Disease Markers http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family Sun, 04 Oct 2015 15:16:24 +0000 http://www.hindawi.com/journals/dm/2015/828970/ Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition. Delfien Syx, Sofie Symoens, Wouter Steyaert, Anne De Paepe, Paul J. Coucke, and Fransiska Malfait Copyright © 2015 Delfien Syx et al. All rights reserved. Impaired Fasting Glucose in Nondiabetic Range: Is It a Marker of Cardiovascular Risk Factor Clustering? Sun, 04 Oct 2015 13:32:29 +0000 http://www.hindawi.com/journals/dm/2015/804739/ Background. Impaired fasting glucose (IFG) through the nondiabetic range (100–125 mg/dL) is not considered in the cardiovascular (CV) risk profile. Aim. To compare the clustering of CV risk factors (RFs) in nondiabetic subjects with normal fasting glucose (NFG) and IFG. Material and Methods. Cross-sectional study in 3739 nondiabetic subjects. Demographics, medical history, and CV risk factors were collected and lipid profile, fasting glucose levels (FBG), C-reactive protein (hsCRP), blood pressure (BP), anthropometric measurements, and aerobic capacity were determined. Results. 559 (15%) subjects had IFG: they had a higher mean age, BMI, waist circumference, non-HDL cholesterol, BP, and hsCRP () and lower HDL () and aerobic capacity (). They also had a higher prevalence of hypertension (34% versus 25%; ), dyslipidemia (79% versus 74%; ), and obesity (29% versus 16%; ) and a higher Framingham risk score (8% versus 6%; ). The probability of presenting 3 or more CV RFs adjusted by age and gender was significantly higher in the top quintile of fasting glucose (≥98 mg/dL; OR = 2.02; 1.62–2.51). Conclusions. IFG in the nondiabetic range is associated with increased cardiovascular RF clustering. Giovanna Valentino, Verónica Kramer, Lorena Orellana, María José Bustamante, Cinthia Casasbellas, Marcela Adasme, Alejandra Salazar, Carlos Navarrete, and Mónica Acevedo Copyright © 2015 Giovanna Valentino et al. All rights reserved. Bone Marrow Stromal Antigen 2 Is a Novel Plasma Biomarker and Prognosticator for Colorectal Carcinoma: A Secretome-Based Verification Study Thu, 01 Oct 2015 11:49:57 +0000 http://www.hindawi.com/journals/dm/2015/874054/ Background. The cancer cell secretome has been recognized as a valuable reservoir for identifying novel serum/plasma biomarkers for different cancers, including colorectal cancer (CRC). This study aimed to verify four CRC cell-secreted proteins (tumor-associated calcium signal transducer 2/trophoblast cell surface antigen 2 (TACSTD2/TROP2), tetraspanin-6 (TSPAN6), bone marrow stromal antigen 2 (BST2), and tumor necrosis factor receptor superfamily member 16 (NGFR)) as potential plasma CRC biomarkers. Methods. The study population comprises 152 CRC patients and 152 controls. Target protein levels in plasma and tissue samples were assessed by ELISA and immunohistochemistry, respectively. Results. Among the four candidate proteins examined by ELISA in a small sample set, only BST2 showed significantly elevated plasma levels in CRC patients versus controls. Immunohistochemical analysis revealed the overexpression of BST2 in CRC tissues, and higher BST2 expression levels correlated with poorer 5-year survival (46.47% versus 65.57%; ). Further verification confirmed the elevated plasma BST2 levels in CRC patients (2.35 ± 0.13 ng/mL) versus controls (1.04 ± 0.03 ng/mL) (), with an area under the ROC curve (AUC) being 0.858 comparable to that of CEA (0.867). Conclusion. BST2, a membrane protein selectively detected in CRC cell secretome, may be a novel plasma biomarker and prognosticator for CRC. Sum-Fu Chiang, Chih-Yen Kan, Yung-Chin Hsiao, Reiping Tang, Ling-Ling Hsieh, Jy-Ming Chiang, Wen-Sy Tsai, Chien-Yuh Yeh, Pao-Shiu Hsieh, Ying Liang, Jinn-Shiun Chen, and Jau-Song Yu Copyright © 2015 Sum-Fu Chiang et al. All rights reserved. HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach Thu, 01 Oct 2015 08:46:48 +0000 http://www.hindawi.com/journals/dm/2015/234851/ Objectives. HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC. Results. HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases. Conclusions. HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions. A. Ieni, V. Barresi, L. Rigoli, R. A. Caruso, and G. Tuccari Copyright © 2015 A. Ieni et al. All rights reserved. Oxidative Stress Parameters in Saliva and Its Association with Periodontal Disease and Types of Bacteria Thu, 01 Oct 2015 08:39:15 +0000 http://www.hindawi.com/journals/dm/2015/653537/ Objective. To determine the association between oxidative stress parameters with periodontal disease, bleeding, and the presence of different periodontal bacteria. Methods. A cross-sectional study in a sample of eighty-six patients, divided into three groups depending on their periodontal status. Thirty-three with chronic periodontitis, sixteen with gingivitis, and thirty-seven with periodontal healthy as control. Oxidative stress biomarkers (8-OHdG and MDA), total antioxidant capacity (TAOC), and the activity of two antioxidant enzymes (GPx and SOD) were determined in saliva. Subgingival