and oxaliplatin 130 mg/m2 intravenous infusion on day 1, and capecitabine 1000 mg/m2 orally twice daily on d1–14); treatment was repeated every 3 weeks. Results. All 37 patients were assessable for evaluation. The numbers of patients with complete response (CR), partial responses (PR), stable disease (SD), and progressive disease (PD) were 1, 10, 23, and 3, respectively. The objective response rate (ORR) was 29.7%, with the disease control rate (DCR) of 91.9%. Median progression-free survival (mPFS) and overall survival (mOS) were 197 days and 364 days, respectively. The most common grade 3/4 toxicities were hematological toxicities. The most common grade 3/4 nonhematological toxicities were fatigue, nausea, vomiting, anorexia, diarrhea, and hand-foot syndrome. Conclusion. The DOX regimen demonstrated a promising efficacy as the first line regimen in treating advanced gastric cancer patients with good performance status, the toxicities were tolerated and controllable. Large-scale clinical observation is necessary to get further evidence. Ying Liu, Zhengbao Ye, Wenqi Xi, Tao Ma, Min Shi, Liu Yang, Zhenggang Zhu, and Jun Zhang Copyright © 2013 Ying Liu et al. All rights reserved. Heart Rate Variability Is Associated with Survival in Patients with Brain Metastasis: A Preliminary Report Thu, 12 Sep 2013 13:33:05 +0000 http://www.hindawi.com/journals/bmri/2013/503421/ Impaired heart rate variability (HRV) has been demonstrated as a negative survival prognosticator in various diseases. We conducted this prospective study to evaluate how HRV affects brain metastasis (BM) patients. Fifty-one BM patients who had not undergone previous brain operation or radiotherapy (RT) were recruited from January 2010 to July 2012, and 40 patients were included in the final analysis. A 5-minute electrocardiogram was obtained before whole brain radiotherapy. Time domain indices of HRV were compared with other clinical factors on overall survival (OS). In the univariate analysis, Karnofsky performance status (KPS) <70 () and standard deviation of the normal-to-normal interval (SDNN) <10 ms () significantly predict poor survival. The multivariate analysis revealed that KPS <70 and SDNN <10 ms were independent negative prognosticators for survival in BM patients with hazard ratios of 2.657 and 2.204, respectively. In conclusion, HRV is associated with survival and may be a novel prognostic factor for BM patients. Yu-Ming Wang, Hau-Tieng Wu, Eng-Yen Huang, Yu Ru Kou, and Shu-Shya Hseu Copyright © 2013 Yu-Ming Wang et al. All rights reserved. The Human Cell Surfaceome of Breast Tumors Mon, 09 Sep 2013 19:05:42 +0000 http://www.hindawi.com/journals/bmri/2013/976816/ Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. Júlia Pinheiro Chagas da Cunha, Pedro Alexandre Favoretto Galante, Jorge Estefano Santana de Souza, Martin Pieprzyk, Dirce Maria Carraro, Lloyd J. Old, Anamaria Aranha Camargo, and Sandro José de Souza Copyright © 2013 Júlia Pinheiro Chagas da Cunha et al. All rights reserved. Total Marrow Irradiation as Part of Autologous Stem Cell Transplantation for Asian Patients with Multiple Myeloma Sun, 08 Sep 2013 11:17:28 +0000 http://www.hindawi.com/journals/bmri/2013/321762/ To compare the outcomes of melphalan 200 mg/m2 (HDM200) and 8 Gy total marrow irradiation (TMI) delivered by helical tomotherapy plus melphalan 140 mg/m2 (HDM140 + TMI 8 Gy) in newly diagnosed symptomatic multiple myeloma (MM) Asian patients. Between 2007 and 2010, nine consecutive myeloma patients who were scheduled to undergo autologous stem cell transplantation (ASCT) were studied. The patients received three cycles of vincristine-adriamycin-dexamethasone (VAD) regimen as induction chemotherapy, and if they had a partial response, peripheral blood stem cells were collected by dexamethasone-etoposide-cyclophosphamide-cisplatin (DECP). In arm A, six patients received the HDM200. In arm B, three patients received HDM140 + TMI 8 Gy. In arm B, the neutropenic duration was slightly longer than in arm A (). However, hematologic recovery (except for neutrophils), transfusion requirement, median duration of hospitalization, and the dose of G-CSF were similar in both arms. The median duration of overall survival and event-free survival was similar in the two arms (). As a conditioning regiment, HDM140 + TMI 8 Gy provide another chance for MM Asian patients who were not feasible for HDM200. Shih-Chiang Lin, Pei-Ying Hsieh, Pei-Wei Shueng, Hui-Ju Tien, Li-Ying Wang, and Chen-Hsi Hsieh Copyright © 2013 Shih-Chiang Lin et al. All rights reserved. Electrical Impedance Spectroscopy as Electrical Biopsy for Monitoring Radiation Sequelae of Intestine in Rats Wed, 04 Sep 2013 15:07:46 +0000 http://www.hindawi.com/journals/bmri/2013/974614/ Electrical impedance is one of the most frequently used parameters for characterizing material properties. The resistive and capacitive characteristics of tissue may be revealed by electrical impedance spectroscopy (EIS) as electrical biopsy. This technique could be used to monitor the sequelae after irradiation. In this study, rat intestinal tissues after irradiation were assessed by EIS system based on commercially available integrated circuits. The EIS results were fitted to a resistor-capacitor circuit model to determine the electrical properties of the tissue. The variations in the electrical characteristics of the tissue were compared to radiation injury score (RIS) by morphological and histological findings. The electrical properties, based on receiver operation curve (ROC) analysis, strongly reflected the histological changes with excellent diagnosis performance. The results of this study suggest that electrical biopsy reflects histological changes after irradiation. This approach may significantly augment the evaluation of tissue after irradiation. It