Causal associations between dietary factors and colorectal cancer risk: a Mendelian randomization study

BackgroundPrevious epidemiological studies have found a link between colorectal cancer (CRC) and human dietary habits. However, the inherent limitations and inevitable confounding factors of the observational studies may lead to the inaccurate and doubtful results. The causality of dietary factors to CRC remains elusive.MethodsWe conducted two-sample Mendelian randomization (MR) analyses utilizing the data sets from the IEU Open GWAS project. The exposure datasets included alcoholic drinks per week, processed meat intake, beef intake, poultry intake, oily fish intake, non-oily fish intake, lamb/mutton intake, pork intake, cheese intake, bread intake, tea intake, coffee intake, cooked vegetable intake, cereal intake, fresh fruit intake, salad/raw vegetable intake, and dried fruit intake. In our MR analyses, the inverse variance weighted (IVW) method was employed as the primary analytical approach. The weighted median, MR-Egger, weighted mode, and simple mode were also applied to quality control. Heterogeneity and pleiotropic analyses were implemented to replenish the accuracy of the results.ResultsMR consequences revealed that alcoholic drinks per week [odds ratio (OR): 1.565, 95% confidence interval (CI): 1.068–2.293, p = 0.022], non-oily fish intake (OR: 0.286; 95% CI: 0.095–0.860; p = 0.026), fresh fruit intake (OR: 0.513; 95% CI: 0.273–0.964; p = 0.038), cereal intake (OR: 0.435; 95% CI: 0.253–0.476; p = 0.003) and dried fruit intake (OR: 0.522; 95% CI: 0.311–0.875; p = 0.014) was causally correlated with the risk of CRC. No other significant relationships were obtained. The sensitivity analyses proposed the absence of heterogeneity or pleiotropy, demonstrating the reliability of the MR results.ConclusionThis study indicated that alcoholic drinks were associated with an increased risk of CRC, while non-oily fish intake, fresh fruit intake, cereal intake, and dried fruit were associated with a decreased risk of CRC. This study also indicated that other dietary factors included in this research were not associated with CRC. The current study is the first to establish the link between comprehensive diet-related factors and CRC at the genetic level, offering novel clues for interpreting the genetic etiology of CRC and replenishing new perspectives for the clinical practice of gastrointestinal disease prevention

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Comparison between Endoscopic Submucosal Dissection and Surgery in Gastric Cancer: A Systematic Review and Meta-Analysis

Aims. There are two treatment modalities for early gastric cancer (EGC)—surgery and endoscopic submucosal dissection (ESD). We aimed to compare the safety and efficacy of ESD with surgery. Method. The article was performed by searching PubMed databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) calculated and P value. Results. 13 studies were identified. The incidence of perforation in two groups was different [OR = 6.18 (95% CI: 1.37–27.98), P=0.02]. The prevalences of synchronous and metachronous cancer in the ESD group were higher than those in the surgery group [OR = 8.52 (95% CI: 1.99–36.56), P = 0.004 and OR = 7.15 (95% CI: 2.95–17.32), P<0.0001]. The recurrence and complete resection rates were different [OR = 6.93 (95% CI: 2.83–16.96), P<0.0001 and OR = 0.32 (95% CI: 0.20–0.52), P<0.00001]. Compared with the surgery group, the hospital stay was shorter [IV = −7.15 (95% CI: −9.08–5.22), P<0.00001], the adverse event rate was lower, and the quality of life (QOL) was better in the ESD group. The difference of bleeding was not found. Conclusion. ESD appears to be preferable for EGC, due to a lower rate of adverse events, shorter hospital stay, cheaper cost, and higher QOL

Systematic genome editing of the genes on zebrafish Chromosome 1 by CRISPR/Cas9

Genome editing by the well-established CRISPR/Cas9 technology has greatly facilitated our understanding of many biological processes. However, a complete whole-genome knockout for any species or model organism has rarely been achieved. Here, we performed a systematic knockout of all the genes (1333) on Chromosome 1 in zebrafish, successfully mutated 1029 genes, and generated 1039 germline-transmissible alleles corresponding to 636 genes. Meanwhile, by high-throughput bioinformatics analysis, we found that sequence features play pivotal roles in effective gRNA targeting at specific genes of interest, while the success rate of gene targeting positively correlates with GC content of the target sites. Moreover, we found that nearly one-fourth of all mutants are related to human diseases, and several representative CRISPR/Cas9-generated mutants are described here. Furthermore, we tried to identify the underlying mechanisms leading to distinct phenotypes between genetic mutants and antisense morpholino-mediated knockdown embryos. Altogether, this work has generated the first chromosome-wide collection of zebrafish genetic mutants by the CRISPR/Cas9 technology, which will serve as a valuable resource for the community, and our bioinformatics analysis also provides some useful guidance to design gene-specific gRNAs for successful gene editing