An integrated microfluidics platform with high-throughput single-cell cloning array and concentration gradient generator for efficient cancer drug effect screening.

BACKGROUND: Tumor cell heterogeneity mediated drug resistance has been recognized as the stumbling block of cancer treatment. Elucidating the cytotoxicity of anticancer drugs at single-cell level in a high-throughput way is thus of great value for developing precision therapy. However, current techniques suffer from limitations in dynamically characterizing the responses of thousands of single cells or cell clones presented to multiple drug conditions. METHODS: We developed a new microfluidics-based "SMART" platform that is Simple to operate, able to generate a Massive single-cell array and Multiplex drug concentrations, capable of keeping cells Alive, Retainable and Trackable in the microchambers. These features are achieved by integrating a Microfluidic chamber Array (4320 units) and a six-Concentration gradient generator (MAC), which enables highly efficient analysis of leukemia drug effects on single cells and cell clones in a high-throughput way. RESULTS: A simple procedure produces 6 on-chip drug gradients to treat more than 3000 single cells or single-cell derived clones and thus allows an efficient and precise analysis of cell heterogeneity. The statistic results reveal that Imatinib (Ima) and Resveratrol (Res) combination treatment on single cells or clones is much more efficient than Ima or Res single drug treatment, indicated by the markedly reduced half maximal inhibitory concentration (IC50). Additionally, single-cell derived clones demonstrate a higher IC50 in each drug treatment compared to single cells. Moreover, primary cells isolated from two leukemia patients are also found with apparent heterogeneity upon drug treatment on MAC. CONCLUSION: This microfluidics-based "SMART" platform allows high-throughput single-cell capture and culture, dynamic drug-gradient treatment and cell response monitoring, which represents a new approach to efficiently investigate anticancer drug effects and should benefit drug discovery for leukemia and other cancers.

Analysis of the Primary and Post-Treatment Antibiotic Resistance of Helicobacter pylori in the Nanjing Area.

BACKGROUND: Resistance of Helicobacter pylori (H. pylori) to antibiotics is increasing worldwide. The study was aimed to understand the current situation of antibiotic resistance in Nanjing and to provide a reasonable basis for clinical selection of antibiotics to cure H. pylori. OBJECTIVE: To investigate the current status of H. pylori antibiotics resistance in the Nanjing area, and analyze the primary and post-treatment antibiotic resistance of H. pylori in this area. METHODS: During the period from July 2017 to December 2019, 1533 gastric mucosal specimens from patients with positive H. pylori confirmed by a breath test or rapid urease test were collected for isolation and identification of H. pylori. The agar dilution method was used for the antibiotic resistance test. RESULTS: The result showed that the resistance rates of H. pylori to amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline and metronidazole were 2.74%, 47.03%, 33.59%, 0.91%, 0.52% and 80.76%, respectively in the period of July 2017 to December 2019. The resistance rates of H. pylori (primary vs. post-treatment) to amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline and metronidazole were 1.83% vs. 6.08%, 38.62% vs. 77.81%, 27.41% vs. 56.23%, 0.58% vs. 2.13%, 0.33% vs. 1.22%, 78.57% vs. 88.75%, respectively. CONCLUSION: Antibiotic resistance of H. pylori remained a problem for the effective eradication of this pathogen and its associated diseases in the Nanjing area. For post-treatment eradication patients, clinicians should take into account regional antibiotic resistance rate, personal antibiotic exposure history, economic benefit ratio, adverse antibiotic reactions, antibiotic availability and other aspects.

MiR-142-3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer.

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment.