could provide rapid results for decision making in monitoring radiation sequelae prospectively. Pei-Ju Chao, Eng-Yen Huang, Kuo-Sheng Cheng, and Yu-Jie Huang Copyright © 2013 Pei-Ju Chao et al. All rights reserved. Control of Respiratory Motion by Hypnosis Intervention during Radiotherapy of Lung Cancer I Wed, 04 Sep 2013 10:53:14 +0000 http://www.hindawi.com/journals/bmri/2013/574934/ The uncertain position of lung tumor during radiotherapy compromises the treatment effect. To effectively control respiratory motion during radiotherapy of lung cancer without any side effects, a novel control scheme, hypnosis, has been introduced in lung cancer treatment. In order to verify the suggested method, six volunteers were selected with a wide range of distribution of age, weight, and chest circumference. A set of experiments have been conducted for each volunteer, under the guidance of the professional hypnotist. All the experiments were repeated in the same environmental condition. The amplitude of respiration has been recorded under the normal state and hypnosis, respectively. Experimental results show that the respiration motion of volunteers in hypnosis has smaller and more stable amplitudes than in normal state. That implies that the hypnosis intervention can be an alternative way for respiratory control, which can effectively reduce the respiratory amplitude and increase the stability of respiratory cycle. The proposed method will find useful application in image-guided radiotherapy. Rongmao Li, Jie Deng, and Yaoqin Xie Copyright © 2013 Rongmao Li et al. All rights reserved. Helical Tomotherapy for Inoperable Breast Cancer: A New Promising Tool Mon, 02 Sep 2013 15:39:55 +0000 http://www.hindawi.com/journals/bmri/2013/264306/ Background. We investigated the feasibility of helical tomotherapy (HT) for inoperable large breast tumors, after failing to achieve adequate treatment planning with conformal radiation techniques. Material and Methods. Five consecutive patients with locally advanced breast cancer (LABC) were treated by preoperative HT. All patients received up-front chemotherapy before HT. Irradiated volumes included breast and nodal areas (45–50 Gy) in 4 patients. One patient received a simultaneous integrated boost (55 Gy) to gross tumor volume (GTV) without lymph node irradiation. Acute toxicity was assessed with Common Toxicity Criteria for Adverse Events v.4. Patients were evaluated for surgery at the end of treatment. Results. Patients were staged IIB to IIIC (according to the AJCC staging system 2010). HT was associated in 4 patients with concomitant chemotherapy (5-fluorouracil and vinorelbine). Two patients were scored with grade 3 skin toxicity (had not completed HT) and one with grade 3 febrile neutropenia. One patient stopped HT with grade 2 skin toxicity. All patients were able to undergo mastectomy at a median interval of 43 days (31–52) from HT. Pathological partial response was seen in all patients. Conclusions. HT is feasible with acceptable toxicity profiles, potentially increased by chemotherapy. These preliminary results prompt us to consider a phase II study. Ciprian Chira, Youlia M. Kirova, Xavier Liem, François Campana, Dominique Peurien, Malika Amessis, Nathalie Fournier-Bidoz, Jean-Yves Pierga, Rémi Dendale, Pierre Bey, and Alain Fourquet Copyright © 2013 Ciprian Chira et al. All rights reserved. Digital Microscopy Assessment of Angiogenesis in Different Breast Cancer Compartments Sun, 01 Sep 2013 14:02:52 +0000 http://www.hindawi.com/journals/bmri/2013/286902/ Background/Aim. Tumour angiogenesis defined by microvessel density (MVD) is generally accepted as a prognostic factor in breast cancer. However, due to variability of measurement systems and cutoffs, it is questionable to date whether it contributes to predictive outline. Our study aims to grade vascular heterogeneity by comparing clear-cut compartments: tumour associated stroma (TAS), tumour parenchyma, and tumour invasive front. Material and Methods. Computerized vessel area measurement was performed using a tissue cytometry system (TissueFAXS) on slides originated from 50 patients with breast cancer. Vessels were marked using immunohistochemistry with CD34. Regions of interest were manually defined for each tumour compartment. Results. Tumour invasive front vascular endothelia area was 2.15 times higher than that in tumour parenchyma and 4.61 times higher than that in TAS (). Worth to mention that the lymph node negative subgroup of patients show a slight but constant increase of vessel index in all examined compartments of breast tumour. Conclusion. Whole slide digital examination and region of interest (ROI) analysis are a valuable tool in scoring angiogenesis markers and disclosing their prognostic capacity. Our study reveals compartments’ variability of vessel density inside the tumour and highlights the propensity of invasive front to associate an active process of angiogenesis with potential implications in adjuvant therapy. Anca Haisan, Radu Rogojanu, Camelia Croitoru, Daniela Jitaru, Cristina Tarniceriu, Mihai Danciu, and Eugen Carasevici Copyright © 2013 Anca Haisan et al. All rights reserved. A Review on the Use of Grid-Based Boltzmann Equation Solvers for Dose Calculation in External Photon Beam Treatment Planning Tue, 27 Aug 2013 13:27:03 +0000 http://www.hindawi.com/journals/bmri/2013/692874/ Deterministic linear Boltzmann transport equation (D-LBTE) solvers have recently been developed, and one of the latest available software codes, Acuros XB, has been implemented in a commercial treatment planning system for radiotherapy photon beam dose calculation. One of the major limitations of most commercially available model-based algorithms for photon dose calculation is the ability to account for the effect of electron transport. This