BioMed Research International The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. A Functional Variant at miR-520a Binding Site in PIK3CA Alters Susceptibility to Colorectal Cancer in a Chinese Han Population Thu, 05 Mar 2015 07:44:06 +0000 An increasing body of evidence has indicated that polymorphisms in the miRNA binding site of target gene can alter the ability of miRNAs to bind their target genes and modulate the risk of cancer. We aimed to investigate the association between a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR and the risk of colorectal cancer (CRC) in a Chinese Han population. The polymorphism rs141178472 was analyzed in a case-control study, including 386 CRC patients and 394 age- and sex-matched controls; the relationship between the polymorphism and the risk of colorectal cancer was examined. Individuals carrying the rs141178472 CC genotype or C allele had an increased risk of developing CRC (CC versus TT, OR (95% CI): 1.716 (1.084–2.716), ; C versus T, OR (95% CI): 1.258 (1.021–1.551), . Furthermore, the expression of PIK3CA was detected in the peripheral blood mononucleated cell of CRC patients, suggesting that mRNA levels of PIK3CA might be associated with SNP rs141178472. These findings provide evidence that a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR may play a role in the etiology of CRC. Lifang Ding, Zao Jiang, Qiaoyun Chen, Rong Qin, Yue Fang, and Hao Li Copyright © 2015 Lifang Ding et al. All rights reserved. Technological Advances in Instrumental Assessment in Rehabilitation Thu, 05 Mar 2015 07:42:50 +0000 Giorgio Ferriero, Stefano Carda, Sasa Moslavac, and Alessia Rabini Copyright © 2015 Giorgio Ferriero et al. All rights reserved. Gold Nanotheranostics: Photothermal Therapy and Imaging of Mucin 7 Conjugated Antibody Nanoparticles for Urothelial Cancer Thu, 05 Mar 2015 06:54:15 +0000 Objective. To kill urothelial cancer cells while preserving healthy cells, this study used photothermal therapy (PTT). PTT techniques target urothelial cancer cells using gold nanoparticles (GNPs) and a green light laser. Materials and Methods. The GNPs were conjugated with anti-Mucin 7 antibodies, which acted as a probe for targeting tumor cells. Conjugated GNPs were exposed to a green light laser (532 nm) with sufficient thermal energy to kill the transitional cell carcinomas (TCCs). Results. According to our results, nanoparticles conjugated with Mucin 7 antibodies damaged all types of cancer cells (MBT2, T24, 9202, and 8301) at relatively low energy levels (i.e., 500 laser shots at 10 W/cm2 in power, 1.6 Hz in frequency, and 300 ms in duration). Nonconjugated nanoparticles required 30 W/cm2 or more to achieve the same effect. Cell damage was directly related to irradiation time and applied laser energy. Conclusions. The minimally invasive PTT procedure combined with Mucin 7 targeted GNPs is able to kill cancer cells and preserve healthy cells. The success of this treatment technique can likely be attributed to the lower amount of energy required to kill targeted cancer cells compared with that required to kill nontargeted cancer cells. Our in vitro pilot study yielded promising results; however, additional animal studies are required to confirm these findings. Chieh Hsiao Chen, Yi-Jhen Wu, and Jia-Jin Chen Copyright © 2015 Chieh Hsiao Chen et al. All rights reserved. A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma Thu, 05 Mar 2015 06:54:05 +0000 Increasing evidence indicates tumor-stromal interactions play a crucial role in cancer. An in vivo esophageal squamous cell carcinoma (ESCC) orthotopic animal model was developed with bioluminescence imaging established with a real-time monitoring platform for functional and signaling investigation of tumor-stromal interactions. The model was produced by injection of luciferase-labelled ESCC cells into the intraesophageal wall of nude mice. Histological examination indicates this orthotopic model is highly reproducible with 100% tumorigenesis among the four ESCC cell lines tested. This new model recapitulates many clinical and pathological properties of human ESCC, including esophageal luminal stricture by squamous cell carcinoma with nodular tumor growth, adventitia invasion, lymphovascular invasion, and perineural infiltration. It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed. In conclusion, this ESCC orthotopic mouse model allows investigation of gene functions of cancer cells in a more natural tumor microenvironment and has advantages over previous established models. It provides a versatile platform with potential application for metastasis and therapeutic regimen testing. Joseph Chok Yan Ip, Josephine Mun Yee Ko, Valen Zhuoyou Yu, Kwok Wah Chan, Alfred K. Lam, Simon Law, Daniel King Hung Tong, and Maria Li Lung Copyright © 2015 Joseph Chok Yan Ip et al. All rights reserved. Effectiveness of the Lower Eyelid Suspension Using Fascia Lata Graft for the Treatment of Lagophthalmos due to Facial Paralysis Wed, 04 Mar 2015 14:24:14 +0000 Purpose. To evaluate of functional and cosmetic effectiveness of lower