High intake of cruciferous vegetables reduces the risk of gastrointestinal cancers: results from observational studies.

The relationship between cruciferous vegetables (CV) and the risk of gastrointestinal (GI) cancers has been extensively investigated. However, epidemiologic investigations have produced inconsistent results. This meta-analysis investigated the association between CV intake and the risk of GI cancers. Due to the heterogeneity, fixed- or random-effects models were used for the analyses. The final analysis included 81 articles covering 89 studies. In comparison to the lowest consumption categories, the highest consumption categories of CV were associated with a lower risk for all GI cancers [rate ratio (RR): 0.81, 95% confidence interval (95% CI) 0.76-0.87]. Compared to a CV intake of 75 g/day, subjects with CV intake <75 g/day experienced a 7% reduction in risk (RR: 0.93; 95% CI: 0.84-0.96) for each 50 g increase in consumption. A negative correlation was identified between CV intake and the risk of esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer (CRC), but not gallbladder cancer (RR: 0.70; 95% CI: 0.38-1.27). High intake of broccoli and cabbage was associated with a decreased risk of gastric cancer (RR: 0.64; 95% CI: 0.47-0.87) and gallbladder cancer (RR: 0.46; 95% CI: 0.29-0.75). These results confirm the association between high intake of CV with a reduced risk of GI cancers.

Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients.

Improved diagnostic and treatment methods are needed for chronic graft-versus-host disease (cGVHD), the leading cause of late nonrelapse mortality (NRM) in long-term survivors of allogenic hematopoietic cell transplantation. Validated biomarkers that facilitate disease diagnosis and classification generally are lacking in cGVHD. Here, we conducted whole serum proteomics analysis of a well-established murine multiorgan system cGVHD model. We discovered 4 upregulated proteins during cGVHD that are targetable by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8, and CCL9 chemokines. Donor T cells lacking CRK/CRKL prevented the generation of cGVHD, germinal center reactions, and macrophage infiltration seen with wild-type T cells. Whereas antibody blockade of CCL8 or CXCL7 was ineffective in treating cGVHD, CCL9 blockade reversed cGVHD clinical manifestations, histopathological changes, and immunopathological hallmarks. Mechanistically, elevated CCL9 expression was present predominantly in vascular smooth muscle cells and uniquely seen in cGVHD mice. Plasma concentrations of CCL15, the human homolog of mouse CCL9, were elevated in a previously published cohort of 211 cGVHD patients compared with controls and associated with NRM. In a cohort of 792 patients, CCL15 measured at day +100 could not predict cGVHD occurring within the next 3 months with clinically relevant sensitivity/specificity. Our findings demonstrate for the first time the utility of preclinical proteomics screening to identify potential new targets for cGVHD and specifically CCL15 as a diagnosis marker for cGVHD. These data warrant prospective biomarker validation studies.

Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors.

Glioblastoma multiforme (GBM) is the most aggressive and common kind of primary brain tumor in adults, and is thought to be driven by a subpopulation of glioma stem cells (GSCs). GSCs reside in a specialized hypoxic niche, which can regulate the tumorigenic capacity of GSCs primarily through the hypoxia-inducible factors (HIFs), HIF1α and HIF2α. ZNF217 is an oncogene frequently amplified in many kinds of tumors. It is associated with aggressive tumor behavior and poor clinical prognosis, but its role in gliomas is poorly known. Gene expression and copy number analysis from TCGA data reveal that ZNF217 is amplified in 32% and overexpressed in 71.2% of GBMs. Quantitative RT-PCR and western blotting of a cohort of glioma samples showed that ZNF217 was highly expressed in gliomas and increased with tumor grade. Analysis of a molecular database demonstrated that ZNF217 expression correlated with poor survival of glioma patients. Investigation of ZNF217 expression in GSCs, non-GSCs and normal neural stem cells (NSCs) indicated that ZNF217 was more highly expressed in GSCs than in non-GSCs and NSCs. Knockdown of ZNF217 in GSCs by small-interfering RNA (siRNA) inhibited their growth and promoted their differentiation. Interestingly, ZNF217 was upregulated in GSCs and the GBM cell line U87 when exposed to the hypoxic environment of 1% oxygen. Knockdown of either HIF1α or HIF2α, which has a central role in the hypoxia-induced responses of these cells, inhibited ZNF217 expression. In addition, ZNF217 upregulation was compromised under hypoxia in U87 and GSCs when either HIF1α or HIF2α was targeted by siRNA. HIF2α knockdown inhibited ZNF217 expression more efficiently in both normoxia and hypoxia than HIF1α knockdown. Therefore, ZNF217 is overexpressed in GBMs and contributes to the maintenance of GSCs, which is regulated by HIFs released by the hypoxic environment of the tumor.