induces some errors in patient dose calculations, especially near heterogeneous interfaces between low and high density media such as tissue/lung interfaces. D-LBTE solvers have a high potential of producing accurate dose distributions in and near heterogeneous media in the human body. Extensive previous investigations have proved that D-LBTE solvers were able to produce comparable dose calculation accuracy as Monte Carlo methods with a reasonable speed good enough for clinical use. The current paper reviews the dosimetric evaluations of D-LBTE solvers for external beam photon radiotherapy. This content summarizes and discusses dosimetric validations for D-LBTE solvers in both homogeneous and heterogeneous media under different circumstances and also the clinical impact on various diseases due to the conversion of dose calculation from a conventional convolution/superposition algorithm to a recently released D-LBTE solver. Monica W. K. Kan, Peter K. N. Yu, and Lucullus H. T. Leung Copyright © 2013 Monica W. K. Kan et al. All rights reserved. New Hypothesis on Pathogenesis of Ovarian Cancer Lead to Future Tailored Approaches Sun, 25 Aug 2013 13:40:11 +0000 http://www.hindawi.com/journals/bmri/2013/852839/ In the last decades, management of epithelial ovarian cancer (EOC) has been based on the staging system of the International Federation of Gynecology and Obstetrics (FIGO), and different classifications have been proposed for EOC that take account of grade of differentiation, histological subtype, and clinical features. However, despite taxonomic efforts, EOC appears to be not a unique disease; its subtypes differ for epidemiological and genetic risk factors, precursor lesions, patterns of spread, response to chemotherapy, and prognosis. Nevertheless, carboplatin plus paclitaxel combination represents the only standard treatment in adjuvant and advanced settings. This paper summarizes theories about the classification and origin of EOC and classical and new prognostic factors. It presents data about standard treatment and novel agents. We speculate about the possibility to create tailored therapy based on specific mutations in ovarian cancer and to personalize prevention. P. Rescigno, I. Cerillo, R. Ruocco, C. Condello, S. De Placido, and M. Pensabene Copyright © 2013 P. Rescigno et al. All rights reserved. Interferon-α Enhances 5′-Deoxy-5-Fluorouridine-Induced Apoptosis by ERK-Dependant Upregulation of Thymidine Phosphorylase Tue, 20 Aug 2013 12:33:25 +0000 http://www.hindawi.com/journals/bmri/2013/132793/ 5-Florouracil (5-FU) is the basic agent used in the treatment of gastric cancer. Capecitabine, a prodrug of 5-FU, displays increased antitumor efficacy compared with 5-FU in the clinic. -Deoxy-5-fluorouracil (-DFUR), the metabolite of capecitabine, is converted to 5-FU by the enzyme thymidine phosphorylase (TP), which is present at high concentrations in human tumors. In this study, we investigated the effect of interferon-α (IFN-α) on the sensitivity of gastric cancer cells to treatment with -DFUR and its relationship with TP expression. Preincubation of gastric cancer cells with IFN-α enhanced -DFUR-induced apoptosis via IFN-α-mediated upregulation of TP. The depletion of TP with small interfering RNA (siRNA) obviously inhibited IFN-α-induced upregulation of TP expression and thus prevented apoptosis induced by IFN-α and -DFUR. Treatment with IFN-α and combined IFN-α and -DFUR treatment were also associated with concomitant activation of ERK signaling. Treatment with the ERK inhibitor PD98059 or depletion of ERK with siRNA partially reversed IFN-α-induced upregulation of TP expression, thus partially preventing apoptosis induced by IFN-α and -DFUR. Taken together, our study shows that IFN-α enhanced -DFUR-induced apoptosis in gastric cancer cells by upregulation of TP expression, which is partially regulated by activation of ERK signaling. Yike Zhu, Ling Xu, Yibo Fan, Ce Li, Ye Zhang, Huachuan Zheng, Kezuo Hou, Xiujuan Qu, and Yunpeng Liu Copyright © 2013 Yike Zhu et al. All rights reserved. Clinicopathological Impact of ABCC1/MRP1 and ABCC4/MRP4 in Epithelial Ovarian Carcinoma Mon, 19 Aug 2013 10:04:38 +0000 http://www.hindawi.com/journals/bmri/2013/143202/ Ovarian cancer is the main cause of death from gynaecological malignancies. In spite of the efficacy of platinum-paclitaxel treatment in patients with primary epithelial ovarian carcinoma, platinum-based chemotherapy is not curative and resistance remains one of the most important causes of treatment failure. Although ABC transporters have been implicated in cellular resistance to multiple drugs, the clinical relevance of these efflux pumps is still poorly understood. Thus, we examined the prognostic role of transporters of the MRP family (i.e., ABCC1/MRP1, ABCC4/MRP4) to gain insights into their clinical impacts. A case material of 127 patients with ovarian carcinoma at different stages and histotypes was used. The expression of MRP1 and MRP4 was examined by immunohistochemistry using tissue microarrays in tumor specimens collected at the time of initial surgery expression. We found an association between MRP1 expression and grading, and we observed that MRP4 displayed an unfavourable impact on disease relapse in multivariate analysis (HR = 2.05, 95% CI: 1.01–4.11; ). These results suggest that in epithelial ovarian cancer, MRP1 may be a marker for aggressiveness because its expression was associated with tumor grade and support that MRP4 may play an unfavourable role in disease outcome. Marina Bagnoli, Giovanni L. Beretta, Laura Gatti, Silvana Pilotti, Paola Alberti, Eva Tarantino, Mattia Barbareschi, Silvana Canevari, Delia Mezzanzanica, and Paola Perego Copyright © 2013 Marina Bagnoli et al. All rights reserved. Emerging Metabolic Targets in the Therapy of Hematological