plaque samples were obtained from the deepest periodontal pocket and PCR was used to determine the presence of the 6 fimA genotypes of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Treponema denticola. Results. Periodontal disease was found to be associated with increased oxidative stress parameter levels. These levels rose according to the number and type of different periodontal bacteria found in the periodontal pockets. The presence of different types of periodontal bacteria is predictive independent variables in linear regresion models of oxidative stress parameters as dependent variable, above all 8-OHdG. Conclusions. Oxidative stress parameter levels are correlated with the presence of different types of bacteria. Determination of these levels and periodontal bacteria could be a potent tool for controlling periodontal disease development. Jose Manuel Almerich-Silla, Jose María Montiel-Company, Sara Pastor, Felipe Serrano, Miriam Puig-Silla, and Francisco Dasí Copyright © 2015 Jose Manuel Almerich-Silla et al. All rights reserved. Helicobacter pylori Antibody Titer and Gastric Cancer Screening Thu, 01 Oct 2015 07:08:31 +0000 http://www.hindawi.com/journals/dm/2015/156719/ The “ABC method” is a serum gastric cancer screening method, and the subjects were divided based on H. pylori serology and atrophic gastritis as detected by serum pepsinogen (PG): Group A [H. pylori (−) PG (−)], Group B [H. pylori (+) PG (−)], Group C [H. pylori (+) PG (+)], and Group D [H. pylori (−) PG (+)]. The risk of gastric cancer is highest in Group D, followed by Groups C, B, and A. Groups B, C, and D are advised to undergo endoscopy, and the recommended surveillance is every three years, every two years, and annually, respectively. In this report, the reported results with respect to further risk stratification by anti-H. pylori antibody titer in each subgroup are reviewed: (1) high-negative antibody titer subjects in Group A, representing posteradicated individuals with high risk for intestinal-type cancer; (2) high-positive antibody titer subjects in Group B, representing active inflammation with high risk for diffuse-type cancer; and (3) low-positive antibody titer subjects in Group C, representing advanced atrophy with increased risk for intestinal-type cancer. In these subjects, careful follow-up with intervals of surveillance of every three years in (1), every two years in (2), and annually in (3) should be considered. Hiroshi Kishikawa, Kayoko Kimura, Sakiko Takarabe, Shogo Kaida, and Jiro Nishida Copyright © 2015 Hiroshi Kishikawa et al. All rights reserved. The Relation between eNOS −786 C/T, 4 a/b, MMP-13 rs640198 G/T, Eotaxin 426 C/T, −384 A/G, and 67 G/A Polymorphisms and Long-Term Outcome in Patients with Coronary Artery Disease Wed, 30 Sep 2015 13:46:30 +0000 http://www.hindawi.com/journals/dm/2015/232048/ Aim. The purpose of this study is to determine the association between eotaxin 426 C/T, −384 A/G, 67 G/A, eNOS −786 T/C, 4 a/b, and MMP-13 rs640198 G/T and prognosis of patients with known CAD. Methods. From total of 1161 patients referred to coronary angiography, 532 patients with angiographically confirmed CAD were selected. Their long-term outcome was followed up using hospital database. Subsequent events were assessed in this study: death or combined endpoint-myocardial infarction, unstable angina pectoris, revascularization, heart failure hospitalization, and cardioverter-defibrillator implantation. Results. The multivariate Cox regression model identified age, smoking, and 3-vessel disease as significant predictors of all-cause death. Further analysis showed that eotaxin 67 G/A (GA + AA versus GG) and eotaxin −384 A/G (GG versus GA + AA) were significant independent prognostic factors when added into the model: HR (95% CI) 2.81 (1.35–5.85), ; HR (95% CI) 2.63 (1.19–5.83), ; eotaxin −384 A/G was significantly associated with the event-free survival, but it did not provide the prognostic information above the effect of two- or three-vessel disease. Conclusion. The A allele in eotaxin 67 G/A polymorphism is associated with worse survival in CAD patients. Vladimír Kincl, Jan Máchal, Adéla Drozdová, Roman Panovský, and Anna Vašků Copyright © 2015 Vladimír Kincl et al. All rights reserved. Assessment of Immunological Biomarkers in the First Year after Heart Transplantation Wed, 30 Sep 2015 09:14:14 +0000 http://www.hindawi.com/journals/dm/2015/678061/ Background. Pharmacodynamic biomarkers that detect changes of immunological functions have been recognized as a helpful tool to increase the efficacy of immunosuppressive drug therapies. However, physiological changes of immunological biomarkers following transplantation are not investigated. Therefore, we assessed frequently used immunological biomarkers of the circulating blood in the first year following heart transplantation (HTx). Methods. Activation markers CD25 and CD95, intracellular cytokines IL-2 and IFNγ, chemokines IP10 and MIG, and subsets of dendritic cells as well as antibodies against human leukocyte antigens (HLA) and major histocompatibility complex class