Network Pharmacology along with Molecular Docking to Explore the Mechanism of Danshen Injection against Anthracycline-induced Cardiotoxicity and Transcriptome Validation.

INTRODUCTION: Although anthracyclines have demonstrated efficacy in cancer therapy, their utilization is constrained by cardiotoxicity. In contrast, Danshen injection (DSI), derived from Salvia miltiorrhiza, has a longstanding tradition of being employed to ameliorate cardiovascular ailments, including anthracycline- induced cardiotoxicity (AIC). Nonetheless, there is a notable dearth of comprehensive systematic investigation into the molecular mechanisms underlying DSI's effects on AIC. Consequently, this study was undertaken to explore the underlying mechanism by which DSI acted against AIC. METHODS: Employing network pharmacology approach, the current investigation undertook a comprehensive analysis of the impact of DSI on AIC, which was further validated by transcriptome sequencing with in vitro AIC model. Additionally, molecular docking was conducted to evaluate the binding of active ingredients to core targets. A total of 3,404 AIC-related targets and 12 active ingredients in DSI, including chrysophanol, luteolin, tanshinone IIA, isoimperatorin, among others, were collected by differentially expressed analysis and database search, respectively. RESULTS: The network pharmacology and enrichment analysis suggested 102 potential targets and 29 signaling pathways associated with the protective effect of DSI on AIC. Three core targets (CA12, NOS3, and POLH) and calcium signaling pathways were further validated by transcriptomic analysis of the in-vitro model. The high affinity of the active ingredients binding to corresponding targets was confirmed by molecular docking. CONCLUSION: The present study suggested that DSI might exert a cardioprotective effect on AIC via the inhibition of CA12, NOS3, and POLH, as well as the modulation of calcium signaling. Further experiments are warranted to verify the findings.

Elevated Preoperative NMPR Predicts an Unfavorable Chance of Survival in Resectable Esophageal Squamous Cell Carcinoma.

Background and objectives: Combined peripheral neutrophil−platelet indexes reflecting the systemic inflammatory status have been reported to predict the clinical outcome in patients with various types of cancer. However, the prognostic value of combined neutrophil−platelet indexes in operable esophageal squamous cell carcinoma (ESCC) remains unclear. The study introduced a novel combined neutrophil−meanplateletvolume−platelet ratio (NMPR) index and investigated its clinical and prognostic value in patients with operable ESCC receiving curative surgery. Materials and Methods: A retrospective analysis of the clinicopathologic data of 277 consecutive ESCC patients who received curative resection at Zhejiang Cancer Hospital in China between January 2007 and December 2010 was conducted (the training cohort). In addition, the clinicopathologic data of 101 resectable ESCC patients at Renmin Hospital of Hubei University of Medicine between December 2018 and June 2021 were collected (the external validation cohort). The optimal cutoff value of NMPR concerning overall survival (OS) in the training cohort was determined by X-tile software. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of NMPR along with other variables in the training cohort, which was further validated with the same cutoff value in the external validation cohort. Significant predictors of OS were used to construct the nomogram, of which the discrimination and calibration was evaluated by concordance index (C-index) and calibration plots. Results: With a cutoff value of 16.62, the results from both the training and external validation cohorts supported the association of high NMPR (>16.62) with increased tumor length and advanced T stage but not with other variables. In the training cohort, a significant association between shorter OS and high NMPR (p = 0.04) as well as high CRP (p < 0.001), poor tumor differentiation (p = 0.008), advanced T stage (p = 0.006), advanced N stage (p < 0.001) and high CEA (p = 0.007) was revealed. Additionally, the high NMPR was verified to independently predict unfavorable OS (p = 0.049) in the external validation cohort. The C-index of the OS nomogram cooperating significant predictors in the training cohort was 0.71 and the calibration plots of the OS nomogram fitted well. Conclusions: The present study demonstrates that high NMPR is an independent predictor of unfavorable OS in resectable ESCC patients without neoadjuvant therapy.