Malignancies Sun, 18 Aug 2013 08:59:35 +0000 http://www.hindawi.com/journals/bmri/2013/946206/ During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the “Warburg effect”, which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies. Zaira Leni, Geetha Parakkal, and Alexandre Arcaro Copyright © 2013 Zaira Leni et al. All rights reserved. Low-Dose-Area-Constrained Helical TomoTherapy-Based Whole Breast Radiotherapy and Dosimetric Comparison with Tangential Field-in-Field IMRT Wed, 14 Aug 2013 11:02:34 +0000 http://www.hindawi.com/journals/bmri/2013/513708/ Background and Purpose. To present a novel helical TomoTherapy-based method for whole breast radiotherapy that has better dosimetry and also has acceptable low-dose regions for lungs, heart, and contralateral breast compared with tangential field-in-field IMRT (FIF-IMRT). Material and Methods. Ten patients with left-side breast cancer were planned with low-dose-area-constrained helical TomoTherapy (LDC-HT) and FIF-IMRT. Dosimetry was compared for all techniques. Results. Coverage of the whole breast was adequate with both techniques. Homogeneity index (HI) and conformity index (CI) were better with LDC-HT. LDC-HT showed dosimetry advantages over FIF-IMRT for ipsilateral lung and heart in not only high-dose levels but also in low-dose levels such as and . For contralateral lung, both techniques can provide good protection, although the mean dose of LDC-HT is higher than that of FIF-IMRT. Conclusions. With LDC-HT, we obtained adequate target coverage, better HI and CI of target volume, better sparing of organs at risk, and acceptably low-dose areas compared with FIF-IMRT. LDC-HT could be a feasible method in whole breast radiotherapy. Clinical benefits of LDC-HT need further investigation. Jie Qiu, Zhikai Liu, Bo Yang, Xiaorong Hou, and Fuquan Zhang Copyright © 2013 Jie Qiu et al. All rights reserved. Stereotactic Body Radiotherapy as an Alternative to Brachytherapy in Gynecologic Cancer Tue, 13 Aug 2013 11:56:10 +0000 http://www.hindawi.com/journals/bmri/2013/898953/ Introduction. Brachytherapy plays a key role in the treatment of many gynecologic cancers. However, some patients are unable to tolerate brachytherapy for medical or other reasons. For these patients, stereotactic body radiotherapy (SBRT) offers an alternative form of treatment. Methods. Retrospective review of patients prospectively collected on SBRT database is conducted. A total of 11 gynecologic patients who could not have brachytherapy received SBRT for treatment of their malignancies. Five patients have been candidates for interstitial brachytherapy, and six have required tandem and ovoid brachytherapy. Median SBRT dose was 25 Gy in five fractions. Results. At last followup, eight patients were alive, and three patients had died of progressive disease. One patient had a local recurrence. Median followup for surviving patients was 420 days (median followup for all patients was 120 days). Two patients had acute toxicity (G2 dysuria and G2 GI), and one patient had late toxicity (G3 GI, rectal bleeding requiring cauterization). Conclusions. Our data show acceptable toxicity and outcome for gynecologic patients treated with SBRT who were unable to receive a brachytherapy boost. This treatment modality should be further evaluated in a phase II study. Gregory J. Kubicek, Jinyu Xue, Qianyi Xu, Sucha O. Asbell, Leslie Hughes, Noel Kramer, Ashraf Youssef, Yan Chen, James Aikens, Howard Saul, Niraj Pahlajani, and Tamara LaCouture Copyright © 2013 Gregory J. Kubicek et al. All rights reserved. Long-Term Nitric Oxide Exposure Enhances Lung Cancer Cell Migration Wed, 31 Jul 2013 09:44:00 +0000 http://www.hindawi.com/journals/bmri/2013/186972/ Nitric oxide (NO) found in the vicinity of lung cancer cells may play a role in the regulation of cancer cell behaviors. To explore the possible effects of NO on cell motility, human lung cancer cells were exposed to nontoxic concentrations of NO for 0–14 days, and the migratory characteristics of the cells were determined. The present study found that long-term treatment with NO significantly enhanced cell migration in a dose- and time-dependent manner. Furthermore, we found that the increased migratory action was associated with the increased expression of caveolin-1 (Cav-1), which in turn activated the focal adhesion kinase (FAK) and ATP-dependent tyrosine kinase (Akt) pathways. Notably, the NO-treated cells exhibited an increased number of filopodia per cell, as well as an increase in the levels of cell division cycle 42 (Cdc42) protein. Together, these results indicate that extended NO exposure has a novel effect on cell migration through a Cav-1-dependent mechanism, a finding that strengthens our understanding of cancer biology. Arpasinee Sanuphan, Preedakorn Chunhacha, Varisa Pongrakhananon, and Pithi Chanvorachote Copyright © 2013 Arpasinee Sanuphan et al. All rights reserved. An Attempted Substitute Study of Total Skin Electron Therapy Technique by Using Helical Photon Tomotherapy with Helical Irradiation of the Total Skin Treatment: A Phantom Result Wed, 31 Jul 2013 08:59:37 +0000 http://www.hindawi.com/journals/bmri/2013/108794/ An anthropomorphic phantom was used to investigate a treatment technique and analyze the dose distributions for helical irradiation of the total skin (HITS) by helical tomotherapy (HT). Hypothetical bolus of thicknesses of 0, 10, and 15 mm was added around the phantom body to account for the dose homogeneity and setup uncertainty. A central core structure was assigned as a “complete block” to force the dose tangential delivery. HITS technique with prescribed dose () of 36 Gy in 36 fractions was generated. The radiochromic EBT2 films were used for the dose measurements. The target region with 95.0% of the received by more than 95% of the PTV