I-related chain A (MICA) antigens were analyzed at different time points using flow cytometry and Luminex xMAP technology. Results. Expression of IL-2, IFNγ, and plasmacytoid dendritic cells (pDCs) significantly increased during the first year. Anti-HLA antibodies decreased continuously, while anti-MICA antibodies showed minor increase within the first year. An association between percentage of pDCs and anti-MICA antibody positivity was proven. pDCs, IFNγ-producing T cells, and IP10 concentration were associated in a stronger way with age and gender of HTx recipients than with antibodies against HLA or MICA. Conclusions. We conclude that certain immunological biomarkers of the circulating blood change during the first year after HTx. These changes should be considered for interpretation of biomarkers after transplantation. Maja-Theresa Dieterlen, Katja John, Hartmuth B. Bittner, Meinhard Mende, Attila Tarnok, Friedrich W. Mohr, and Markus J. Barten Copyright © 2015 Maja-Theresa Dieterlen et al. All rights reserved. Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status Tue, 29 Sep 2015 06:49:34 +0000 http://www.hindawi.com/journals/dm/2015/536041/ The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, ] or hypertension [odd ratio (OR) = 1.02, ]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, ] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, ). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population. Habiba Alsafar, Ahmed Hassoun, Shaikha Almazrouei, Wala Kamal, Mustafa Almaini, Unini Odama, and Naushad Rais Copyright © 2015 Habiba Alsafar et al. All rights reserved. Identification of Novel Epigenetic Markers of Prostate Cancer by NotI-Microarray Analysis Tue, 29 Sep 2015 06:42:16 +0000 http://www.hindawi.com/journals/dm/2015/241301/ A significant need for reliable and accurate cancer diagnostics and prognosis compels the search for novel biomarkers that would be able to discriminate between indolent and aggressive tumors at the early stages of disease. The aim of this work was identification of potential diagnostic biomarkers for characterization of different types of prostate tumors. NotI-microarrays with 180 clones associated with chromosome 3 genes/loci were applied to determine genetic and epigenetic alterations in 33 prostate tumors. For 88 clones, aberrations were detected in more than 10% of tumors. The major types of alterations were DNA methylation and/or deletions. Frequent methylation of the discovered loci was confirmed by bisulfite sequencing on selective sampling of genes: FGF12, GATA2, and LMCD1. Three genes (BHLHE40, BCL6, and ITGA9) were tested for expression level alterations using qPCR, and downregulation associated with hypermethylation was shown in the majority of tumors. Based on these data, we proposed the set of potential biomarkers for detection of prostate cancer and discrimination between prostate tumors with different malignancy and aggressiveness: BHLHE40, FOXP1, LOC285205, ITGA9, CTDSPL, FGF12, LOC440944/SETD5, VHL, CLCN2, OSBPL10/ZNF860, LMCD1, FAM19A4, CAND2, MAP4, KY, and LRRC58. Moreover, we probabilistically estimated putative functional relations between the genes within each set using the network enrichment analysis. Alexey A. Dmitriev, Eugenia E. Rosenberg, George S. Krasnov, Ganna V. Gerashchenko, Vasily V. Gordiyuk, Tatiana V. Pavlova, Anna V. Kudryavtseva, Artemy D. Beniaminov, Anastasia A. Belova, Yuriy N. Bondarenko, Rostislav O. Danilets, Alexander I. Glukhov, Aleksandr G. Kondratov, Andrey Alexeyenko, Boris Y. Alekseev, George Klein, Vera N. Senchenko, and Vladimir I. Kashuba Copyright © 2015 Alexey A. Dmitriev et al. All rights reserved. FGF23 in Acute and Chronic Illness Mon, 28 Sep 2015 08:00:31 +0000 http://www.hindawi.com/journals/dm/2015/358086/ FGF23 is a bone-derived phosphaturic hormone that may become a useful biomarker for the identification of high-risk patients in chronic but also acute disease. It rises early in chronic kidney disease and is strongly and independently associated with excess morbidity and mortality. Emerging data suggest that FGF23 is also elevated in different scenarios of acute illness. In this review, we give an overview on the role of this interesting disease marker and potential and proven interventional strategies and discuss a blueprint for future research. Christian Schnedl, Astrid Fahrleitner-Pammer, Peter Pietschmann, and Karin Amrein Copyright © 2015 Christian Schnedl et al. All rights reserved. Roles of NOTCH1 as a Therapeutic Target and a Biomarker for Lung Cancer: Controversies and Perspectives Sun, 27 Sep 2015 14:36:26 +0000 http://www.hindawi.com/journals/dm/2015/520590/ Lung cancer is one of the most common types of human malignancies and the leading cause of cancer-related death. Patients with surgically resectable early stage lung cancer are more likely curable, but currently only a small population of patients can be diagnosed at such a stage, partly due to our incomplete understanding of the biology of lung cancer and the lack of diagnostic and prognostic biomarkers. Recent studies have shown that NOTCH1 is