Cardioprotective Mechanism and Active Compounds of Folium Ginkgo on Adriamycin-Induced Cardiotoxicity: A Network Pharmacology Study.

Objective: To investigate the mechanism of Folium Ginkgo (FG) against adriamycin-induced cardiotoxicity (AIC) through a network pharmacology approach. Methods: Active ingredients of FG were screened by TCMSP, and the targets of active ingredient were collected by Genclip3 and HERB databases. AIC-related target genes were predicted by Genecards, OMIM, and CTD databases. Protein-protein interaction (PPI) network was constructed by STRING platform and imported into Cytoscape software to construct the FG-active ingredients-targets-AIC network, and CytoNCA plug-in was used to analyze and identify the core target genes. The Metascape platform was used for transcription factor, GO and signaling pathway enrichment analysis. Results: 27 active ingredients of FG and 1846 potential targets were obtained and 358 AIC target genes were retrieved. The intersection of FG and AIC targets resulted in 218 target genes involved in FG action. The top 5 active ingredients with most targets were quercetin, luteolin, kaempferol, isorhamnetin, and sesamin. After constructing the FG-active ingredients-targets-AIC network, CytoNCA analysis yielded 51 core targets, of which the top ranked target was STAT3. Ninety important transcription factors were enriched by transcription factor enrichment analysis, including RELA, TP53, NFKB1, SP1, JUN, STAT3, etc. The results of GO enrichment analysis showed that the effective active ingredient targets of FG were involved in apoptotic signaling, response to growth factor, cellular response to chemical stress, reactive oxygen species metabolic process, etc. The signaling pathway enrichment analysis showed that there were many signaling pathways involved in AIC, mainly including pathways in cancer, FOXO signaling pathway, AGE-RAGE signaling pathway in diabetic complications, signaling by interleukins, and PI3K-AKT signaling pathway,. Conclusions: The study based on a network pharmacology approach demonstrates that the possible mechanisms of FG against AIC are the involvement of multicomponents, multitargets, and multipathways, and STAT3 may be a key target. Further experiments are needed to verify the results.

Weighted gene co-expression network-based approach to identify key genes associated with anthracycline-induced cardiotoxicity and construction of miRNA-transcription factor-gene regulatory network.

BACKGROUND: Cardiotoxicity is a common complication following anthracycline chemotherapy and represents one of the serious adverse reactions affecting life, which severely limits the effective use of anthracyclines in cancer therapy. Although some genes have been investigated by individual studies, the comprehensive analysis of key genes and molecular regulatory network in anthracyclines-induced cardiotoxicity (AIC) is lacking but urgently needed. METHODS: The present study integrating several transcription profiling datasets aimed to identify key genes associated with AIC by weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) and also constructed miRNA-transcription factor-gene regulatory network. A total of three transcription profiling datasets involving 47 samples comprising 41 rat heart tissues and 6 human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) samples were enrolled. RESULTS: The WGCNA and DEA with E-MTAB-1168 identified 14 common genes affected by doxorubicin administrated by 4 weeks or 6 weeks. Functional and signal enrichment analyses revealed that these genes were mainly enriched in the regulation of heart contraction, muscle contraction, heart process, and oxytocin signaling pathway. Ten (Ryr2, Casq1, Fcgr2b, Postn, Tceal5, Ccn2, Tnfrsf12a, Mybpc2, Ankrd23, Scn3b) of the 14 genes were verified by another gene expression profile GSE154603. Importantly, three key genes (Ryr2, Tnfrsf12a, Scn3b) were further validated in a hiPSCMs-based in-vitro model. Additionally, the miRNA-transcription factor-gene regulatory revealed several top-ranked transcription factors including Tcf12, Ctcf, Spdef, Ebf1, Sp1, Rcor1 and miRNAs including miR-124-3p, miR-195-5p, miR-146a-5p, miR-17-5p, miR-15b-5p, miR-424-5p which may be involved in the regulation of genes associated with AIC. CONCLUSIONS: Collectively, the current study suggested the important role of the key genes, oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network in elucidating the molecular mechanism of AIC.