Identification of critically carcinogenesis-related genes in basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is a frequent malignant tumor of skin cancers with high morbidity. The objective of this study was to identify critical genes and pathways related to the carcinogenesis of BCC and gain more insights into the underlying molecular mechanisms of BCC. MATERIALS AND METHODS: The gene expression profiles of GSE7553 and GSE103439 were downloaded from the Gene Expression Omnibus database with 19 tumors and 6 normal skin tissues. Differentially expressed genes (DEGs) were screened between BCC samples and normal tissues, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, protein-protein interaction (PPI) network was constructed for these DEGs, and module analysis was performed. RESULTS: A total of 313 DEGs were obtained. Among them, 222 genes were upregulated and 91 genes were downregulated. Enrichment analysis indicated that the upregulated genes were significantly enriched in cell cycle and mitosis, while the downregulated genes were mainly associated with unsaturated fatty acid metabolic process and cell differentiation. In addition, TOP2A, CDK1, and CCNB1 were identified as the top three hub genes ranked by degrees in the PPI network. Meanwhile, three subnetworks were derived, which indicated that these DEGs were significantly enriched in pathways, including "cell cycle", "extracellular matrix-receptor interaction", "basal cell carcinoma", and "hedgehog signaling pathway". CONCLUSIONS: The novel critical DEGs and pathways identified in this study may serve pivotal roles in the carcinogenesis of BCC and indicate more molecular targets for the treatment of BCC.

microRNA-485-5p Functions as a Tumor Suppressor in Colorectal Cancer Cells by Targeting CD147.

Colorectal cancer(CRC) is a prevalent malignancy in the world. There is growing evidence that microRNAs (miRNAs) as crucial modulator are in connection with many tumor-related diseases including CRC. Though miR-485-5p has been reported as an anti-oncogene in certain cancers, it remains unclear in CRC. In this research, we found that miR-485-5p was at lower level expression in CRC tissues and cell lines compared to the paired paracancerous tissues and the normal colon epithelial cell line FHC, correspondingly. Furthermore, Experimental up-regulation miR-485-5p in DLD-1 and SW480 cells with mimic could inhibit the ability of proliferation, migration, invasion of CRC cell lines and facilitate cells apoptosis. Also, we confirmed that CD147 existed typically negative regulation by miR-485-5p through binding a conserved sequence specifically within the CD147 3'-untranslated region (3'UTR) and reintroduction of CD147 could rescue the phenotypic changes caused by miR-485-5p. The findings provide evidence to demonstrate the role of miR-485-5p/CD147 interaction in CRC and indicate that miR-485-5p might be exploited therapeutically in CRC.

Methylation of Tcf712 promoter by high-fat diet impairs ß-cell function in mouse pancreatic islets.

BACKGROUND: The TCF7L2 (transcription factor 7 like 2) gene is strongly associated with type 2 diabetes risk. However, many people without the TCF7L2 at-risk allele develop T2D. The aim of this study was to investigate altered Tcf7l2 DNA methylation and gene expression caused by high-fat diets (HFDs). METHODS: C57BL/6 mice were fed either an HFD or normal diet for 8 weeks, and intraperitoneal glucose tolerance tests were performed. Pancreatic islets were sorted for bisulfite sequencing polymerase chain reaction to determine DNA methylation status. We cloned the Tcf7l2 promoter, methylated it with methyltransferase, and transfected this construct into MIN-6 cells to confirm the effects of promoter methylation on Tcf7l2 expression. RESULTS: Aberrant methylation at position -165 bp relative to the transcriptional start site of Tcf7l2 was present in mice fed an HFD. Accordingly, expression of Tcf7l2 mRNA and its corresponding protein was lower in the HFD group (P < .05). Methylation of the Tcf7l2 promoter suppressed gene expression in MIN-6 cells. CONCLUSION: An HFD was shown to induce aberrant methylation of the Tcf7l2 promoter in mouse islets, which resulted in diminished gene expression. This study provides an evidence of the association between nutrient consumption and gene expression.

The Predictive and Prognostic Role of Stromal Tumor-infiltrating Lymphocytes in HER2-positive Breast Cancer with Trastuzumab-based Treatment: a Meta-analysis and Systematic Review.