a critical regulator of human carcinogenesis and has been implicated in multiple steps of cancer development and progression. Herein, we review recent findings about the role of NOTCH1 in lung cancer and discuss its potential usefulness as both a therapeutic target and a biomarker for lung cancer. Lixia Guo, Ting Zhang, Ying Xiong, and Yanan Yang Copyright © 2015 Lixia Guo et al. All rights reserved. The Association of Serum IL-33 and sST2 with Breast Cancer Sun, 20 Sep 2015 14:30:55 +0000 http://www.hindawi.com/journals/dm/2015/516895/ Breast cancer is one of the most common malignant diseases in women. The main cause of death from breast cancer is its metastases at distant sites in the body. Interleukin-33 (IL-33) is a cytokine of the IL-1 family and found overexpressed in various cancers. The aim of the present study was to explore the association of serum IL-33 and sST2 with breast cancer. Here, the serum levels of Interleukin-33 (IL-33) and sST2 were found significantly higher in breast cancer patients than in healthy volunteers. Serum levels of vascular endothelial growth factor (VEGF), metalloproteinase-11 (MMP-11), and platelet-derived growth factor-C (PDGF-C) were also greater in breast cancer patients compared to healthy volunteers. We found that serum levels of IL-33 or sST2 were positively correlated with the serum levels of VEGF, MMP-11, and PDGF-C. Moreover, breast cancer dataset downloaded from The Cancer Genome Atlas showed that patients with higher level of MMP-11 or PDGF-C expression had shorter survival time than those with lower level of these proteins. In conclusion, IL-33 and sST2 may serve as noninvasive diagnosis markers for breast cancer. IL-33 and sST2 were significantly associated with MMP-11 or PDGF-C which indicated poor prognosis of breast cancer patients. Zhi-Ping Yang, Dan-Yan Ling, Yong-Hong Xie, Wan-Xin Wu, Jin-Rui Li, Jin Jiang, Jia-Lian Zheng, Yao-Hua Fan, and Ye Zhang Copyright © 2015 Zhi-Ping Yang et al. All rights reserved. Association of Plasma Myeloperoxidase Level with Risk of Coronary Artery Disease in Patients with Type 2 Diabetes Wed, 16 Sep 2015 12:06:55 +0000 http://www.hindawi.com/journals/dm/2015/761939/ Aims. This study aimed to investigate whether the change of plasma myeloperoxidase (MPO) level would be associated with the incidence of coronary artery disease (CAD) among diabetic patients. Methods. 339 patients with type 2 diabetes mellitus (DM) underwent coronary angiography. Of them, 204 cases had CAD and were assigned to CAD group and 135 cases without CAD were assigned to non-CAD group. Results. Compared to non-CAD group, CAD group had higher level of plasma MPO (). Multiple linear regression analysis showed that plasma MPO level was correlated with Gensini score. Multiple logistic analysis showed that the odds ratios for CAD across increasing tertiles of MPO level were 1.191 (0.971–1.547) and 1.488 (1.115–2.228) (, versus 1st tertile of MPO level, resp.) by adjusting for age, sex, and other conventional risk factors for CAD. The subjects were stratified into nine groups according to tertiles of MPO and HbA1c. The odds ratio for CAD was significantly higher in group with highest levels of MPO and HbA1c (OR = 4.08, ). Conclusion. Plasma MPO level was positively correlated with the degree of coronary artery stenosis in type 2 diabetic patients, and increasing blood glucose might amplify the association between MPO and CAD. Ping Song, Jin Xu, Yongfeng Song, Shiliang Jiang, Haitao Yuan, and Xu Zhang Copyright © 2015 Ping Song et al. All rights reserved. High-Dose versus Low-Dose Vitamin D Supplementation and Arterial Stiffness among Individuals with Prehypertension and Vitamin D Deficiency Wed, 16 Sep 2015 11:26:18 +0000 http://www.hindawi.com/journals/dm/2015/918968/ Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD). However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. Methods. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP), carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. Results. There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all ). High-dose vitamin D decreased augmentation index and pressure by 12.3 ± 5.3% () and 4.0 ± 1.5 mmHg (), respectively. However, these decreases in arterial stiffness were not associated with increases in serum 25-hydroxyvitamin D over 6 mo (). Conclusion. High-dose vitamin D supplementation appears to lower surrogate measures of arterial stiffness but not indices of central pulse wave velocity. Clinical Trial Registration. This trial is registered with www.clinicaltrials.gov (Unique Identifier: NCT01240512). Amanda Zaleski, Gregory Panza, Heather Swales, Pankaj Arora, Christopher Newton-Cheh, Thomas Wang, Paul D. Thompson, and Beth Taylor Copyright © 2015 Amanda Zaleski et al. All rights reserved. Serum Survivin Levels and Outcome of Chemotherapy in Patients with Malignant Mesothelioma Wed, 16 Sep 2015 08:23:34 +0000 http://www.hindawi.com/journals/dm/2015/316739/ Background. Survivin is an inhibitor of apoptosis protein involved in the regulation of cell proliferation that could be used as a marker