High C-Reactive Protein to Albumin Ratio Predicts Inferior Clinical Outcomes in Extranodal Natural Killer T-Cell Lymphoma.

OBJECTIVE: The prognostic value of C-reactive protein to albumin ratio (CAR) has been identified in several cancers but not in extranodal natural killer T-cell lymphoma (ENKTL) as yet. We aimed to evaluate the prognostic value of CAR in ENKTL. METHODS: A retrospective study with 246 patients with ENKTL was performed to determine the prognostic value of pretreatment CAR and examine the prognostic performance of CAR incorporating with International Prognostic Index (IPI) or natural killer/T-cell lymphoma prognostic index (NKPI) by nomogram. RESULTS: The Cox regression analyses showed that high CAR (>0.3) independently predicted unfavorable progression-free survival (PFS, P = .011) and overall survival (OS, P = .012). In the stratification analysis, the CAR was able to separate patients into different prognoses regarding both OS and PFS in Ann Arbor stage I+II as well as III+IV, IPI score 0 to 1, and NKPI score 1 to 2 subgroups (all P < .05). Additionally, the predictive accuracy of the IPI-based nomogram incorporating CAR, albumin to globulin ratio (AGR), and IPI for OS and PFS appeared to be lower than the NKPI-based nomogram incorporating CAR, age, AGR, extranodal site, and NKPI. CONCLUSION: Pretreatment CAR is a simple and easily accessible parameter for independently predicting OS and PFS in patients with ENKTL.

MiR-15b-5p is Involved in Doxorubicin-Induced Cardiotoxicity via Inhibiting Bmpr1a Signal in H9c2 Cardiomyocyte.

The wide use of anthracyclines represented by doxorubicin (DOX) has benefited cancer patients, yet the clinical application is limited due to its cardiotoxicity. Although numerous evidences have supported a role of microRNAs (miRNAs) in DOX-induced myocardial damage, the exact etiology and pathogenesis remain largely obscure. In this study, we focused on the role of miR-15b-5p in DOX-induced cardiotoxicity. We employed a public miRNA and gene microarray to screen differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in rat cardiomyocytes, and 33 DEMs including miR-15b-5p and 237 DEGs including Bmpr1a and Gata4 were identified. The Gene ontology (GO) and pathway enrichment analysis of 237 DEGs indicated that the DEGs were mainly enriched in heart development and ALK pathway in cardiomyocyte which included the main receptor Bmpr1a and transcription factor Gata4. The up-regulated miR-15b-5p and down-regulated Bmpr1a and Gata4 mRNA expressions were further validated in H9c2 cardiomyocytes exposed to DOX. Moreover, the results showed overexpression of miR-15b-5p or inhibition of Bmpr1a may enhance the DOX-induced apoptosis, oxidative stress and mitochondria damage in H9c2 cardiomyocytes. The Bmpr1a was suggested as a potential target of miR-15b-5p by bioinformatics prediction. We further verified the negatively regulatory effect of miR-15b-5p on Bmpr1a signaling. Moreover, we also confirmed that overexpression of miR-15b-5p may exacerbate the DOX-induced apoptosis of H9c2 cardiomyocytes by affecting the protein expression ratio of Bcl-2/Bax and Akt activation, while this pro-apoptotic effect was able to be suppressed by Bmpr1a agonist. Collectively, the results suggest that miR-15b-5p is likely involved in doxorubicin-induced cardiotoxicity via inhibiting Bmpr1a signaling in H9c2 cardiomyocytes. Our study provides a novel insight for investigating DOX-induced cardiotoxicity.

Bioinformatics identification of potential candidate blood indicators for doxorubicin-induced heart failure.