eyelid sling technique with fascia lata graft in patients with lagophthalmos due to facial paralysis. Material and Method. Ten patients with a mean age of years who underwent lower eyelid sling surgery with a fascia lata graft between September 2011 and January 2014 were included in this prospective study. Preoperatively and postoperatively patients were evaluated in terms of corneal epithelial defects, Schirmer’s test, and tear break-up time (TBUT). Cosmetically, vertical eyelid aperture, margin reflex distances 1 and 2 (MRD1 and MRD2) and scleral show were evaluated preoperatively and postoperatively. Results. One patient had facial paralysis on the right side whereas the other 9 patients had facial paralysis on the left side. Preoperatively, 3 patients were detected with corneal ulcer, whereas 7 patients were detected with persistent corneal epithelial defects localized in the lower half of the cornea. In the 3 patients with preoperative corneal ulcer, the ulcer recovered with corneal opacity, whereas in the 7 patients with punctate epitheliopathy, postoperative corneal transparency was obtained. Discussion. Lower eyelid sling technique with fascia lata graft is an effective technique for the repositioning of the lower eyelid and preventing the corneal complications. Selam Yekta Sendul, Halil Huseyin Cagatay, Burcu Dirim, Mehmet Demir, Zeynep Acar, Ali Olgun, Efe Can, and Dilek Guven Copyright © 2015 Selam Yekta Sendul et al. All rights reserved. Hydroxyapatite Whisker Reinforced 63s Glass Scaffolds for Bone Tissue Engineering Wed, 04 Mar 2015 14:24:13 +0000 Bioactive glass (BG) is widely used for bone tissue engineering. However, poor mechanical properties are the major shortcomings. In the study, hydroxyapatite nanowhisker (HANw) was used as a reinforcement to improve the mechanical properties. 63s glass/HANw scaffolds were successfully fabricated by selective laser sintering (SLS). It was found that the optimal compressive strength and fracture toughness were achieved when 10 wt.% HANw was added. This led to 36% increase in compressive strength and 83% increase in fracture toughness, respectively, compared with pure 63s glass scaffolds. Different reinforcement mechanisms were analyzed based on the microstructure investigation. Whisker bridging and whisker pulling-out were efficient in absorbing crack propagating energy, resulting in the improvement of the mechanical properties. Moreover, bioactivity and biocompatibility of the scaffolds were evaluated in vitro. The results showed that composite scaffolds with 10 wt.% HANw exhibited good apatite-forming ability and cellular affinity. Cijun Shuai, Yiyuan Cao, Chengde Gao, Pei Feng, Tao Xiao, and Shuping Peng Copyright © 2015 Cijun Shuai et al. All rights reserved. Elevated Serum Levels of Cysteine and Tyrosine: Early Biomarkers in Asymptomatic Adults at Increased Risk of Developing Metabolic Syndrome Wed, 04 Mar 2015 14:14:31 +0000 As there is effective intervention for delaying or preventing metabolic diseases, which are often present for years before becoming clinically apparent, novel biomarkers that would mark metabolic complications before the onset of metabolic disease should be identified. We investigated the role of fasting serum amino acids and their associations with inflammatory markers, adipokines, and metabolic syndrome (MetS) components in subjects prior to the onset of insulin resistance (IR). Anthropometric measurements, food records, adipokines, biochemical markers, and serum levels of amino acids were determined in 96 asymptomatic subjects aged 25–49 years divided into three groups according to the number of MetS components present. Cysteine and tyrosine were significantly higher already in group with one component of MetS present compared to subjects without MetS components. Serum amino acid levels correlated with markers of inflammation and adipokines. Alanine and glycine explained 10% of insulin resistance variability. The role of tyrosine and cysteine, that were higher already with 1 component of MetS present, should be further investigated as they might point to future insulin disturbances. Nina Mohorko, Ana Petelin, Mihaela Jurdana, Gianni Biolo, and Zala Jenko-Pražnikar Copyright © 2015 Nina Mohorko et al. All rights reserved. Triggers, Inhibitors, Mechanisms, and Significance of Eryptosis: The Suicidal Erythrocyte Death Wed, 04 Mar 2015 11:26:34 +0000 Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry, ceramide formation, stimulation of caspases, calpain activation, energy depletion, oxidative stress, and dysregulation of several kinases. Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson’s disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders. Elisabeth Lang and Florian Lang Copyright © 2015 Elisabeth Lang and Florian Lang. All rights reserved. Ox-LDL Induces Dysfunction of Endothelial Progenitor Cells via Activation of NF-B Wed, 04 Mar 2015 07:53:19 +0000 Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity. Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. Oxidized low-density lipoprotein (ox-LDL) can induce EPC dysfunction, but the underlying mechanism is not well understood. Human EPCs were cultured in endothelial growth medium supplemented with VEGF (10 ng/mL) and bFGF (10 ng/mL). The cells were treated with ox-LDL (50 µg/mL). EPC proliferation was assayed by using CCK8 kits. Expression and translocation of nuclear factor-kabba B (NF-κB) were evaluated. The level of reactive oxygen species (ROS) in cells was measured using H2DCF-DA as a fluorescence probe. The activity of NADPH oxidase activity was determined by colorimetric assay. Ox-LDL significantly decreased the proliferation, migration, and adhesion capacity of EPCs, while significantly increased ROS production and NADPH oxidase expression. Ox-LDL induced NF-κB P65 mRNA expression and translocation in EPCs. Thus ox-LDL can induce EPC dysfunction at least by increasing expression and translocation of NF-κB P65 and NADPH oxidase activity, which represents a new mechanism of lipidemia-induced vascular injury. Kang-ting Ji, Lu Qian, Jin-liang Nan, Yang-jing Xue, Su-qin Zhang, Guo-qiang Wang, Ri-peng Yin, Yong-jin Zhu, Lu-ping Wang, Jun Ma, Lian-ming Liao, and Ji-fei Tang Copyright © 2015 Kang-ting Ji et al. All rights reserved. Macrophage Migration Inhibitory Factor Polymorphism Is Associated with Susceptibility to Inflammatory Coronary Heart Disease Wed, 04 Mar 2015 06:59:23 +0000 Background. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. This study explored the association of 173G/C polymorphism of the MIF gene with coronary heart disease (CHD). Methods. Sequencing was carried out after polymerase chain reaction with DNA specimens from 186 volunteers without CHD and 70 patients with CHD. Plasma MIF levels on admission were measured by ELISA. Patients were classified into either stable angina pectoris (SAP) or unstable angina pectoris (UAP). Genotype distribution between cases and controls and the association of patients’ genotypes with MIF level and plaque stability were statistically evaluated (ethical approval number: 2012-01). Results. The frequency of the C genotype was higher in CHD patients than in the control (). The frequency of the 173*CC genotype was higher in CHD patients than in the control (). The plasma MIF level was higher in MIF173*C carriers than in MIF173*G carriers (). CHD patients had higher plasma MIF levels than the control (). Patients with UAP had higher plasma MIF levels than patients with SAP (). Conclusions. These data suggest that MIF −173G/C polymorphism may be related to the development of CHD in a Chinese population. Plasma MIF level is a predictor of plaque stability. This trial is registered with NCT01750502 . Kangting Ji, Xiaoyan Wang, Ji Li, Qin Lu, Guoqiang Wang, Yangjing Xue, Suqin Zhang, Lu Qian, Wenwu Wu, Yongjin Zhu, Luping Wang, Lianming Liao, and Jifei Tang Copyright © 2015 Kangting Ji et al. All rights reserved. Roles of Autophagy Induced by Natural Compounds in Prostate Cancer Wed, 04 Mar 2015 06:17:46 +0000 Autophagy is a homeostatic mechanism through which intracellular organelles and proteins are degraded and recycled in response to increased metabolic demand or stress. Autophagy dysfunction is often associated with many diseases, including cancer. Because of its role in tumorigenesis, autophagy can represent a new therapeutic target for cancer treatment. Prostate cancer (PCa) is one of the most common cancers in aged men. The evidence on alterations of autophagy related genes and/or protein levels in PCa cells suggests a potential implication of autophagy in PCa onset and progression. The use of natural compounds, characterized by low toxicity to normal tissue associated with specific anticancer effects at physiological levels in vivo, is receiving increasing attention for prevention and/or treatment of PCa. Understanding the mechanism of action of these compounds could be crucial for the development of new therapeutic or chemopreventive options. In this review we focus on the current evidence showing the capacity of natural compounds to exert their action through autophagy modulation in PCa cells. V. Naponelli, A. Modernelli, S. Bettuzzi, and F. Rizzi Copyright © 2015 V. Naponelli et al. All rights reserved. A Low-Dose Combination of Fluvastatin and Valsartan: A New “Drug” and a New Approach for Decreasing the Arterial Age Tue, 03 Mar 2015 13:47:31 +0000 We have developed a new “drug” and approach that appear to be effective in reducing arterial age. This “drug” represents a low, subtherapeutic dose of statin and sartan and particularly their low-dose combination. The improvement of arterial wall characteristics, also reflecting in a decrease of arterial age, was achieved after a short period of treatment (one month) with the above-mentioned drugs. In addition, we have also implemented a new, innovative therapeutic approach, consisting of intermittent (cyclic) treatment—alternating short “treatment” periods and much longer “rest” periods (when the beneficial effects are still present but gradually decline). This new “drug” and approach both merit further investigation in order to confirm their