for cancer diagnosis or prognosis. Our aim was to evaluate whether serum survivin levels influence the outcome of cisplatin-based chemotherapy in patients with malignant mesothelioma (MM). Methods. Serum survivin levels were determined using human survivin enzyme-linked immunosorbent assay in 78 MM patients before chemotherapy, after chemotherapy, and at disease progression. The influence on tumor response and survival was evaluated using nonparametric tests and Cox regression. Results. A median serum survivin level at diagnosis was 4.1 (0–217.5) pg/mL. Patients with a progressive disease had significantly higher survivin levels before chemotherapy (p = 0.041). A median serum survivin level after chemotherapy was 73.1 (0–346.2) pg/mL. If survivin levels increased after chemotherapy, patients had, conversely, better response (p = 0.001, OR = 5.40, 95% CI = 1.98–14.72). Unexpectedly, patients with increased survivin levels after chemotherapy also had longer progression-free (p < 0.001, HR = 0.33, 95% CI = 0.20–0.57) and overall survival (p = 0.001, HR = 0.29, 95% CI = 0.14–0.58). Conclusions. These results suggest that serum survivin levels before and during chemotherapy could serve as a biomarker predicting MM treatment response. Katja Goričar, Viljem Kovač, Alenka Franko, Metoda Dodič-Fikfak, and Vita Dolžan Copyright © 2015 Katja Goričar et al. All rights reserved. Tissue Kallikrein Activity, Detected by a Novel Method, May Be a Predictor of Recurrent Stroke: A Case-Control Study Mon, 14 Sep 2015 14:05:02 +0000 http://www.hindawi.com/journals/dm/2015/159750/ Aim. Tissue kallikrein (TK) protein content in plasma has been shown to be negatively associated with both incident and recurrent strokes. The aims of this study were to develop a novel method for detecting TK activity and to investigate its association with event-free survival over 5 years in Chinese first-ever stroke patients. Methods. We designed a case-control study with 321 stroke patients (174: ischemic stroke, 147: hemorrhagic stroke) and 323 healthy local controls. TK activity was measured by a novel assay utilizing the immunological characteristics of TK and the catalysis of benzoyl arginine ethyl ester hydrochloride (BAEE). Results. TK protein levels above 0.200 mg/L in plasma were not associated with urinary TK activity or the risk of stroke recurrence. TK activity was significantly lower in stroke patients compared with controls (1.583 ± 0.673 Eu/mL versus 1.934 ± 0.284 Eu/mL, ). After adjusting for traditional risk factors, TK activity was negatively associated, in a dose-response manner, with the risk of overall stroke recurrence and positively associated with event-free survival during a 5-year follow-up (relative risk (RR), 0.69; 95% CI, 0.57–0.84; ). Conclusions. Our findings suggest that urinary TK activity may be a stronger predictor of stroke recurrence than plasma TK levels. Xiao Ran, Qin Zhang, and Dao Wen Wang Copyright © 2015 Xiao Ran et al. All rights reserved. CSF Levels of Angiopoietin-2 Do Not Differ between Patients with CSF Fluid Leakage Syndrome and Controls Thu, 10 Sep 2015 14:31:52 +0000 http://www.hindawi.com/journals/dm/2015/343818/ CSF abnormalities have been reported in CSF leakage syndrome. However, the mechanism for these CSF changes is actually unknown and they may indicate impaired CSF flow or blood-CSF barrier. Angiopoietin-2 (Ang-2), a protein which is expressed and released by endothelial cells, has been associated with increased vascular permeability. In the assumption that CSF changes are due to an impaired blood-CSF barrier, we hypothesized that subjects with persistent CSF leakage may have increased CSF Ang-2 levels. We enrolled 10 subjects with a clinically definite diagnosis of persisting CSF leakage syndrome and 10 control subjects. In CSF analyses, CSF to serum albumin ratio (Qalb) was the most frequently increased parameter indicating a disturbed blood-CSF barrier function. Comparison of the mean CSF Ang-2 levels, CSF to serum Ang-2 ratio (QAng-2), and QAng-2/Qalb between the control and CSF leakage patients did not show any significant difference. We suggest that the increase of Qalb results from a low CSF flow. Future studies with phase contrast-MRI in conjunction with CSF analyses before and after epidural blood patch treatment are required to address this question. It would be of particular interest whether Qalb can be used as a marker for successful nontargeted epidural blood patch treatment. Refik Pul, Özlem Yildiz, Franco Morbiducci, Thomas Skripuletz, Philipp Schwenkenbecher, Martin Stangel, Friedrich Götz, Georg Berding, Corinna Trebst, and Frank Donnerstag Copyright © 2015 Refik Pul et al. All rights reserved. Identification of Circulating miRNAs in a Mouse Model of Nerve Allograft Transplantation under FK506 Immunosuppression by Illumina Small RNA Deep Sequencing Tue, 08 Sep 2015 11:18:55 +0000 http://www.hindawi.com/journals/dm/2015/863192/ Background. This study aimed to establish the expression profile of circulating microRNAs (miRNAs) during nerve allotransplantation in the presence and absence of FK506 