The care of individual patients requiring anthracyclines remains challenging as uncertainty persists on predictors of cardiotoxicity. The aim of the present study was to identify potential candidate blood indicators of doxorubicin-induced heart failure. The gene expression profiles of GSE40447 and GSE9128 microarray data were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) using the R/Limma package or GEO2R. Functional and pathway enrichment analysis on DEGs were performed using DAVID database. The cardiovascular disease (CVD)-related DEGs were screen out based on the CardioGenBase database. The protein-protein interaction (PPI) network was constructed with STRING database and visualized by using Cytoscape. Then, the CVD-related DEGs were validated by intersection analysis with DEGs in GSE9128. The overlapping DEGs with a consistent expression pattern in GSE40447 and GSE9128 were identified as candidate indicators for doxorubicin-induced heart failure. A total of 516 DEGs potentially associated with doxorubicin-induced heart failure in GSE40447 were identified, which were mainly enriched in the gene ontology terms related to B cells, leukocytes, lymphocyte activation and B cell receptor signaling pathway. Of the DEGs, 42 were screened out as CVD-related DEGs by using CardioGenBase. Seven genes with high connectivity degree were presented in the PPI network. Finally, 5/6 CVD-related DEGs revealed by the intersection analysis were validated by GSE9128 and highlighted as candidate indicators of doxorubicin-induced heart failure: CD163, CD28, SLC25A20, ANPEP and TLR5. Several genes, including the 5 previously mentioned, were proposed as potential candidate blood indicators for doxorubicin-induced heart failure. Further experimental validations are greatly warranted for future clinical application.

Survival Benefit of Metformin Adjuvant Treatment For Pancreatic Cancer Patients: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Previous studies on the effect of metformin therapy on survival of pancreatic cancer patients obtained inconsistent findings. To reevaluate the prognostic value of metformin adjuvant treatment, a meta-analysis was carried out. METHODS: Relevant articles addressing the association between metformin use and pancreatic cancer survival were electronically searched to identify eligible studies. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. RESULTS: Totally, seventeen studies involving 36791 participants were included. Overall, metformin use was found to be significantly associated with a favorable OS (HR=0.88, 95% CI=0.80-0.97). Subgroup analyses by ethnicity showed a significantly reduced risk of death for metformin users compared with non-users in Asians (HR=0.74, 95% CI=0.58-0.94) but nonsignificant in Caucasians. When stratified by clinical stage, a remarkable reduction of mortality risk in patients at stage I-II treated with metformin (HR=0.76, 95% CI=0.68-0.86) was found as well as the group at stage I-IV (HR=0.88, 95% CI=0.79-0.99), but not in patients at stage III-IV. In the stratification analyses based on treatment strategy, metformin therapy was found to be associated with a better clinical outcome in patients receiving surgery or comprehensive therapy (HR=0.73, 95% CI=0.62-0.87; HR=0.88, 95% CI=0.79-0.97) but not chemotherapy. However, the overall analysis failed to show a significant association between metformin use and DFS (HR=1.54, 95% CI=0.94 -2.50) with only 2 studies enrolled. CONCLUSION: The current study has evidenced a significant association of metformin adjuvant treatment with the survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment. Further investigation is needed.

Triglyceride to high density lipoprotein cholesterol ratio may serve as a useful predictor of major adverse coronary event in female revascularized ST-elevation myocardial infarction.

BACKGROUND: Elevated triglyceride to high density lipoprotein cholesterol (TG/HDL-C) ratio has been identified as a surrogate marker of insulin resistance and an independent predictor for cardiovascular events in the general population. However, the prognostic value of TG/HDL-C ratio in revascularized ST-elevation myocardial infarction(STEMI) patients remains unclear. We examined the association between TG/HDL-C ratio and clinical outcome of revascularized STEMI patients in the Chinese population. METHODS: 464 STEMI patients who underwent successful revascularization were enrolled to determine the relationship between TG/HDL-C ratio and major adverse coronary events(MACEs) with a 30-month follow-up. The Kaplan-Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of TG/HDL-C ratio. RESULTS: TG/HDL-C ratio was found to be significantly associated with age (p = 0.017), history of diabetes(p = 0.017), heart rate(p = 0.011), TG(p < 0.001), HDL-C(p < 0.001) and Gensini score(p = 0.034). The multivariate Cox regression analysis revealed that elevated TG/HDL-C ratio was an independent prognostic factor for MACE in female patients (HR = 2.624,95%CI = 1.211-5.687,p = 0.014) but not in male patients(HR = 0.756, 95%CI = 0.484-1.179,p = NS) after adjustment with other MACE-related prognostic factors. CONCLUSION: The TG/HDL-C ratio may be independently associated with MACEs in female revascularized STEMI patients in the Chinese population.