Background Tumor-infiltrating lymphocytes (TILs) are white blood cells that have left the bloodstream and migrated into a tumor, involving in the prognosis of breast cancer (BC) patients. Published studies reported the value of TILs in patients with HER2-positive receiving trastuzumab-based treatment. However, the results obtained remain controversial. Here, we conducted this study to explore the predictive and prognostic role of TILs for HER2-positive BC patients receiving trastuzumab therapies. Method To identify the related published studies, a comprehensive literature search dating up to July 2017 was performed in the databases of PubMed, PMC, Web of Science and China National Knowledge Infrastructure (CNKI) according to predefined selection criteria. The pathologic complete response (pCR) and survival outcome of patients were measured by odds ratio (OR) and hazard ratio (HR) with corresponding 95% confidence interval (95% CI), respectively. The association between TILs and trastuzumab benefit was analyzed by using STATA version 11.0. Result Eleven eligible studies comprising 3228 patients were identified in the present study. The pooled results showed that high level of TILs was associated with a significantly improved pCR rate (OR = 1.32; 95% CI = 1.10-1.60) and longer survival (HR = 0.97; 95% CI = 0.96-0.99), particularly in the subgroups of retrospective study design and 10% INC cut-off value. Moreover, stratified analysis revealed that elevated TILs was a predictor of higher pCR rate in the Asian population and improved survival in the subgroups of Caucasian population and multivariate analysis. Conclusion This meta-analysis indicated that the level of stromal TILs was an independent predictive and prognostic marker for better outcome in HER2-positive BC patients receiving trastuzumab-based treatment. High level of TILs was significantly associated with trastuzumab benefit.

Association between SNPs in Long Non-coding RNAs and the Risk of Female Breast Cancer in a Chinese Population.

Long non-coding RNAs (LncRNAs) have been reported to be involved in tumorigenesis and tumor progression. Single nucleotide polymorphisms (SNPs) in the lncRNAs also play a vital role in carcinogenesis. The aim of this study was to assess the relationships between the four selected tagSNPs (rs944289, rs3787016, rs1456315, rs7463708) in the lncRNAs and the risk of female breast cancer in a Chinese population. A case-control study was carried out involving in a total of 439 breast cancer patients and 439 age-matched healthy controls. The genotyping was performed with Sequenom MassARRAY and the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) in tumor tissues was measured by the immunohistochemistry (IHC) assay. We found that rs3787016 TT genotype (adjusted odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.09-2.41, P = 0.018) was associated with an increased risk of female breast cancer, especially among the patients with premenopausal status (adjusted OR = 2.55, 95% CI = 1.30-4.97, P = 0.006). Moreover, a statistically significant increased risk of the rs3787016 TT genotype was observed among the patients with advanced tumor stage (Ⅲ and Ⅳ), poor histological grade (G3-G4), positive lymph node involvement, positive expression of ER and PR and negative expression of HER-2; rs7463708 GT and GT/GG genotype were associated with decreased risk of breast cancer in the subgroup of patients with postmenopausal status (GT versus (vs.) TT: adjusted OR = 0.67, 95% CI = 0.46-0.99, P = 0.043; GT/GG vs. TT: adjusted OR = 0.68, 95% CI = 0.47-0.98, P = 0.041) and tumor late-stage (GT vs. TT: adjusted OR = 0.65, 95% CI = 0.43-0.97, P = 0.037; GT/GG vs. TT: adjusted OR = 0.65, 95% CI = 0.44-0.96, P = 0.029). In short, rs3787016 TT genotype was associated with increased breast cancer risk and clinicopathologic features of the tumor, especially among premenopausal women.

Association of Genetic Polymorphisms in the LncRNAs with Gastric Cancer Risk in a Chinese Population.

Background: Genome-wide association studies have identified that polymorphisms in 8q24 confer susceptibility to gastric cancer. Polymorphisms in the lncRNA PRNCR1, PCAT1, and CCAT2 transcribed from the 8q24 locus have a potential risk for gastric cancer. Methods: To evaluate whether there is such an association in Chinese population, a case-control study enrolled 494 patients and 494 healthy controls was carried out. Sequenom MassARRAY platform was used for genotyping. Results: This study showed that rs16901946 G allele was associated with increased risk of gastric cancer (AG: adjusted OR = 1.33, 95% CI =1.02-1.73, p=0.033; GG: adjusted OR = 2.07; 95% CI = 1.11-3.86, p=0.023, AG/GG: adjusted OR = 1.39, 95% CI = 1.08-1.1.79, p=0.011; additive model: adjusted OR = 1.37; 95% CI = 1.10-1.70, p=0.004). Stratified analysis revealed that the increased risk was more evident in the cohort of younger subjects (adjusted OR = 1.84, 95% CI = 1.18-2.87, p=0.007), males (adjusted OR = 1.55, 95% CI = 1.15-2.08, p=0.004), positive Helicobacter pylori infection (adjusted OR = 1.44, 95% CI = 1.02-2.03, p=0.041), gastric cardia adenocarcinoma (adjusted OR = 1.61, 95% CI = 1.10-2.35, p=0.014), and tumor stage T1-T2 (adjusted OR = 1.58, 95% CI = 1.10-2.28, p=0.013). Conclusions: Our study suggested that rs16901946 G allele carriers have an increased risk of gastric cancer, and the risk could be enhanced by the interactions between the polymorphism and age, sex, Helicobacter pylori infection.