antiaging efficacy. Miodrag Janić, Mojca Lunder, and Mišo Šabovič Copyright © 2015 Miodrag Janić et al. All rights reserved. Elaborating the Role of Natural Products-Induced Autophagy in Cancer Treatment: Achievements and Artifacts in the State of the Art Tue, 03 Mar 2015 12:35:49 +0000 Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging. Ning Wang and Yibin Feng Copyright © 2015 Ning Wang and Yibin Feng. All rights reserved. Retrograde Intrarenal Surgery versus Percutaneous Lithotripsy to Treat Renal Stones 2-3 cm in Diameter Tue, 03 Mar 2015 12:21:43 +0000 Objective. Retrograde intrarenal surgery (RIRS) performed using a flexible ureterorenoscope marked the beginning of a new era in urology. Today, even staghorn stones are successfully treated via RIRS. The recommended treatment for larger stones is percutaneous nephrolithotomy (PNL). However, the question of whether PNL or RIRS should be the first-line treatment option for larger stones remains controversial. In this study, we contribute to the debate by comparing the success and complication rates of PNL and RIRS that were used to treat renal pelvis stones 2-3 cm in diameter. Materials and Methods. The medical records of 154 patients (74 PNL, 80 RIRS) were retrospectively evaluated. PNL patients were placed in Group 1 and RIRS patients in Group 2. Results. The complete stone-free rates were 95.5% in the PNL group and 80.6% in the RIRS group 1 month postoperatively (). The respective complication rates (evaluated using the Clavien system) were 13.5% and 8.8% (). Conclusions. RIRS affords a comparable success rate, causes fewer complications than PNL, and seems to be a promising alternative to PNL when larger stones are to be treated. Prospective randomized controlled trials are needed to confirm these findings. Kursad Zengin, Serhat Tanik, Nihat Karakoyunlu, Nevzat Can Sener, Sebahattin Albayrak, Can Tuygun, Hasan Bakirtas, M. Abdurrahim Imamoglu, and Mesut Gurdal Copyright © 2015 Kursad Zengin et al. All rights reserved. Calcium Homeostasis and ER Stress in Control of Autophagy in Cancer Cells Tue, 03 Mar 2015 12:01:06 +0000 Autophagy is a basic catabolic process, serving as an internal engine during responses to various cellular stresses. As regards cancer, autophagy may play a tumor suppressive role by preserving cellular integrity during tumor development and by possible contribution to cell death. However, autophagy may also exert oncogenic effects by promoting tumor cell survival and preventing cell death, for example, upon anticancer treatment. The major factors influencing autophagy are Ca2+ homeostasis perturbation and starvation. Several Ca2+ channels like voltage-gated T- and L-type channels, IP3 receptors, or CRAC are involved in autophagy regulation. Glucose transporters, mainly from GLUT family, which are often upregulated in cancer, are also prominent targets for autophagy induction. Signals from both Ca2+ perturbations and glucose transport blockage might be integrated at UPR and ER stress activation. Molecular pathways such as IRE 1-JNK-Bcl-2, PERK-eIF2α-ATF4, or ATF6-XBP 1-ATG are related to autophagy induced through ER stress. Moreover ER molecular chaperones such as GRP78/BiP and transcription factors like CHOP participate in regulation of ER stress-mediated autophagy. Autophagy modulation might be promising in anticancer therapies; however, it is a context-dependent matter whether inhibition or activation of autophagy leads to tumor cell death. Elżbieta Kania, Beata Pająk, and Arkadiusz Orzechowski Copyright © 2015 Elżbieta Kania et al. All rights reserved. Thermal Tomography Imaging in Photonic Traditional Chinese Medicine Information Therapy with Holistic Effect for Health Whole Nursing Tue, 03 Mar 2015 11:49:32 +0000 A photonic traditional Chinese medicine (TCM) information therapy was developed that has applications in whole health nursing including the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases as well as the conditioning of the subhealth state. This therapy utilizes the beam of a 630 nm LED light to irradiate the oropharynx, while simultaneously employing two beams of 650 nm LED light to irradiate corresponding acupuncture points resulting in a synergistic outcome. This method was named “1 + 2 phototherapy.” The principle mechanism of the therapy is a series of photon induced biological effects that are triggered by stimulating the photosensitive tissues of the oropharynx. This tissue includes the oral mucosa, capillaries, lymph nodes, saliva glands, nerves, and Jingluo and is stimulated by light beams of certain photon energy and imitative acupuncture information. Thermal tomography imaging shows that the average temperature of the upper-body was improved significantly after oropharyngeal irradiation under irradiation of “Futu point”: the heat radiation of the spine, as well as chest, shoulders, arms, and clavicle, increased under irradiation of “Hoku,” whereas the overall average temperature was below the temperature before irradiation. The experiment indicates that this therapy can promote blood circulation, regulate