was obtained. The calculated mean doses for the organs at risk (OARs) were 4.69, 3.10, 3.20, and 2.94 Gy for the lung, heart, liver, and kidneys, respectively. The measurement doses on a phantom surface for a plan with 10 mm hypothetical bolus and bolus thicknesses of 0, 1, 2, and 3 mm are 89.5%, 111.4%, 116.9%, and 117.7% of , respectively. HITS can provide an accurate and uniform treatment dose in the skin with limited doses to OARs and is safe to replace a total skin electron beam regimen. Chi-Ta Lin, An-Cheng Shiau, Hui-Ju Tien, Hsin-Pei Yeh, Pei-Wei Shueng, and Chen-Hsi Hsieh Copyright © 2013 Chi-Ta Lin et al. All rights reserved. Association Study of Single Nucleotide Polymorphisms in XRCC1 Gene with Risk of Hepatocellular Carcinoma in Chinese Han Population Tue, 30 Jul 2013 11:13:51 +0000 http://www.hindawi.com/journals/bmri/2013/138785/ Hepatocellular carcinoma (HCC) is one of the most frequently causing cancer-related deaths worldwide. Previous evidence suggests that the X-ray repair cross-complementing group 1 gene (XRCC1) is an important candidate gene for influencing the risk of HCC. The aim of this study was to assess the association of XRCC1 genetic polymorphisms with the risk of HCC in Chinese Han population. A total of 1314 subjects, including 651 HCC patients and 663 healthy controls, were enrolled in this case-control study. Two genetic variants (c.1254C>T and c.1517G>C) in XRCC1 gene were genotyped by created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. Our data indicated that the allele and genotype frequencies of these two genetic variants were statistical difference in HCC cases and healthy controls. Association analyses suggested that these two genetic variants were statistically associated with the increased risk of HCC in all genetic models (for c.1254C>T, TT versus CC: OR = 2.30, 95% CI 1.61–3.28; CT versus CC: OR = 1.32, 95% CI 1.05–1.67; TT/CT versus CC: OR = 1.50, 95% CI 1.20–1.86; TT versus CT/CC: OR = 2.00, 95% CI 1.43–2.80; T versus C: OR = 1.47, 95% CI 1.25–1.73; for c.1517G>C, CC versus GG: OR = 1.90, 95% CI 1.34–2.69; GC versus GG: OR = 1.56, 95% CI 1.24–1.97; CC/GC versus GG: OR = 1.63, 95% CI 1.31–2.03; CC versus GC/GG: OR = 1.52, 95% CI 1.10–2.11; C versus G: OR = 1.45, 95% CI 1.23–1.70). The allele-T of c.1254C>T and allele-C of c.1517G>C genetic variants may contribute to HCC susceptibility in Chinese Han population. Jingwang Bi, Chen Zhong, Kainan Li, Huili Chu, and Baocheng Wang Copyright © 2013 Jingwang Bi et al. All rights reserved. Expression of Bmi-1 in Pediatric Brain Tumors as a New Independent Prognostic Marker of Patient Survival Sun, 28 Jul 2013 10:51:04 +0000 http://www.hindawi.com/journals/bmri/2013/192548/ Objectives. The B-cell-specific moloney leukemia virus insertion site 1 (the Bmi-1) gene is an important member in the family of polycomb group (PcG) genes that plays an oncogenic role in several types of cancer, but it’s expression as a prognostic marker in pediatric brain tumors has not been indicated. Materials and Methods. The Bmi-1 gene expression, clinic pathological and prognostic significance in a series of pediatric brain tumors were examined by real-time PCR method in 56 pediatric brain tumors. Results. The Bmi-1 gene expression in various types of pediatric brain tumors compared to that in normal brain tissue was 4.85-fold. The relative expression varied from 8.64-fold in ependymomas to 2.89-fold in other types. Expression level in high-grade tumors compared to that in low-grade tumors was 2.5 times. In univariate survival analysis of the pediatric brain tumors, a significant association of high expression of the Bmi-1 with patient survival was demonstrated. In multivariate analysis, the Bmi-1 high expression provided significant independent prognostic factors. Conclusion. Increased expression of the Bmi-1 in pediatric brain tumors may be important in the acquisition of an aggressive phenotype. In addition, it can be used as a strong and independent molecular marker of prognosis in pediatric brain tumors. Shirin Farivar, Reza Zati Keikha, Reza Shiari, and Farzaneh Jadali Copyright © 2013 Shirin Farivar et al. All rights reserved. Identifying the Association Rules between Clinicopathologic Factors and Higher Survival Performance in Operation-Centric Oral Cancer Patients Using the Apriori Algorithm Thu, 25 Jul 2013 14:11:06 +0000 http://www.hindawi.com/journals/bmri/2013/359634/ This study computationally determines the contribution of clinicopathologic factors correlated with 5-year survival in oral squamous cell carcinoma (OSCC) patients primarily treated by surgical operation (OP) followed by other treatments. From 2004 to 2010, the program enrolled 493 OSCC patients at the Kaohsiung Medical Hospital University. The clinicopathologic records were retrospectively reviewed and compared for survival analysis. The Apriori algorithm was applied to mine the association rules between these factors and improved survival. Univariate analysis of demographic data showed that grade/differentiation, clinical tumor size, pathology tumor size, and OP grouping were associated with survival longer than 36 months. Using the Apriori algorithm, multivariate correlation analysis identified the factors that coexistently provide good survival rates with higher lift values, such as grade/differentiation = 2, clinical stage group = early, primary site = tongue, and group = OP. Without the OP, the lift values are lower. In conclusion, this hospital-based analysis suggests that early OP and other treatments starting from OP are the key to improving the survival of OSCC patients, especially for early stage tongue cancer with moderate differentiation, having a better survival (>36 months) with varied OP approaches. Jen-Yang Tang, Li-Yeh Chuang, Edward Hsi, Yu-Da Lin, Cheng-Hong