Contribution of the polymorphism rs1800469 of transforming growth factor ß in the development of myocardial infarction: meta-analysis of 5460 cases and 8413 controls (MOOSE-compliant article).

Studies investigating the association between transforming growth factor (TGF-ß-509C/T, rs1800469) promoter polymorphism and myocardial infarction (MI) risk reported inconsistent results. The aim of our study was to assess the association between the 509C/T polymorphism of the TGF-ß gene (rs1800469) and MI risk.A total of 5460 cases and 8413 controls in 7 case-control studies were incorporated in our current meta-analysis. The original studies were selected through searching the databases of the PubMed and EMBASE. The odds ratio (OR) and 95% confidence interval (95% CI) of TGF-ß 509C/T (rs1800469) for MI risk were applied to estimate the strength of the association.Our results showed that T allele carriers had a 13% increased risk of MI, when compared with the C allele carriers (OR = 1.13, 95% CI: 1.00-1.27). In the subset analysis by the type of MI, significantly elevated risk of MI was associated with the homozygote TT and heterozygote C/T in no-AMI subjects, when compared with the CC homozygote carriers (OR = 1.12, 95% CI:1.02-1.23).Our meta-analysis shows that the polymorphism with homozygote TT and heterozygote C/T of TGF-ß 509C/T (rs1800469) is significantly associated with the increased risk of MI.

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.

CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia.

BACKGROUND: A proportion of glioblastoma stemlike cells (GSCs) expressing endothelial cell marker CDH5 (vascular-endothelial-cadherin or CD144) can transdifferentiate into endothelial cells and form blood vessels. However, the implications of CDH5 expression in gliomas and how it is regulated in GSCs remain to be clarified. METHODS: The mRNA and protein levels of CDH5 were detected in glioma samples and cultured cell lines, and the prognostic value of the CDH5 expression level for GBM patients was evaluated. Bioinformatics analysis was performed to reveal the potential functional roles of CDH5 in glioblastoma multiforme. Gene knockdown induced by short hairpin RNA, chromatin immunoprecipitation analysis, and a vasculogenic tube formation assay were performed to investigate the relationships among hypoxia, CDH5 expression level, and angiogenesis. RESULTS: CDH5 was overexpressed in gliomas, correlated with tumor grades, and was an independent adverse prognostic predictor for glioblastoma multiforme patients. CDH5 was specifically activated in GSCs but not in non-GSCs or neural stem cells, and CDH5(+) cells could produce xenografts in immunocompromised mice. Bioinformatics analysis demonstrated that CDH5 might interact directly with hypoxia-inducible factor (HIF)2α. CDH5 expression was significantly upregulated in GSCs, but not in non-GSCs or normal neural stem cells, under a 1% O2 condition. Both HIF1α and HIF2α positively regulated CDH5 level in GSCs and could bind to the promoter of CDH5. Furthermore, CDH5 contributed to the vasculogenic mimicry of GSCs, especially under hypoxic conditions. CONCLUSIONS: The specific expression of CDH5 in GSCs may contribute to GSC-derived neovasculogenesis in glioblastoma multiforme, especially under hypoxic conditions, revealing novel tumorigenic mechanisms contributed by GSCs.