varied physiological parameters, and have holistic effects in whole health nursing. Binggang Ye, Zhouyi Guo, Hanchuan Huang, and Xicheng Yang Copyright © 2015 Binggang Ye et al. All rights reserved. Nucleofection of Rat Pheochromocytoma PC-12 Cells with Human Mutated Beta-Amyloid Precursor Protein Gene (APP-sw) Leads to Reduced Viability, Autophagy-Like Process, and Increased Expression and Secretion of Beta Amyloid Tue, 03 Mar 2015 11:35:53 +0000 Pheochromocytoma PC-12 cells are immune to physiological stimuli directed to evoke programmed cell death. Besides, metabolic inhibitors are incapable of sensitizing PC-12 cells to extrinsic or intrinsic apoptosis unless they are used in toxic concentrations. Surprisingly, these cells become receptive to cell deletion after human APP-sw gene expression. We observed reduced cell viability in GFP vector + APP-sw-nucleofected cells (drop by 36%) but not in GFP vector − or GFP vector + APP-wt-nucleofected cells. Lower viability was accompanied by higher expression of A 1-16 and elevated secretion of A 1-40 (in average 53.58 pg/mL). At the ultrastructural level autophagy-like process was demonstrated to occur in APP-sw-nucleofected cells with numerous autophagosomes and multivesicular bodies but without autolysosomes. Human APP-sw gene is harmful to PC-12 cells and cells are additionally driven to incomplete autophagy-like process. When stimulated by TRAIL or nystatin, CLU protein expression accompanies early phase of autophagy. Beata Pająk, Elżbieta Kania, and Arkadiusz Orzechowski Copyright © 2015 Beata Pająk et al. All rights reserved. Combined Epidermal Growth Factor Receptor and Beclin1 Autophagic Protein Expression Analysis Identifies Different Clinical Presentations, Responses to Chemo- and Radiotherapy, and Prognosis in Glioblastoma Tue, 03 Mar 2015 09:54:03 +0000 Dysregulated EGFR in glioblastoma may inactivate the key autophagy protein Beclin1. Each of high EGFR and low Beclin1 protein expression, independently, has been associated with tumor progression and poor prognosis. High (H) compared to low (L) expression of EGFR and Beclin1 is here correlated with main clinical data in 117 patients after chemo- and radiotherapy. H-EGFR correlated with low Karnofsky performance and worse neurological performance status, higher incidence of synchronous multifocality, poor radiological evidence of response, shorter progression disease-free (PDFS), and overall survival (OS). H-Beclin1 cases showed better Karnofsky performance status, higher incidence of objective response, longer PDFS, and OS. A mutual strengthening effect emerges in correlative power of stratified L-EGFR and H-Beclin1 expression with incidence of radiological response after treatment, unifocal disease, and better prognosis, thus identifying an even longer OS group (30 months median OS compared to 18 months in L-EGFR, 15 months in H-Beclin1, and 11 months in all GBs) (). Combined L-EGFR + H-Beclin1 expression may represent a biomarker in identifying relatively favorable clinical presentations and prognosis, thus envisaging possible EGFR/Beclin1-targeted therapies. Paolo Tini, Giuseppe Belmonte, Marzia Toscano, Clelia Miracco, Silvia Palumbo, Pierpaolo Pastina, Giuseppe Battaglia, Valerio Nardone, Marie Aimée Gloria Munezero Butorano, Armando Masucci, Alfonso Cerase, and Luigi Pirtoli Copyright © 2015 Paolo Tini et al. All rights reserved. Gene Network Exploration of Crosstalk between Apoptosis and Autophagy in Chronic Myelogenous Leukemia Tue, 03 Mar 2015 09:24:08 +0000 Background. Gene expression levels change to adapt the stress, such as starvation, toxin, and radiation. The changes are signals transmitted through molecular interactions, eventually leading to two cellular fates, apoptosis and autophagy. Due to genetic variations, the signals may not be effectively transmitted to modulate apoptotic and autophagic responses. Such aberrant modulation may lead to carcinogenesis and drug resistance. The balance between apoptosis and autophagy becomes very crucial in coping with the stress. Though there have been evidences illustrating the apoptosis-autophagy interplay, the underlying mechanism and the participation of the regulators including transcription factors (TFs) and microRNAs (miRNAs) remain unclear. Results. Gene network is a graphical illustration for exploring the functional linkages and the potential coordinate regulations of genes. Microarray dataset for the study of chronic myeloid leukemia was obtained from Gene Expression Omnibus. The expression profiles of those genes related to apoptosis and autophagy, including MCL1, BCL2, ATG, beclin-1, BAX, BAK, E2F, cMYC, PI3K, AKT, BAD, and LC3, were extracted from the dataset to construct the gene networks. Conclusion. The network analysis of these genes explored the underlying mechanisms and the roles of TFs and miRNAs for the crosstalk between apoptosis and autophagy. Fengfeng Wang, William C. S. Cho, Lawrence W. C. Chan, S. C. Cesar Wong, Nancy B. Y. Tsui, Parco M. Siu, S. P. Yip, and Benjamin Y. M. Yung Copyright © 2015 Fengfeng Wang et al. All rights reserved. The Relationship of CSF and Plasma Cytokine Levels in HIV Infected Patients with Neurocognitive Impairment Tue, 03 Mar 2015 09:19:15 +0000 Although HAD is now rare due to HAART, the milder forms of HAND persist in HIV-infected patients. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. The levels of cytokines in CSF were associated with neurocognitive impairment in HIV infection. However, the changes of cytokines involved in cognition impairment in plasma have not been shown, and their relationships between CSF and plasma require to be addressed. We compared cytokine levels in paired CSF and plasma samples from HIV-infected individuals with or without neurocognitive impairment. Cytokine concentrations were measured by Luminex xMAP. In comparing the expression levels of cytokines in plasma and CSF, IFN-α2, IL-8, IP-10, and MCP-1 were significantly higher in CSF. Eotaxin was significantly higher in plasma, whereas G-CSF showed no difference between plasma and CSF. G-CSF , IL-8 , IP-10 , and MCP-1 in CSF showed significant difference between HIV-CI and HIV-NC group, which may indicate their relationship to HIV associated neurocognitive impairment. In addition, G-CSF and IP-10 in plasma were significantly higher in HIV-CI than HIV-NC. The consistent changes of G-CSF and IP-10 in paired plasma and CSF samples might enhance their potential for predicting HAND. Lin Yuan, An Liu, Luxin Qiao, Bo Sheng, Meng Xu, Wei Li, and Dexi Chen Copyright © 2015 Lin Yuan et al. All rights reserved. An Open-Label Uncontrolled, Multicenter Study for the Evaluation of the Efficacy and Safety of the Dermal Filler Princess VOLUME in the Treatment of Nasolabial Folds Tue, 03 Mar 2015 09:19:14 +0000 The dermal filler Princess VOLUME is a highly cross-linked, viscoelastic hyaluronic acid injectable gel implant used for aesthetic treatment. To evaluate the efficacy and safety of Princess VOLUME in the treatment of nasolabial folds, an open-label uncontrolled, multicenter study was conducted. Forty-eight subjects were recruited who had moderate to deep wrinkles, according to the Modified Fitzpatrick Wrinkle Scale (MFWS). Subjects received Princess VOLUME in both nasolabial folds at Day 0. Nasolabial fold severity was evaluated at 30, 90, 180, and 270 days after treatment, using the MFWS and the Global Aesthetic Improvement Scale (GAIS). Adverse events and treatment site reactions were recorded. Among the 48 subjects, 93.8% were female with a median age of 52 years. There were significant improvements in the MFWS scores at 30, 180, and 270 days after treatment compared with those at baseline, with a mean decrease of 1.484 (±0.408), 1.309 (±0.373), and 1.223 (±0.401), respectively; hence the primary endpoint was achieved and clinical efficacy demonstrated. Princess VOLUME was well tolerated, and most adverse events were injection site reactions of mild to moderate severity. Subject satisfaction (97.9%), subject recommendation of the treatment (93.6%), and investigators GAIS scores (97.9% improvement) were high. Daisy Kopera, Michael Palatin, Rolf Bartsch, Katrin Bartsch, Maria O’Rourke, Sonja Höller, Renate R. Baumgartner, and Martin Prinz Copyright © 2015 Daisy Kopera et al. All rights reserved. Localized and Sustained Delivery of Erythropoietin from PLGA Microspheres Promotes Functional Recovery and Nerve Regeneration in Peripheral Nerve Injury Tue, 03 Mar 2015 09:16:11 +0000 Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degraded in vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Both in vitro and in vivo release assays showed that the EPO-PLGA microspheres allowed sustained release of EPO within a period of two weeks. After administration of such EPO-PLGA microspheres, the peripheral nerve injured rats had significantly better recovery compared with those which received daily intraperitoneal injection of EPO, empty PLGA microspheres, or saline treatments. This was supported by the functional, electrophysiological, and histological evaluations of the recovery done at week 8 postoperatively. We conclude that sustained delivery of EPO could be achieved by using EPO-PLGA microspheres, and such delivery method could further enhance the recovery function of EPO in nerve injury recovery. Wei Zhang, Yuan Gao, Yan Zhou, Jianheng Liu, Licheng Zhang, Anhua Long, Lihai Zhang, and Peifu Tang Copyright © 2015 Wei Zhang et al. All rights reserved. Controversial Indications for Sentinel Lymph Node Biopsy in Breast Cancer Patients Tue, 03 Mar 2015 07:48:13 +0000 Sentinel lymph node biopsy (SLNB) emerged in the 1990s as a new technique in the surgical management of the axilla for patients with early breast cancer, resulting in lower complication rates and better quality of life than axillary lymph node dissection (ALND). Today SLNB is firmly established in the armamentarium of clinicians treating breast cancer, but several questions remain. The goal of this paper is to review recent work addressing 4 questions that have been the subject of debate in the use of SLNB in the past few years: (a) What is the implication of