Yang, and Hsueh-Wei Chang Copyright © 2013 Jen-Yang Tang et al. All rights reserved. Bovine Papillomavirus Clastogenic Effect Analyzed in Comet Assay Mon, 15 Jul 2013 14:03:43 +0000 http://www.hindawi.com/journals/bmri/2013/630683/ Bovine papillomavirus (BPV) is an oncogenic virus related to serious livestock diseases. Oncoproteins encoded by BPV are involved in several steps of cellular transformation and have been reported as presenting clastogenic effects in peripheral lymphocytes and primary culture cells. The aim of this study was to evaluate the clastogenic potential of BPV types 1, 2, and 4 by comet assay. Peripheral blood was collected from 37 bovines, 32 infected with different levels of papillomatosis (12 animals have no affection) and five calves, virus free (negative control). The viral identification showed presence of more than one virus type in 59.375% of the infected animals. Comet assay was performed according to alkaline technique. The Kruskal-Wallis test showed statistical difference between the negative control group and infected animals (). The Dunn post hoc test showed difference comparing the infected animals with calves. Mann-Whitney test verified no difference between animals infected with only one viral type and animals presenting more than one viral type. The comet assay is considered an efficient tool for assessment of damage in the host chromatin due to viral action, specifically highlighting viral activity in blood cells. R. P. Araldi, T. C. Melo, N. Diniz, J. Mazzuchelli-de-Souza, R. F. Carvalho, W. Beçak, and R. C. Stocco Copyright © 2013 R. P. Araldi et al. All rights reserved. Detection of the Epstein-Barr Virus and DNA-Topoisomerase II-α in Recurrent and Nonrecurrent Giant Cell Lesion of the Jawbones Mon, 15 Jul 2013 09:05:20 +0000 http://www.hindawi.com/journals/bmri/2013/327424/ The aims of this study were to determine whether the expression of Topo II- correlates with presence of EBV in giant cell lesion of the jawbones and whether it is predictive of clinical biologic behavior of these lesions. Paraffin-embedded tissues from 8 recurrent and 7 nonrecurrent cases of bony GCLs and 9 peripheral giant cell lesions (PGCLs) as a control group were assessed for the expression of EBV and Topo II- using immunohistochemistry. The results showed positive staining for Topo II- in mononuclear stromal cells (MSCs) and multinucleated giant cells (MGCs). Student t-test showed that mean Topo II- labelling index (LI) in recurrent cases was significantly higher than that in non-recurrent cases (). Moreover, Spearman's correlation coefficients method showed a significant correlation between DNA Topo II- LI and both of gender and site in these lesions. Moderate EBV expression in relation to the highest Topo II- LI was observed in two cases of GCT. It was concluded that high Topo II- LIs could be identified as reliable predicators for the clinical behavior of GCLs. Moreover, EBV has no etiological role in the benign CGCLs in contrast to its role in the pathogenesis of GCTs. Manal M. Zyada and Nagla M. Salama Copyright © 2013 Manal M. Zyada and Nagla M. Salama. All rights reserved. Analysis of Activated Platelet-Derived Growth Factor β Receptor and Ras-MAP Kinase Pathway in Equine Sarcoid Fibroblasts Thu, 11 Jul 2013 09:44:46 +0000 http://www.hindawi.com/journals/bmri/2013/283985/ Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1) and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor β receptor (PDGFβR) causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGFβR is phosphorylated and binds downstream molecules related to Ras-mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGFβR in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm. Gennaro Altamura, Annunziata Corteggio, Lubna Nasir, Zheng Qiang Yuan, Franco Roperto, and Giuseppe Borzacchiello Copyright © 2013 Gennaro Altamura et al. All rights reserved. Investigating Mechanisms of Alkalinization for Reducing Primary Breast Tumor Invasion Wed, 10 Jul 2013 13:56:06 +0000 http://www.hindawi.com/journals/bmri/2013/485196/ The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion. Ian F. Robey and Lance A. Nesbit Copyright © 2013 Ian F. Robey and Lance A. Nesbit. All rights reserved. Diffusion-Weighted Magnetic Resonance Application in Response Prediction before, during, and after Neoadjuvant Radiochemotherapy in Primary Rectal Cancer Carcinoma Wed, 10 Jul 2013 13:48:02 +0000 http://www.hindawi.com/journals/bmri/2013/740195/ Introduction. Our interest was to monitor treatment response using ADC value to predict response of rectal tumour to preoperative radiochemotherapy. Materials and Methods. Twenty-two patients were treated with long course of radiochemotherapy, followed by surgery. Patients were examined by diffusion-weighted imaging MRI at three-time points (prior, during, and after radiochemotherapy) and were classified as responders and nonresponders. Results. A statistical significant correlation was found between preradiochemotherapy ADC values and during treatment ADC values, in responders (, value ). An increase in ADC value during treatment was predictive of at least a partial response. Discussion. Response of tumour to neoadjuvant therapy cannot be easily evaluated, and such capability might be of great importance in clinical practice, because the number of irradiated and operated patients may be superior to the number of who will really benefit from this multimodal treatment. A reliable prediction of the final clinical TN stage would allow radiotherapist to adapt multidisciplinary approach to a less invasive management, sparing surgical procedure in responder patients or even allowing an early surgery in nonresponders, which would significantly reduce radiochemotherapy related toxicity. Conclusion. Early evaluation of response during