immunosuppression. Methods. A 1 cm BALB/c donor sciatic nerve graft was transplanted into the sciatic nerve gaps created in recipient C57BL/6 mice with or without daily FK506 immunosuppression [1 mg/(kg·d)]. At 3, 7, and 14 d after nerve allotransplantation, serum samples were collected for miRNA expression analysis by Illumina small RNA deep sequencing. Results. Sequence analysis showed that the dominant size of circulating small RNAs after nerve allotransplantation was 22 nucleotides, followed by 23-nucleotide sequences. Nine upregulated circulating miRNAs (let-7e-5p, miR-101a-3p, miR-151-5p, miR-181a-5p, miR-204-5p, miR-340-5p, miR-381-3p, miR-411-5p, miR-9-5p, and miR-219-2-3p) were identified at 3 d, but none was identified at 7 or 14 d. Among them, miR-9-5p had the highest fold-change of >50-fold, followed by miR-340-5p with 38.8-fold. The presence of these nine miRNAs was not significant at 7 and 14 d after nerve allotransplantation with or without immunosuppression, showing that these miRNAs are not ideal biomarkers for monitoring rejection of deep-buried nerve allografts, a response usually observed later. Conclusions. We identified nine upregulated circulating miRNAs, which may have a biological function, particularly during the early stages after nerve allotransplantation under FK506 immunosuppression. Shao-Chun Wu, Cheng-Shyuan Rau, Johnson Chia-Shen Yang, Tsu-Hsiang Lu, Yi-Chan Wu, Yi-Chun Chen, Siou-Ling Tzeng, Chia-Jung Wu, Chia-Wei Lin, and Ching-Hua Hsieh Copyright © 2015 Shao-Chun Wu et al. All rights reserved. Optimal Vitamin D Supplementation Levels for Cardiovascular Disease Protection Tue, 08 Sep 2015 09:50:47 +0000 http://www.hindawi.com/journals/dm/2015/864370/ First described in relation to musculoskeletal disease, there is accumulating data to suggest that vitamin D may play an important role in cardiovascular disease (CVD). In this review we aim to provide an overview of the role of vitamin D status as both a marker of and potentially causative agent of hypertension, coronary artery disease, heart failure, atrial fibrillation, stroke, and peripheral vascular disease. The role of vitamin D levels as a disease marker for all-cause mortality is also discussed. We review the current knowledge gathered from experimental studies, observational studies, randomised controlled trials, and subsequent systematic reviews in order to suggest the optimal vitamin D level for CVD protection. Sebastian T. Lugg, Phillip A. Howells, and David R. Thickett Copyright © 2015 Sebastian T. Lugg et al. All rights reserved. Influence of GSTM1, GSTT1, and GSTP1 Polymorphisms on Type 2 Diabetes Mellitus and Diabetic Sensorimotor Peripheral Neuropathy Risk Tue, 08 Sep 2015 06:49:38 +0000 http://www.hindawi.com/journals/dm/2015/638693/ Background and Aims. Diabetic neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). Genetic susceptibility and oxidative stress may play a role in the appearance of T2DM and diabetic neuropathy. We investigated the relation between polymorphism in genes related to oxidative stress such as GSTM1, GSTT1, and GSTP1 and the presence of T2DM and diabetic neuropathy (DN). Methods. Samples were collected from 84 patients with T2DM (42 patients with DN and 42 patients without DN) and 98 healthy controls and genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. Results. GSTP1 Ile105Val polymorphism was associated with the risk of developing T2DM () but not with the risk of developing DN in diabetic cases. GSTM1 and GSTT1 gene polymorphisms were associated with neither the risk of developing T2DM nor the risk of DN occurrence in diabetic patients. No association was observed between the patients with T2DM and DSPN (diabetic sensorimotor peripheral neuropathy) and T2DM without DSPN regarding investigated polymorphism. Conclusion. Our data suggest that GSTP1 gene polymorphisms may contribute to the development of T2DM in Romanian population. GSTM1, GSTT1, and GSTP1 gene polymorphisms are not associated with susceptibility of developing diabetic neuropathy in T2DM patients. Adina Stoian, Claudia Bănescu, Rodica Ioana Bălaşa, Anca Moţăţăianu, Mircea Stoian, Valeriu G. Moldovan, Septimiu Voidăzan, and Minodora Dobreanu Copyright © 2015 Adina Stoian et al. All rights reserved. Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus Mon, 07 Sep 2015 11:51:31 +0000 http://www.hindawi.com/journals/dm/2015/613536/ Systemic lupus erythematosus is an autoimmune disease that predominantly affects women and typically manifests in multiple organs. The damage caused by this disorder is characterized by a chronic inflammatory state. Extracellular vesicles (EVs), including microvesicles (also known as microparticles), apoptotic bodies, and exosomes, are recognized vehicles of intercellular communication, carrying autoantigens, cytokines, and surface receptors. Therefore, the evidence of EVs and their cargo as biomarkers of autoimmune disease is rapidly expanding. This review will focus on biogenesis of extracellular vesicles, their pathophysiological roles, and their potential as biomarkers and therapeutics in inflammatory