Combination of preoperative NLR, PLR and CEA could increase the diagnostic efficacy for I-III stage CRC.

BACKGROUND: Inflammation plays an important role in the development and progression of CRC. The members of inflammatory biomarkers, preoperative NLR and PLR, have been proved by numerous studies to be promising prognostic biomarkers for CRC. However, the diagnostic value of the two biomarkers in CRC remains unknown, and no study reported the combined diagnostic efficacy of NLR, PLR and CEA. METHODS: Five hundred and fifty-nine patients with I-III stage CRC undergoing surgical resection and 559 gender- and age-matched healthy controls were enrolled in this retrospective study. NLR and PLR were calculated from preoperative peripheral blood cell count detected using white blood cell five classification by Sysmex XT-1800i Automated Hematology System and serum CEA were measured by electrochemiluminescence by ELECSYS 2010. The diagnostic performance of NLR, PLR and CEA for CRC was evaluated by ROC curve. RESULTS: Levels of NLR and PLR in the cases were significantly higher than them in the healthy controls. ROC curves comparison analyses showed that the diagnostic efficacy of NLR (AUC=.755, 95%CI=.728-.780) alone for CRC was significantly higher than PLR (AUC=.723, 95%CI=.696-.749, P=.037) and CEA (AUC=.690, 95%CI=.662-.717, P=.002) alone. In addition, the diagnostic efficacy of the combination of NLR, PLR and CEA(AUC=.831, 95%CI=.807-.852)for CRC was not only significantly higher than NLR alone but also higher than any combinations of the two of these three biomarkers (P<.05). Moreover, the NLR and PLR in the patients with TNM stage I/II was higher than that in the healthy controls, and patients with stage III had a higher NLR and PLR than those with stage I/II, but no significant difference was observed. CONCLUSION: Our study indicated that preoperative NLR could be a CRC diagnostic biomarker, even for early stage CRC, and the combination of NLR, PLR and CEA could significantly improve the diagnostic efficacy.

Nucleotide excision repair pathway gene polymorphisms are linked to breast cancer risk in a Chinese population.

Polymorphisms in nucleotide excision repair (NER) pathway genes are associated with the risk of breast cancer, but the relevance of these associations appeared to vary according to the ethnicity of the subjects. To systemically evaluate the potential associations between NER polymorphisms and breast cancer risk in a Chinese population, we carried out a case-control study on 450 breast cancer patients and 430 healthy controls. Sequenom MassARRAY was used for genotyping, and immunohistochemistry was performed to detect estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression in tumor tissue. Our results showed that ERCC1 rs11615 (additive model: ORadjusted: 1.36, 95% CI: 1.08-1.71, p = 0.009), XPC rs2228000 (additive model: ORadjusted: 1.39, 95% CI: 1.13-1.72, p = 0.002) and ERCC2/XPD rs50872 (additive model: ORadjusted: 1.32, 95% CI: 1.04-1.67, p = 0.021) were associated with an increased risk of breast cancer. Stratified analysis revealed three polymorphisms (rs11615, rs1800975, and rs50872) to be associated with breast cancer in menopausal females. Three polymorphisms were associated with specific breast cancer grades (rs11615 with grade 3, rs2228000 and rs50872 with grade 1-2). Two polymorphisms (rs2228001 and rs50872) were associated with the risk of breast cancer with negative lymph node involvement. rs1800975 and rs50872 were associated with the risk of ER- and PR- breast cancer, whereas rs11615 was associated with the risk of ER+ and PR+ breast cancer. We found that carriers of the T allele of ERCC1 rs11615, XPC rs2228000 and rs50872, particularly in postmenopausal females, have an increased risk of breast cancer.