Screening genes associated with elevated neutrophil­to­lymphocyte ratio in chronic heart failure.

Neutrophil­to­lymphocyte ratio (NLR) is commonly considered a useful prognostic index for many cardiovascular diseases; however, it has limited sensitivity and specificity. Factors associated with elevated NLR may aid in the prediction of prognosis with heart failure (HF) in combination with NLR. The present study sought to identify decisive factors associated with NLR in HF patients and investigate their association with elevated NLR. The gene expression profile for blood samples from 197 individuals with chronic heart failure (CHF), with corresponding hematological parameters and clinical data were obtained from the public database, GSE77343. Differentially expressed genes (DEGs) were identified, and Gene Ontology and pathway enrichment analyses were performed. The protein­protein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes along with Cytoscape. Receiver operating characteristic curves for predictive power, sensitivity and specificity were constructed. The present study identified specific associated DEGs by using Pearson linear correlation and logistic regression analysis. A mean NLR of 3.96 was determined as the cutoff value in the analysis. In total, 31 genes were initially identified as DEGs associated with elevated NLR. They were mainly enriched in neutrophil activation and neutrophil mediated immunity, in fluid shear stress and atherosclerosis, and transcriptional misregulation in cancer. Three focused DEGs, solute carrier family 22 member 4 (SLC22A4), interleukin­1 receptor 2 (IL1R2) and vanin 3 (VNN3), were finally revealed to be independently associated with elevated NLR in CHF patients. The present study demonstrated that the three genes SLC22A4, IL1R2 and VNN3 may be independently associated with elevated NLR in CHF patients as potential decisive factors of NLR.

Association between ERCC2 rs13181 polymorphism and ovarian cancer risk: an updated meta-analysis with 4024 subjects.

BACKGROUND: Genetic variants in the excision repair cross-complimentary group 2 (ERCC2) gene may affect individual susceptibility to cancer by modulating the capability of DNA damage repair. However, the current studies concerning the association of ERCC2 rs13181 polymorphism with ovarian cancer risk provided inconsistent evidence. METHODS: This study was to quantitatively summarize the evidence from the individual studies electronically retrieved by a meta-analysis. RESULTS: Totally, nine eligible case-control studies with 1333 cases and 2691 controls were included for the concerned association. Overall, a significant association between ERCC2 gene rs13181 polymorphism and increased risk of ovarian cancer was revealed (CC+AC vs. AA: OR 1.44, 95% CI 1.11-1.86; CC vs. AA: OR 2.12, 95% CI 1.14-3.97). Similarly, in the subgroup analyses, such association was also evident in non-Caucasian population and hospital-based studies. Noteworthily, the recombined analysis with a significant decrease in between-heterogeneity represented a significant association of the variant with increased risk of ovarian cancer after excluding the individual study not in agreement with HWE. CONCLUSION: The present study suggests that the ERCC2 gene rs13181 polymorphism might be associated with increased risk of ovarian cancer.

Overexpression of Pofut1 and activated Notch1 may be associated with poor prognosis in breast cancer.

PURPOSE: The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. RESULTS: Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage(p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade(p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. CONCLUSION: Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer.

Elevated YKL-40 expression is associated with a poor prognosis in breast cancer patients.