disease, especially in systemic lupus erythematosus. Javier Perez-Hernandez and Raquel Cortes Copyright © 2015 Javier Perez-Hernandez and Raquel Cortes. All rights reserved. Plasma Interleukin-37 Is Elevated in Patients with Rheumatoid Arthritis: Its Correlation with Disease Activity and Th1/Th2/Th17-Related Cytokines Sun, 06 Sep 2015 12:41:18 +0000 http://www.hindawi.com/journals/dm/2015/795043/ Interleukin- (IL-) 37 is a novel anti-inflammatory cytokine that suppresses immune response and inflammation. This study was performed to determine whether IL-37 was elevated in patients with rheumatoid arthritis (RA) and investigate the correlation between IL-37 level and disease activity and the concentration of Th1/Th2/Th17-related cytokines. Clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP), were collected in 34 RA patients and 34 age- and sex-matched healthy controls. Plasma IL-37 was measured by ELISA. Plasma levels of TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, and MIP-1β were analyzed using the Bio-Plex suspension array system. It was found that IL-37 levels were elevated markedly in RA patients and almost undetectable in healthy controls. In addition, IL-37 levels in patients with active RA were significantly enhanced as compared with those in patients of remission. More importantly, IL-37 showed a significant correlation with disease activity (DAS28) and IL-4, IL-7, IL-10, IL-12, and IL-13 concentrations in RA patients. These findings suggest that IL-37 plays an important role in the pathogenesis of RA and may prove to be a potential biomarker of active RA. Ting Xia, Xing-feng Zheng, Bao-hua Qian, He Fang, Jun-jie Wang, Lan-ling Zhang, Ya-fei Pang, Ju Zhang, Xiao-qing Wei, Zhao-fan Xia, and Dong-bao Zhao Copyright © 2015 Ting Xia et al. All rights reserved. Clinical Significance of SASH1 Expression in Glioma Sun, 06 Sep 2015 12:04:40 +0000 http://www.hindawi.com/journals/dm/2015/383046/ Objective. SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. Methods. We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher’s exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. Results. SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. Conclusions. SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma. Liu Yang, Haitao Zhang, Qi Yao, Yingying Yan, Ronghua Wu, and Mei Liu Copyright © 2015 Liu Yang et al. All rights reserved. Aerobic Glycolysis as a Marker of Tumor Aggressiveness: Preliminary Data in High Grade Human Brain Tumors Thu, 03 Sep 2015 14:44:55 +0000 http://www.hindawi.com/journals/dm/2015/874904/ Objectives. Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG), is a hallmark of active cancer cells that is not directly measured with standard 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. Methods. Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF), oxygen (CMRO2) and glucose (CMRGlu) metabolism, and AG, using 15O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. Results. Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. Conclusions. Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET. Andrei G. Vlassenko, Jonathan McConathy, Lars E. Couture, Yi Su, Parinaz Massoumzadeh, Hayden S. Leeds, Michael R. Chicoine, David D. Tran, Jiayi Huang, Sonika Dahiya, Daniel S. Marcus, Sarah Jost Fouke, Keith M. Rich, Marcus E. Raichle, and Tammie L. S. Benzinger Copyright © 2015 Andrei G. Vlassenko et al. All rights reserved. Serum and Vitreous Concentrations of Omentin-1 in Diabetic Retinopathy Thu, 03 Sep 2015 14:03:07 +0000 http://www.hindawi.com/journals/dm/2015/754312/ Objective. Omentin, a new discovered adipokine, is implicated to inhibit inflammation. Inflammation is one important mechanism of diabetic retinopathy (DR). The purpose of this work was to evaluate serum and vitreous concentrations of omentin-1 in patients with diabetic retinopathy (DR). Methods. This study enrolled 204 diabetic patients (60 without DR, 49 with NPDR, and 95 with PDR) and 65 control subjects. Results. Serum and vitreous omentin-1 levels in PDR patients were markedly decreased compared with those in the other three groups. NPDR patients showed reduced vitreous omentin-1 compared with patients without DR. In addition, control subjects had significantly higher levels of serum and vitreous omentin-1 compared with diabetic patients without DR, NPDR patients, and PDR patients. In addition, serum/vitreous omentin-1 ratio was positively correlated with the development and severity of DR. Conclusion. Serum and vitreous omentin-1 levels, as well as serum/vitreous omentin-1 ratio, are correlated with the presence and severity of DR. Wencui Wan, Qiuming Li, Fengyan Zhang, Guangying Zheng, Yong Lv, Guangming Wan, and Xuemin Jin Copyright © 2015 Wencui Wan et al. All rights reserved. Activated Complement Factors as Disease Markers for Sepsis Wed, 02 Sep 2015 13:38:49 +0000 http://www.hindawi.com/journals/dm/2015/382463/ Sepsis is a leading cause of death in the United States and worldwide. Early recognition and effective management are essential for improved outcome. However, early recognition is impeded