MiR-608, pre-miR-124-1 and pre-miR26a-1 polymorphisms modify susceptibility and recurrence-free survival in surgically resected CRC individuals.

Genetic variation within microRNA (miRNA) may result in its abnormal folding or aberrant expression, contributing to colorectal turmorigenesis and metastasis. However, the association of six polymorphisms (miR-608 rs4919510, miR-499a rs3746444, miR-146a rs2910164, pre-miR-143 rs41291957, pre-miR-124-1 rs531564 and pre-miR-26a-1 rs7372209) with colorectal cancer (CRC) risk, therapeutic response and survival remains unclear. A retrospective study was carried out to investigate the association in 1358 0-III stage resected CRC patients and 1079 healthy controls using Sequenom's MassARRAY platform. The results showed that rs4919510 was significantly associated with a decreased susceptibility to CRC in co-dominant, allele and recessive genetic models, and the protective role of rs4919510 allele G and genotype GG was more pronounced among stage 0-II cases; significant association between rs531564 and poor RFS was observed in cases undergoing adjuvant chemo-radiotherapy in co-dominant, allele and dominant models; moreover, there was a positive association between rs7372209 and recurrence-free survival in stage II cases in co-dominant and over-dominant models; additionally, a cumulative effect of rs531564 and rs7372209 at-risk genotypes with hazard ratio at 1.30 and 1.95 for one and two at-risk genotypes was examined in stage II cases, respectively. Our findings indicated that rs4919510 allele G and genotype GG were protective factors for 0-II stage CRC, rs7372209 and rs531564 could decrease RFS in II stage individuals and resected CRC patients receiving adjuvant chemo-radiology.

MicroRNA expression profiles predict progression and clinical outcome in lung adenocarcinoma.

Lung cancer is one of the leading causes of cancer death worldwide. Accumulating evidence has indicated that microRNAs (miRNAs) can be proposed as promising diagnostic and prognostic markers for various cancers. The current study analyzed the miRNA expression profiles of 418 lung adenocarcinoma (LUAD) cases obtained from The Cancer Genome Atlas dataset, with the aim to investigate the relationship of miRNAs with progression and prognosis of LUAD. A total of 185 miRNAs were found to be differentially expressed between LUAD tumor tissues and adjacent normal tissues. Among them, 13, 10, 0, and 10 miRNAs were discovered to be associated with pathologic T, N, M, and Stage, respectively. Interestingly, mir-200 family (mir-200a, mir-200b, and mir-429) was shown to play a critical role in the progression of LUAD. In the multivariate Cox regression analysis, mir-1468 (P=0.009), mir-212 (P=0.026), mir-3653 (P=0.012), and mir-31 (P=0.002) were significantly correlated with recurrence-free survival. With regard to overall survival, mir-551b (P=0.011), mir-3653 (P=0.016), and mir-31 (P=0.001) were proven as independent prognostic markers. In summary, this study identified the cancer-specific miRNAs that may predict the progression and prognosis of LUAD.

Platelet-to-lymphocyte ratio could be a promising prognostic biomarker for survival of colorectal cancer: a systematic review and meta-analysis.

