Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study.

BACKGROUND: Metabolic disorders are a hallmark feature of cancer. However, the evidence for the causality of circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed a two-sample Mendelian randomization (MR) analysis to assess the causality from genetically proxied 486 blood metabolites to CRC. METHODS: Genome-wide association study (GWAS) data for exposures were extracted from 7824 Europeans GWAS on metabolite levels. GWAS data for CRC from the GWAS catalog database GCST012879 were used for the preliminary analysis. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and weighted median as complementary analyses. Cochran Q test, MR-Egger intercept test, MR-PRESSO, Radial MR, and leave-one-out analysis were used for sensitivity analyses. For significant associations, additional independent CRC GWAS data GCST012880 were used for replication analysis and meta-analysis. For the final identification of metabolites, Steiger test, linkage disequilibrium score regression, and colocalization analysis were performed for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on CRC. RESULTS: The results of this study indicated significant associations between six metabolites pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32-0.77, p = 0.002), 1,6-anhydroglucose (OR: 1.33, 95% CI: 1.11-1.59, p = 0.002), nonadecanoate (19:0) (OR: 0.40, 95% C I:0.4-0.68, p = 0.0008), 1-linoleoylglycerophosphoethanolamine (OR: 0.47, 95% CI: 0.30-0.75, p = 0.001), 2-hydroxystearate (OR: 0.39, 95% CI: 0.23-0.67, p = 0.0007), gamma-glutamylthreonine (OR: 2.14, 95% CI: 1.02-4.50, p = 0.040) and CRC. MVMR analysis revealed that genetically predicted pyruvate, 1-linoleoylglycerophosphoethanolamine and gamma-glutamylthreonine can directly influence CRC independently of other metabolites. CONCLUSION: The current work provides evidence to support the causality of the six circulating metabolites on CRC and a new perspective on the exploration of the biological mechanisms of CRC by combining genomics and metabolomics. These findings contribute to the screening, prevention and treatment of CRC.

Processed meat, red meat, white meat, and digestive tract cancers: A two-sample Mendelian randomization study.

Background: Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods: Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results: The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07-4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14-13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions: Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.

Improvement of Early Death in Acute Promyelocytic Leukemia: A Population-Based Analysis.

BACKGROUND: Early death is a major factor of treatment failure in acute promyelocytic leukemia (APL), however, the recent trends in the incidence of early death based on the population-level are not clear. Hence, this study is aimed at describing the incidence, recent trends, causes and characteristics of early death in APL based on the real world. MATERIALS AND METHODS: APL patients diagnosed from 1986 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) dataset were enrolled, and categorized based on gender, age, year of diagnosis, race, marital status, resident county and socioeconomic status (SES). The risk factors for all-cause and acute myelocytic leukemia (AML) specific early death were determined by univariate and multivariate logistic regression analyses, and stratified analysis was conducted by age. RESULTS: Overall, 3212 APL patients were included in analysis between 1986 and 2015, of which a total of 683 (21.3%) patients were noted for early death. Significant differences were recognized for patient distribution by age, year of diagnosis, marital status, and SES. The early death rate of APL patients diagnosed during 2006-2015 was significantly lower than that of the early stage, but this trend was not evident in juvenile patients. At the same time, older age, and lower SES score were independent risk factors for early death in the multivariate analysis. CONCLUSION: We established that the early death trend in APL has decreased over the past few years, but the early death rate remains high, especially in older patients and those with lower SES.

Tanshinone IIa Induces Autophagy and Apoptosis via PI3K/Akt/mTOR Axis in Acute Promyelocytic Leukemia NB4 Cells.

Tanshinone IIa (TanIIa), an ingredient of Radix Salviae Miltiorrhizae, has an anticancer effect on various solid tumors with high efficiency and low toxicity. Nonetheless, the underlying role of TanIIa in acute promyelocytic leukemia (APL) remains unclear. Here, we revealed that TanIIa drastically inhibited NB4 cell viability with an IC50 value of 31.25 µmol/L. Using flow cytometry apoptosis assay, we identified that TanIIa dose-dependently exacerbated NB4 cell apoptosis. Mechanistically, TanIIa upregulated apoptotic factor levels, namely, cleaved-caspase 9, cleaved-caspase 3, and cleaved-PARP-1. Moreover, we noticed that TanIIa dose-dependently suppressed the PI3K/Akt/mTOR axis. This axis not only functions as an essential antiapoptotic modulator but also serves as a suppressant regulator of autophagy. Correspondingly, we detected the levels of autophagic marker, namely, LC3B, which were increased after the TanIIa treatment. Furthermore, the autophagy inhibitor Baf-A1 could effectively reverse the TanIIa-induced apoptosis, manifesting that TanIIa eliminated NB4 cells in an autophagy-dependent manner. In conclusion, tanshinone IIa exerts anti-APL effects through triggering autophagy and apoptosis in NB4 cells.

Oral herbal medicine for women with intrahepatic cholestasis in pregnancy: a systematic review of randomized controlled trials.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication whose range has been calculated to be between 0.01 and 15.6% all around the world. We wanted to systematically evaluate the effect and safety of oral herbal medicine on treatment for ICP. METHODS: Details of the methods could be found in the registered protocol on PROSPERO (CRD42018096013). Trials assessing the effectiveness of herbal medicine for ICP were searched from seven electronic databases from inception to 28th February 2020. RevMan 5.3 software was used to perform all statistical analysis. Meta-analysis, additional analysis, Trial Sequential Analysis (TSA) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were conducted if data permitted. RESULTS: Totally 43 randomized controlled trials with 3556 patients were included. Meta-analysis showed potential good adjunctive effect of herbal medicine on decreasing the pruritus scores (MD -0.58, 95% CI - 0.79 to - 0.36), the serum TBA scores (MD - 3.99 µmol/L, 95% CI - 4.24 to - 3.74) on the basis with Ursodesoxycholic acid. Compared to the medicine alone, significantly lower incidence of fetal distress (RR 0.41, 95% CI 0.32 to 0.51), asphyxia neonatorum (RR 0.35, 95%CI 0.25 to 0.49), cesarean section (RR 0.73, 95% CI 0.63 to 0.85), postpartum hemorrhage (RR 0.45, 95% CI 0.28 to 0.72) were observed in the combination group. But the comparison between herbal medicine and medicine showed inconsistent results among trials. Insufficient information could be used to evaluate the safety of herbal medicine for ICP. CONCLUSION: This review found the current evidence may support the effectiveness of combination of herbal medicine and conventional medicine for decreasing the maternal pruritus scores, the serum TBA, and the number of fetal distress, or asphyxia neonatorum events related to this condition (which was supported by TSA results). Since there were obvious statistical and clinical heterogeneity among trials, and the methodological quality of the included studies was poor, the level of the evidence could only be defined as "very low" according to the GRADE criteria. Further high quality studies are still needed to testify the effectiveness and safety of herbal medicine for ICP.