finding micrometastases in the sentinel nodes? (b) Is ALND necessary in all patients who have a positive SLNB? (c) How accurate is SLNB after neoadjuvant therapy? (d) Can SLNB be used to stage the axilla in locally recurrent breast cancer following breast surgery with or without prior axillary surgery? Hazem Assi, Eman Sbaity, Mahmoud Abdelsalam, and Ali Shamseddine Copyright © 2015 Hazem Assi et al. All rights reserved. Expression of MMP-9 and VEGF in Meningiomas and Their Correlation with Peritumoral Brain Edema Tue, 03 Mar 2015 07:47:40 +0000 Meningiomas constitute up to 13% of all intracranial tumors. The predictive factors for meningioma have not been unambiguously defined; however some limited data suggest that the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) may be associated with the presence of peritumoral brain edema (PTBE) and worse clinical outcome. The aim of this study was to analyze the expressions of MMP-9 and VEGF in a group of meningiomas of various grades and to study associations between these two markers and PTBE. The study included patients with supratentorial meningiomas. The patients were divided into low- (G1) and high-grade meningiomas (G2 and G3). PTBE was assessed on MRI. The expressions of VEGF and MMP-9 were determined immunohistochemically. The expression of MMP-9 was observed significantly more often in G3 meningiomas than in lower grade tumors. The presence of stage II or III PTBE was associated with a significant increase in MMP-9 expression. The expression of VEGF did not differ across the PTBE stages. Our findings point to a significant role of MMP-9 and VEGF in the pathogenesis of peritumoral brain edema in low- and high-grade meningiomas. Joanna Reszec, Adam Hermanowicz, Robert Rutkowski, Grzegorz Turek, Zenon Mariak, and Lech Chyczewski Copyright © 2015 Joanna Reszec et al. All rights reserved. Ankylosing Spondylitis and Posture Control: The Role of Visual Input Tue, 03 Mar 2015 06:24:22 +0000 Objectives. To assess the motor control during quiet stance in patients with established ankylosing spondylitis (AS) and to evaluate the effect of visual input on the maintenance of a quiet posture. Methods. 12 male AS patients (mean age 50.1 ± 13.2 years) and 12 matched healthy subjects performed 2 sessions of 3 trials in quiet stance, with eyes open (EO) and with eyes closed (EC) on a baropodometric platform. The oscillation of the centre of feet pressure (CoP) was acquired. Indices of stability and balance control were assessed by the sway path (SP) of the CoP, the frequency bandwidth (FB1) that includes the 80% of the area under the amplitude spectrum, the mean amplitude of the peaks (MP) of the sway density curve (SDC), and the mean distance (MD) between 2 peaks of the SDC. Results. In severe AS patients, the MD between two peaks of the SDC and the SP of the center of feet pressure were significantly higher than controls during both EO and EC conditions. The MP was significantly reduced just on EC. Conclusions. Ankylosing spondylitis exerts negative effect on postural stability, not compensable by visual inputs. Our findings may be useful in the rehabilitative management of the increased risk of falling in AS. Alessandro Marco De Nunzio, Salvatore Iervolino, Carmela Zincarelli, Luisa Di Gioia, Giuseppe Rengo, Vincenzo Multari, Rosario Peluso, Matteo Nicola Dario Di Minno, and Nicola Pappone Copyright © 2015 Alessandro Marco De Nunzio et al. All rights reserved. cspA Influences Biofilm Formation and Drug Resistance in Pathogenic Fungus Aspergillus fumigatus Tue, 03 Mar 2015 06:09:26 +0000 The microbial cell wall plays a crucial role in biofilm formation and drug resistance. cspA encodes a repeat-rich glycophosphatidylinositol-anchored cell wall protein in the pathogenic fungus Aspergillus fumigatus. To determine whether cspA has a significant impact on biofilm development and sensitivity to antifungal drugs in A. fumigatus, a ΔcspA mutant was constructed by targeted gene disruption, and we then reconstituted the mutant to wild type by homologous recombination of a functional cspA gene. Deletion of cspA resulted in a rougher conidial surface, reduced biofilm formation, decreased resistance to antifungal agents, and increased internalization by A549 human lung epithelial cells, suggesting that cspA not only participates in maintaining the integrity of the cell wall, but also affects biofilm establishment, drug response, and invasiveness of A. fumigatus. Zhongqi Fan, Zhe Li, Zongge Xu, Hongyan Li, Lixiang Li, Cong Ning, Lin Ma, Xiangli Xie, Guangyi Wang, and Huimei Yu Copyright © 2015 Zhongqi Fan et al. All rights reserved. Antioxidant Strategies in the Management of Diabetic Neuropathy Mon, 02 Mar 2015 15:04:39 +0000 Chronic hyperglycaemia (an abnormally high glucose concentration in the blood) resulting from defects in insulin secretion/action, or both, is the major hallmark of diabetes in which it is known to be involved in the progression of the condition to different complications that include diabetic neuropathy. Diabetic neuropathy (diabetes-induced nerve damage) is