neoadjuvant radiochemotherapy treatment shows great promise to predict tumour response. Daniela Musio, Francesca De Felice, Anna Lisa Magnante, Maria Ciolina, Carlo Nicola De Cecco, Marco Rengo, Adriano Redler, Andrea Laghi, Nicola Raffetto, and Vincenzo Tombolini Copyright © 2013 Daniela Musio et al. All rights reserved. Dose Verification in Intensity Modulation Radiation Therapy: A Fractal Dimension Characteristics Study Mon, 08 Jul 2013 08:37:51 +0000 http://www.hindawi.com/journals/bmri/2013/349437/ Purpose. This study describes how to identify the coincidence of desired planning isodose curves with film experimental results by using a mathematical fractal dimension characteristic method to avoid the errors caused by visual inspection in the intensity modulation radiation therapy (IMRT). Methods and Materials. The isodose curves of the films delivered by linear accelerator according to Plato treatment planning system were acquired using Osiris software to aim directly at a single interested dose curve for fractal characteristic analysis. The results were compared with the corresponding planning desired isodose curves for fractal dimension analysis in order to determine the acceptable confidence level between the planning and the measurement. Results. The film measured isodose curves and computer planning curves were deemed identical in dose distribution if their fractal dimensions are within some criteria which suggested that the fractal dimension is a unique fingerprint of a curve in checking the planning and film measurement results. The dose measured results of the film were presumed to be the same if their fractal dimension was within 1%. Conclusions. This quantitative rather than qualitative comparison done by fractal dimension numerical analysis helps to decrease the quality assurance errors in IMRT dosimetry verification. Jia-Ming Wu, Chung-Ming Kuo, and Ching-Jiang Chen Copyright © 2013 Jia-Ming Wu et al. All rights reserved. Nonsmall Cell Lung Cancer Therapy: Insight into Multitargeted Small-Molecule Growth Factor Receptor Inhibitors Mon, 01 Jul 2013 13:38:59 +0000 http://www.hindawi.com/journals/bmri/2013/964743/ To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics. Mridul Roy, Yu-Hao Luo, Mao Ye, and Jing Liu Copyright © 2013 Mridul Roy et al. All rights reserved. Total Body Irradiation with Step Translation and Dynamic Field Matching Mon, 01 Jul 2013 09:47:51 +0000 http://www.hindawi.com/journals/bmri/2013/216034/ The purpose of this study is to develop a total body irradiation technique that does not require additional devices or sophisticated processes to overcome the space limitation of a small treatment room. The technique aims to deliver a uniform dose to the entire body while keeping the lung dose within the tolerance level. The technique treats the patient lying on the floor anteriorly and posteriorly. For each AP/PA treatment, two complementary fields with dynamic field edges are matched over an overlapped region defined by the marks on the body surface. A compensator, a spoiler, and lung shielding blocks were used during the treatment. Moreover, electron beams were used to further boost the chest wall around the lungs. The technique was validated in a RANDO phantom using GAFCHROMIC films. Dose ratios at different body sites along the midline ranged from 0.945 to 1.076. The dose variation in the AP direction ranged from 96.0% to 104.6%. The dose distribution in the overlapped region ranged from 98.5% to 102.8%. Lateral dose profiles at abdomen and head revealed 109.8% and 111.7% high doses, respectively, at the body edges. The results confirmed that the technique is capable of delivering a uniform dose distribution to the midline of the body in a small treatment room while keeping the lung dose within the tolerance level. Ho-Hsing Chen, Jay Wu, Keh-Shih Chuang, Jia-Fu Lin, Jia-Cheng Lee, and Jin-Ching Lin Copyright © 2013 Ho-Hsing Chen et al. All rights reserved. Meta-Analysis of Microarray Data Identifies GAS6 Expression as an Independent Predictor of Poor Survival in Ovarian Cancer Thu, 27 Jun 2013 09:33:09 +0000 http://www.hindawi.com/journals/bmri/2013/238284/ Seeking new biomarkers for epithelial ovarian cancer, the fifth most common cause of death from all cancers in women and the leading cause of death from gynaecological malignancies, we performed a meta-analysis of three independent studies and compared the results in regard to clinicopathological parameters. This analysis revealed that GAS6 was highly expressed in ovarian cancer and therefore was selected as our candidate of choice. GAS6 encodes a secreted protein involved in physiological processes including cell proliferation, chemotaxis, and cell survival. We performed immunohistochemistry on various ovarian cancer tissues and found that GAS6 expression was elevated in tumour tissue samples compared to healthy control samples (). In addition, GAS6 expression was also higher in tumours from patients with residual disease compared to those without. Our data propose GAS6 as an independent predictor of poor survival, suggesting GAS6, both on the mRNA and on the protein level, as a potential biomarker for ovarian cancer. In clinical practice, the staining of a tumour biopsy for GAS6 may be useful to assess cancer prognosis and/or to monitor disease progression. Michelle Buehler, Brian Tse, Alix Leboucq, Francis Jacob, Rosmarie Caduff, Daniel Fink, Darlene R. Goldstein, and Viola Heinzelmann-Schwarz Copyright © 2013 Michelle Buehler et al. All rights reserved. Expression and In Silico Analysis of the Recombinant Bovine Papillomavirus E6 Protein as a Model for Viral Oncoproteins Studies Wed, 26 Jun 2013 11:25:49 +0000 http://www.hindawi.com/journals/bmri/2013/421398/ Bovine papillomaviruses (BPVs) are recognized as the causal agents of economical