Numerous studies have investigated the prognostic role of YKL-40 in breast cancer, but yielded inconsistent results. To derive a more precise evaluation, relevant publications assessing the association between YKL-40 expression and clinical outcome of breast cancer patients were electronically searched and identified. A combined analysis of included studies was performed using fixed- or random-effect model to calculate the pooled hazard ratio (HR) or odds ratio(OR) and 95% confidence interval (95%CI) for the assessment of the association. Ten eligible studies involving 1250 patients were ultimately included in the meta-analysis. Overall, the pooled analysis showed that elevated YKL-40 expression was significantly associated with a poor overall survival(OS: HR=1.48, 95%CI= 1.11-1.97) and disease-free survival(DFS: HR=1.51, 95%CI= 1.10-2.07). The subgroup analysis by detection methods revealed an unfavorable OS in breast cancer patients with elevated YKL-40 expression evaluated by IHC(HR=1.39, 95%CI=1.12-1.71) but not by ELISA/RIA. Also, the stratification analysis by ethnicity showed a significant association between increased YKL-40 expression and shorter OS of breast cancer patients in western population(HR=1.51, 95%CI=1.03-2.21) as well as Asian population (HR=1.40, 95%CI= 1.05-1.86). Similarly, the subgroup analysis by detection methods revealed a significantly inferior DFS in breast cancer patients with increased YKL-40 expression disregarding the use of IHC(HR=2.02, 95%CI=1.47-2.79) or ELISA/RIA(HR=1.06, 95%CI= 1.02 -1.10). Additionally, increased YKL-40 expression was found to significantly correlate with larger tumor size (OR=2.38, 95%CI=1.41-4.05).The present meta-analysis indicate that elevated YKL-40 expression is associated with a poor prognosis in breast cancer patients. YKL-40 may serve as a promising predictive biomarker of prognosis of breast cancer.

Associations between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer: a meta-analysis of 39,736 subjects.

BACKGROUND: Previous studies have investigated the associations between the common polymorphisms in FAS/FASL genes and lung cancer risk; however, the results remain inconsistent and inconclusive. Hence, we performed a meta-analysis to reassess the relationships between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer. METHODS: Eligible studies retrieved by an electronic search were pooled to calculate the strength of the associations using the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: A total of 13 case-control studies involving 39,736 subjects (9,237 cases and 10,838 controls on FAS rs2234767 and 8,957 cases and 10,704 controls on FASL rs763110) were included in the meta-analysis. The results showed a significant association between FAS rs2234767 polymorphism and increased risk of lung cancer (A vs G: OR =1.07, 95% CI =1.01-1.13; AA vs GG: OR =1.23, 95% CI =1.06-1.43; AA vs GA + GG: OR =1.24, 95% CI =1.08-1.43). Similar association was also observed in Asian population (AA vs GA + GG: OR =1.30, 95% CI =1.01-1.67) and in the studies with large sample size (A vs G: OR =1.07, 95% CI =1.00-1.14; AA vs GG: OR =1.30, 95% CI =1.07-1.58). However, no significant association between FASL rs763110 polymorphism and lung cancer risk was found other than in the Asian population (CC vs TC + TT: OR =1.35, 95% CI =1.01-1.80). CONCLUSION: The meta-analysis indicated that FAS rs2234767 polymorphism was significantly associated with an increased risk of lung cancer and FASL rs763110 polymorphism may not contribute to susceptibility to lung cancer other than in Asian population.

Metformin therapy associated with survival benefit in lung cancer patients with diabetes.