Inflammation is one of the most important causes leading to colorectal carcinogenesis, and inflammatory biomarkers such as the platelet-to-lymphocyte ratio (PLR) might predict survival in colorectal cancer (CRC). However, the prognostic value of PLR in CRC patients remains controversial. The prognostic value of PLR was comprehensively analyzed in 12 articles including 3541 CRC patients (10 for overall survival (OS), seven for disease-free survival (DFS), three for recurrence-free survival (RFS), and three for cancer-specific survival (CSS)) in this study. The overall pooled hazard ratios (HRs) of PLR for OS, DFS, and CSS were significant at 1.29 (95% confidence interval, CI = 1.13-1.47, P H = 0.149), 1.43 (95% CI = 1.03-1.97, P H = 0.025), and 1.26 (95% CI = 1.04-1.52, P H = 0.223), respectively. However, there was no evidence of significance for RFS (HR = 1.29, 95% CI = 0.98-1.70, P H = 0.231) in our study. Stratified analyses indicated elevated PLR was a predictor of poor OS (metastatic patients) and DFS (Caucasian population) and was also significantly associated with OS in univariate analysis (HR = 1.35, 95% CI = 1.14-1.60, P H = 0.532) and those only treated surgically (HR = 1.37, 95% CI = 1.10-1.70, P H = 1.080). However, our findings indicated that elevated PLR is a promising prognostic biomarker for colorectal cancer, especially in metastatic Caucasian CRC patients.

Prognostic performance of lymphocyte-to-monocyte ratio in diffuse large B-cell lymphoma: an updated meta-analysis of eleven reports.

PURPOSE: The findings on the prognostic value of lymphocyte-to-monocyte ratio (LMR) in diffuse large B-cell lymphoma (DLBCL) are inconsistent. This meta-analysis was conducted to more precisely evaluate the prognostic significance of LMR in DLBCL. METHODS: This analysis combined eleven studies with 4,578 patients aiming to assess the association of LMR with overall survival (OS) and progression-free survival (PFS) in DLBCL. Data from studies directly reporting a hazard ratio (HR) with 95% corresponding confidence interval (CI) in multivariate analysis were pooled to estimate the effect. RESULTS: Our results suggested that patients with decreased LMR had shorter OS (HR =1.79, 95% CI =1.54-2.08, P<0.001) and PFS (HR =2.21, 95% CI =1.80-2.72, P<0.001) in DLBCL. Stratified analyses indicated that each confounder showed consistent prognostic value in DLBCL. There was no significant heterogeneity for PFS (P H=0.192) and OS (P H=0.212) among the enrolled studies. CONCLUSION: This meta-analysis indicated that decreased LMR might be a marker in the prediction of poor prognosis for patients with DLBCL.

Association of the DISC1 and NRG1 genetic polymorphisms with schizophrenia in a Chinese population.

Polymorphisms in Disrupted-in-Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) might be associated with schizophrenia; however, the conclusions of relevant studies were inconsistent across different ethnic populations. This population-based case-control study was carried out to determine whether polymorphisms in these two genes could be associated with schizophrenia in the Chinese population. A case-control study of 248 schizophrenia patients and 236 controls was performed with the Sequenom MassARRAY platform. The results revealed that the DISC1 rs821616 heterozygous (AT vs. AA: adjusted OR, 1.98, 95%CI: 1.30-3.02) and co-dominant (AT/TT vs. AA: adjusted OR=1.94; 95%CI: 1.29-2.92) patterns were associated with increased risk for developing schizophrenia in all participants and subgroups (stratified by sex and age at onset), respectively. Moreover, in the male subgroup, the DISC1 rs821597 genotype GA or GA/AA exhibited increased risk of schizophrenia. For NRG1 polymorphisms, in the early onset subgroup (≤25years), the rs3924999 G/G genotype was susceptible to schizophrenia. The interaction of DISC1 rs821616 T allele with the NRG1 rs3924999 A allele or that of DISC1 rs821597 A allele with NRG1 rs3924999 A allele had synergic effects on the development of schizophrenia. This study concluded that carriers of the DISC1 rs821616 T allele have increased risk for developing schizophrenia, and that the DISC1 rs821597 A allele was susceptible to schizophrenia for the male, and that there are marked interactions between the DISC1 rs821616 T and/or rs821597 A alleles and the NRG1 rs3924999 A allele for the development of schizophrenia.

Analysis of Diagnostic Value of YKL-40 in Ovarian Cancer.