relevant diseases in cattle, associated with the development of tumors in skin and mucosa. The oncogenesis process is mainly associated with different viral oncoprotein expressions, which are involved in cell transformation. The expression and characterization of recombinant viral oncoproteins represent an attractive strategy to obtain biotechnological products as antibodies and potential vaccines, Thus, the aim of this work was to clone and express the BPV-1 and BPV-2 E6 recombinant proteins and perform in silico analysis in order to develop a strategy for the systematic study of other papillomaviruses oncoproteins. The results demonstrated that BPV-1 and BPV-2 E6 recombinant proteins were expressed and purified from bacterial system as well as its in silico analysis was performed in order to explore and predict biological characteristics of these proteins. J. Mazzuchelli-de-Souza, R. F. Carvalho, R. M. Ruiz, T. C. Melo, R. P. Araldi, E. Carvalho, C. E. Thompson, M. P. Sircili, W. Beçak, and R. C. Stocco Copyright © 2013 J. Mazzuchelli-de-Souza et al. All rights reserved. Interference with RUNX1/ETO Leukemogenic Function by Cell-Penetrating Peptides Targeting the NHR2 Oligomerization Domain Tue, 25 Jun 2013 13:19:48 +0000 http://www.hindawi.com/journals/bmri/2013/297692/ The leukemia-associated fusion protein RUNX1/ETO is generated by the chromosomal translocation t(8;21) which appears in about 12% of all de novo acute myeloid leukemias (AMLs). Essential for the oncogenic potential of RUNX1/ETO is the oligomerization of the chimeric fusion protein through the nervy homology region 2 (NHR2) within ETO. In previous studies, we have shown that the intracellular expression of peptides containing the NHR2 domain inhibits RUNX1/ETO oligomerization, thereby preventing cell proliferation and inducing differentiation of RUNX1/ETO transformed cells. Here, we show that introduction of a recombinant TAT-NHR2 fusion polypeptide into the RUNX1/ETO growth-dependent myeloid cell line Kasumi-1 results in decreased cell proliferation and increased numbers of apoptotic cells. This effect was highly specific and mediated by binding the TAT-NHR2 peptide to ETO sequences, as TAT-polypeptides containing the oligomerization domain of BCR did not affect cell proliferation or apoptosis in Kasumi-1 cells. Thus, the selective interference with NHR2-mediated oligomerization by peptides represents a challenging but promising strategy for the inhibition of the leukemogenic potential of RUNX1/ETO in t(8;21)-positive leukemia. Yvonne Bartel, Manuel Grez, and Christian Wichmann Copyright © 2013 Yvonne Bartel et al. All rights reserved. Bovine Papillomavirus in Brazil: Detection of Coinfection of Unusual Types by a PCR-RFLP Method Mon, 24 Jun 2013 09:32:45 +0000 http://www.hindawi.com/journals/bmri/2013/270898/ Bovine papillomavirus (BPV) is recognized as a causal agent of benign and malignant tumors in cattle. Thirteen types of BPV are currently characterized and classified into three distinct genera, associated with different pathological outcomes. The described BPV types as well as other putative ones have been demonstrated by molecular biology methods, mainly by the employment of degenerated PCR primers. Specifically, divergences in the nucleotide sequence of the L1 gene are useful for the identification and classification of new papillomavirus types. On the present work, a method based on the PCR-RFLP technique and DNA sequencing was evaluated as a screening tool, allowing for the detection of two relatively rare types of BPV in lesions samples from a six-year-old Holstein dairy cow, chronically affected with cutaneous papillomatosis. These findings point to the dissemination of BPVs with unclear pathogenic potential, since two relatively rare, new described BPV types, which were first characterized in Japan, were also detected in Brazil. R. F. Carvalho, S. T. Sakata, D. N. S. Giovanni, E. Mori, P. E. Brandão, L. J. Richtzenhain, C. R. Pozzi, J. R. P. Arcaro, M. S. Miranda, J. Mazzuchelli-de-Souza, T. C. Melo, G. Comenale, S. L. M. R. Assaf, W. Beçak, and R. C. Stocco Copyright © 2013 R. F. Carvalho et al. All rights reserved. Loss of RASSF1A Expression in Colorectal Cancer and Its Association with K-ras Status Sat, 22 Jun 2013 14:36:01 +0000 http://www.hindawi.com/journals/bmri/2013/976765/ Background. The RAS-association domain family 1 A (RASSF1A) is a classical member of RAS effectors regulating cell proliferation and apoptosis. Loss of RASSF1A expression may shift the balance towards a growth-promoting effect without the necessity of activating K-ras mutations. Its potential association with K-ras mutations in colorectal cancer (CRC) is unclear. Methods. RASSF1A expression was examined in normal mucosa, adenoma, and tumor tissues of colon and rectum, respectively. We examined the association of RASSF1A expression, mutations of K-ras, and EGFR status in 76 primary CRCs. The relationship between clinicopathological characteristics and RASSF1A expression was also analyzed. Results. RASSF1A expression level decreased progressively in normal mucosa, adenoma and, tumor tissues, and the loss of RASSF1A expression occurred more frequently in tumor tissues. Of 76 primary CRCs, loss of RASSF1A expression and/or K-ras mutations were detected in 77% cases. Loss of RASSF1A expression was more frequent in K-ras wild-type than in mutation cases (63% versus 32%, ). Conclusions. Our study indicates that loss of RASSF1A may be involved in pathogenesis of CRC, its expression was found predominantly in K-ras wild-type CRCs, suggesting that it may be another way of affecting RAS signaling, in addition to K-ras mutations. Dan Cao, Ye Chen, Yuan Tang, Xing-Chen Peng, Hang Dong, Long-Hao Li, Ke Cheng, Jun Ge, and Ji-Yan Liu Copyright © 2013 Dan Cao et al. All rights reserved.