by lack of clinically utilized biomarkers. Complement factors play important roles in the mechanisms leading to sepsis and can potentially serve as early markers of sepsis and of sepsis severity and outcome. This review provides a synopsis of recent animal and clinical studies of the role of complement factors in sepsis development, together with their potential as disease markers. In addition, new results from our laboratory are presented regarding the involvement of the complement factor, mannose-binding lectin, in septic shock patients. Future clinical studies are needed to obtain the complete profiles of complement factors/their activated products during the course of sepsis development. We anticipate that the results of these studies will lead to a multipanel set of sepsis biomarkers which, along with currently used laboratory tests, will facilitate earlier diagnosis, timely treatment, and improved outcome. Jean Charchaflieh, Julie Rushbrook, Samrat Worah, and Ming Zhang Copyright © 2015 Jean Charchaflieh et al. All rights reserved. Role of MALAT1 as a Prognostic Factor for Survival in Various Cancers: A Systematic Review of the Literature with Meta-Analysis Wed, 02 Sep 2015 06:23:55 +0000 http://www.hindawi.com/journals/dm/2015/164635/ Objectives. The expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a highly abundant and ubiquitously expressed long noncoding RNA (lncRNA), influences clinical parameters and may have prognostic value in cancer. This meta-analysis evaluated the prognostic role of MALAT1 in various cancers. Materials and Methods. Systematic literature searches of PubMed and EMBASE databases were conducted for eligible studies of the prognostic role of MALAT1 in cancer. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were analyzed. Summary hazard ratios (HRs) and 95% confidence intervals (95% CIs) were assessed to evaluate the influence of MALAT1 expression on patient prognosis. Results. Nine studies with a total of 932 patients were included in the analysis. Elevated MALAT1 expression was significantly correlated with poor OS (HR 2.02; 95% CI: 1.62–2.52; ; %). Subgroup analysis indicated that tumor type, histology type, ethnicity, and measurement technique did not affect the prognostic value of MALAT1 for OS. The HR of elevated MALAT1 for DFS was 2.78 (95% CI: 1.87–4.15; ; %). Conclusions. Elevated MALAT1 expression is correlated with poor OS in various types of cancer, suggesting that this gene is a prognostic factor for different types of cancer. Yao Wei and Ben Niu Copyright © 2015 Yao Wei and Ben Niu. All rights reserved. Syndecan-1 in Cancer: Implications for Cell Signaling, Differentiation, and Prognostication Tue, 01 Sep 2015 11:42:13 +0000 http://www.hindawi.com/journals/dm/2015/796052/ Syndecan-1, a cell surface heparan sulfate proteoglycan, is critically involved in the differentiation and prognosis of various tumors. In this review, we highlight the synthesis, cellular interactions, and the signalling pathways regulated by syndecan-1. The basal syndecan-1 level is also crucial for understanding the sequential changes involving malignant transformation, tumor progression, and advanced or disseminated cancer stages. Moreover, we focus on the cellular localization of this proteoglycan as cell membrane anchored and/or shed, soluble syndecan-1 with stromal or nuclear accumulation and how this may carry different, highly tissue specific prognostic information for individual tumor types. Tünde Szatmári, Rita Ötvös, Anders Hjerpe, and Katalin Dobra Copyright © 2015 Tünde Szatmári et al. All rights reserved. Polymorphism on Chromosome 9p21.3 Is Associated with Severity and Early-Onset CAD in Type 2 Diabetic Tunisian Population Mon, 31 Aug 2015 11:05:39 +0000 http://www.hindawi.com/journals/dm/2015/792679/ Multiple association studies found that the human 9p21.3 chromosome locus is a risk factor for atherosclerosis. The purpose of this study was to investigate the association of the severity and early-onset of coronary artery disease with variant rs1333049 on chromosome 9p21.3 polymorphism and the impact of this variant on cardiovascular risk factors in type 2 diabetic patients. The study population consisted of a control CAD group (101 patients) and 273 consecutive type 2 diabetic patients. Severity and extent of coronary atherosclerosis were scored numerically using the Gensini scoring system. The diabetic population was divided into three groups according to Gensini score: Group 1: no stenosis; Group 2: moderate CAD; Group 3, severe CAD. The homozygous CC genotype of rs1333049 was significantly associated with CAD in Group 2 (OR: 1.36; ) and Group 3 (OR: 5.77, ) compared to Group 1 (OR: 0.18; ) and control group (OR: 0.22; ). Among diabetic patients with early-onset CAD, CC genotype carriers had significantly higher Gensini scores than non-CC genotype carriers ( versus ; ). The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and severe CAD in type 2 diabetic Tunisian population. Kaouthar Abid, Donia Mili, and Abderraouf Kenani Copyright © 2015 Kaouthar Abid et al. All rights reserved.