the most common diabetic complication and can be devastating because it can lead to disability. There is an increasing body of evidence associating diabetic neuropathy with oxidative stress. Oxidative stress results from the production of oxygen free radicals in the body in excess of its ability to eliminate them by antioxidant activity. Antioxidants have different mechanisms and sites of actions by which they exert their biochemical effects and ameliorate nerve dysfunction in diabetes by acting directly against oxidative damage. This review will examine different strategies for managing diabetic neuropathy which rely on exogenous antioxidants. Ayodeji Babatunde Oyenihi, Ademola Olabode Ayeleso, Emmanuel Mukwevho, and Bubuya Masola Copyright © 2015 Ayodeji Babatunde Oyenihi et al. All rights reserved. Predictors of Mortality for Nursing Home-Acquired Pneumonia: A Systematic Review Mon, 02 Mar 2015 14:47:55 +0000 Background. Current risk stratification tools, primarily used for CAP, are suboptimal in predicting nursing home acquired pneumonia (NHAP) outcome and mortality. We conducted a systematic review to evaluate current evidence on the usefulness of proposed predictors of NHAP mortality. Methods. PubMed (MEDLINE), EMBASE, and CINAHL databases were searched for articles published in English between January 1978 and January 2014. The literature search elicited a total of 666 references; 580 were excluded and 20 articles met the inclusion criteria for the final analysis. Results. More studies supported the Pneumonia Severity Index (PSI) as a superior predictor of NHAP severity. Fewer studies suggested CURB-65 and SOAR (especially for the need of ICU care) as useful predictors for NHAP mortality. There is weak evidence for biomarkers like C-reactive protein and copeptin as prognostic tools. Conclusion. The evidence supports the use of PSI as the best available indicator while CURB-65 may be an alternative prognostic indicator for NHAP mortality. Overall, due to the paucity of information, biomarkers may not be as effective in this role. Larger prospective studies are needed to establish the most effective predictor(s) or combination scheme to help clinicians in decision-making related to NHAP mortality. Naveen Dhawan, Naushira Pandya, Michael Khalili, Manuel Bautista, Anurag Duggal, Jaya Bahl, and Vineet Gupta Copyright © 2015 Naveen Dhawan et al. All rights reserved. Proteomic Analysis of Human Brain Microvascular Endothelial Cells Reveals Differential Protein Expression in Response to Enterovirus 71 Infection Mon, 02 Mar 2015 12:49:57 +0000 2D DIGE technology was employed on proteins prepared from human brain microvascular endothelial cells (HBMEC), to study the differentially expressed proteins in cells at 0 h, 1 h, 16 h, and 24 h after infection. Proteins found to be differentially expressed were identified with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDITOF/TOF MS) analysis. We identified 43 spots showing changes of at least 2.5 fold up- or downregulated expressions in EV71-infected cells at different time when comparing to control, and 28 proteins could be successfully identified by MALDI TOF/TOF mass spectrometry analysis. 4 proteins were significantly upregulated, and 6 proteins were downregulated, another 18 proteins were different expression at different incubation time. We identified changes in the expression of 12 cellular metabolism-related proteins, 5 molecules involved in cytoskeleton, 3 molecules involved in energy metabolism, 2 molecules involved in signal transduction, 1 molecule involved in the ubiquitin-proteasome pathway, 1 molecule involved in cell cycle, 1 molecule involved in apoptosis-related protein, 1 molecular chaperone, and 2 unknown proteins. These findings build up a comprehensive profile of the HBMEC proteome and provide a useful basis for further analysis of the pathogenic mechanism that underlies EV71 infections to induce severe neural complications. Wenying Luo, Jiayu Zhong, Wei Zhao, Jianjun Liu, Renli Zhang, Liang Peng, Wenxu Hong, Sheng He Huang, and Hong Cao Copyright © 2015 Wenying Luo et al. All rights reserved. Substance P Receptor Antagonism: A Potential Novel Treatment Option for Viral-Myocarditis Mon, 02 Mar 2015 12:27:00 +0000 Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP) is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV). The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA), will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg), a SP-receptor antagonist, or fasudil (10 mg/kg), a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels ( all, ANOVA). Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity ( all, ANOVA). Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac-remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP-receptor antagonism may be a novel therapeutic-option for patients with viral-myocarditis. Prema Robinson, George E. Taffet, Nikita Engineer, Mitra Khumbatta, Bahrom Firozgary, Corey Reynolds, Thuy Pham, Tushar Bulsara, and Gohar Firozgary Copyright © 2015 Prema Robinson et al. All rights reserved.