The purpose of this study is to summarize the currently available evidence regarding the concerned issue by performing a comprehensive meta-analysis. Relevant publications reporting the association of metformin use with survival of lung cancer patients with diabetes were electronically searched to identify eligible studies. The meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures for disease-free survival(DFS) and overall survival(OS) estimates. A total of 17 individual studies from 10 publications were included in the meta-analysis. Overall, the results revealed a significant association of metformin use with a better survival of lung cancer patients with diabetes(for DFS: HR = 0.65, 95%CI = 0.52-0.83; for OS: HR = 0.78, 95%CI = 0.64-0.93). The subgroup analyses showed similar association in Asian region(for DFS:HR = 0.69, 95%CI = 0.59-0.80; for OS: HR = 0.55, 95%CI = 0.46-0.67) but not in Western region. Such association was also presented in small cell lung cancer (for DFS: HR = 0.54, 95%CI = 0.38-0.77; for OS: HR = 0.52, 95%CI = 0.39-0.69) and in non-small cell lung cancer(for DFS: HR = 0.70, 95%CI = 0.51-0.96; for OS: HR = 0.75, 95%CI = 0.58- 0.97). Analyses stratified by treatment strategy showed a reduction in the risk of cancer-related mortality in patients receiving chemotherapy(for DFS: HR = 0.71, 95%CI = 0.64-0.83; for OS: HR = 0.58, 95%CI = 0.47-0.71) but not in patients receiving chemoradiotherapy. The meta-analysis demonstrated that metformin use was significantly associated with a favorable survival outcome of lung cancer patients with diabetes.

Elevated red cell distribution width contributes to a poor prognosis in patients with esophageal carcinoma.

BACKGROUND: The red cell distribution width (RDW) has also been reported to reliably reflect the inflammation and nutrition status and predict the prognosis across several types of cancer, however, the prognostic value of RDW in esophageal carcinoma has seldom been studied. METHODS: A retrospective study was performed to assess the prognostic value of RDW in patients with esophageal carcinoma by the Kaplan-Meier analysis and multivariate Cox regression proportional hazard model. All enrolled patients were divided into high RDW group (≧15%) and low RDW group (<15%) according to the detected RDW values. RESULTS: Clinical and laboratory data from a total of 179 patients with esophageal carcinoma were retrieved. With a median follow-up of 21months, the high RDW group exhibited a shorter disease-free survival (DFS) (p<0.001) and an unfavorable overall survival (OS) (p<0.001) in the univariate analysis. The multivariate analysis revealed that elevated RDW at diagnosis was an independent prognostic factor for shorter PFS (p=0.043, HR=1.907, 95% CI=1.020-3.565) and poor OS (p=0.042, HR=1.895, 95% CI=1.023-3.508) after adjustment with other cancer-related prognostic factors. CONCLUSION: The present study suggests that elevated preoperative RDW(≧15%) at the diagnosis may independently predict poorer disease-free and overall survival among patients with esophageal carcinoma.

Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies.

The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian.

Clinicopathological and prognostic role of SIRT1 in breast cancer patients: a meta-analysis.

BACKGROUND: Silent mating type information regulation 2 homolog-1 (SIRT1) plays an important role in the progression and development of cancer, including breast cancer. However, the association between SIRT1 expression and clinicopathological parameters and prognosis in breast cancer remains inconclusive. To accurately evaluate the significance of SIRT1 expression in breast cancer, a meta-analysis based on published studies was performed. METHODS: The PubMed, Embase, ISI Web of Science, Science Direct, and Chinese National Knowledge Infrastructure databases were screened to retrieve relevant literature. The reported odds ratios (ORs) and hazard ratios (HRs) and their 95% corresponding confidence intervals (CIs) were pooled to estimate the strength of specific associations. RESULTS: Six studies involving 604 patients were included in the meta-analysis. The pooled analyses showed a significant correlation between SIRT1 expression and poor disease-free survival (DFS) (HR = 3.07, 95% CI: 1.92-4.91, Z = 4.69, P < 0.001) and overall survival (OS) (HR = 3.94, 95% CI: 2.19-7.10, Z = 4.57, P < 0.001). SIRT1 expression also significantly correlated with high TNM stage (pooled OR = 2.92, 95% CI: 1.84-4.63) and lymph node metastasis (pooled OR = 3.22, 95% CI: 0.98-10.57). CONCLUSIONS: Our meta-analysis shows that SIRT1 expression correlates with unfavorable clinical outcomes. We suggest that SIRT1 expression may have potential value in the pathological diagnosis and clinical treatment of patients with breast cancer. More studies are warranted to investigate the effect of SIRT1 on the survival of breast cancer patients.