OBJECTIVE: Early diagnosis of ovarian cancer is crucial in clinical practice but is difficult. Accumulating studies have investigated the utility of YKL-40 in early detection of ovarian cancer. The aim of this study was to evaluate the overall accuracy of YKL-40 in diagnosis of ovarian cancer through a meta-analysis of published studies. METHODS: A comprehensive search of related literature was performed in PubMed, Web of Science, and China National Knowledge Infrastructure databases. Meta-DiSc 1.4 and STATA 11.0 were selected for data analysis, and Quality Assessment of Diagnostic Accuracy Studies tool version 2 was used to assess the quality of included studies. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and summary receiver operating characteristic curve. RESULTS: A total of 13 studies dating up to May 2015 with 1623 individuals were enrolled in the present study. The pooled characteristics of these studies were as follows: sensitivity 0.71 (95% confidence interval [CI], 0.68-0.75), specificity 0.90 (95% CI, 0.88-0.92), positive likelihood ratio 7.24 (95% CI, 4.22-12.43), negative likelihood ratio 0.34 (95% CI, 0.27-0.42), and diagnostic odds ratio 24.93 (95% CI, 12.61-49.27), respectively. The area under the curve was 0.8471. CONCLUSIONS: The results indicated that YKL-40 could be regarded as an effective biomarker for diagnosis of ovarian cancer.

FCGR2A, FCGR3A polymorphisms and therapeutic efficacy of anti-EGFR monoclonal antibody in metastatic colorectal cancer.

Anti-EGFR monoclonal antibodies (mAb) such as cetuximab, panitumumab are one kind of efficacious targeted drugs in treatment of metastatic colorectal cancer (mCRC). However, only a small proportion of patients harbored wild-KRAS genotype can benefit from it. We hypothesized that personal genetic heterogeneity might be the main cause leading to obvious difference in its clinical efficacy. A retrospective study including 82 mCRC patients treated with chemotherapy plus cetuximab and a comprehensive meta-analysis containing 2831 cases within sixteen eligible studies were conducted to investigate the possible association between FCGR2A H131R and FCGR3A V158F and clinical outcome of mCRC patients treated with anti-EGFR mAb based therapy. Results of the retrospective study showed that H131R within FCGR2A or V158F within FCGR3A were not associated with clinical outcome in 82 KRAS wild chemorefractory mCRC patients in co-dominant, dominant, recessive, over-dominant, allele genetic models. However, the comprehensive meta-analysis with the largest of sample size obtained the significant result between FCGR3A V158F and PFS (FV/VV vs. FF: Ph = 0.027, MSR = 0.680, 95%CI = 0.549-0.842 in overall population; Ph = 0.12, MSR = 0.728, 95%CI = 0.648-0.818 in KRAS wild population) and OS (VV vs. FF: Ph < 0.001, MSR = 0.733, 95%CI = 0.578-0.930 in overall population). These findings indicate that KRAS wild chemorefractory mCRC individual harbored genotype FF of V158Fcan benefit from anti-EGFR mAb adjuvant therapy in terms of PFS and OS, and it may be useful genetic biomarker to predict clinical survival of mCRC individuals with anti-EGFR mAb based therapy.

Evaluation the susceptibility of five polymorphisms in microRNA-binding sites to female breast cancer risk in Chinese population.

Polymorphisms in microRNA (miRNA) binding site have been widely discussed to be associated with cancer risk; however, the associations were unclear in Chinese population. To investigate the associations of five polymorphisms (rs11097457, rs1434536, rs1970801, rs1044129, rs11169571) in miRNA binding sites with breast cancer risk, a total of 435 female patients with breast cancer and 439 age- and gender-matched tumor-free individuals were enrolled in this case-control study. Sequenom MassARRAY was applied to detect the polymorphisms, and the immunohistochemistry assay was used to measure the expression of estrogen receptor (ER) and progesterone receptor (PR) and CerbB-2. The data showed that these polymorphisms were not associated with breast cancer risk or clinical characters of breast cancer in all participants and sub-group with the exception that, in the sub-group of women with their first menstruation after 14 years old, those who carried rs1970801 T allele (genotype TT/GT) were associated with decreased breast cancer risk. In short, this case-control study provided the evidence that women with their first menstruation after 14 years old and carried rs1970801 T allele (genotype TT/GT) were associated with decreased breast cancer risk.

C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling.

Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1α downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.