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her parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context.

EU Clinical trials register EudraCT Nb 2020-001614-38 . Registered on 22 April 2020.

EU Clinical trials register EudraCT Nb 2020-001614-38 . Registered on 22 April 2020.

Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer’s disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.

Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.

There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P > 0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs), and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR) = 0.959, 95% confidence interval (CI) = 0.941-0.977, P = 3.92 × 10

] and overall use of AHMs (OR = 0.961, 95% CI = 0.944-0.978, P = 5.74 × 10

, SNPs = 52) were associated with a lower risk of AD. Epigenetics inhibitor No notable heterogeneity and directional pleiotropy were identified (all P > 0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.

This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.

This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.

The pathogenic BRCA1/2 germline mutations contributed to Hereditary Breast and Ovarian Cancer (HBOC) susceptibility. The features of BRCA1/2 germline mutations in non-small cell lung cancer (NSCLC) have not been systematically studied. Here we performed the first study investigating the characteristics of pathogenic BRCA1/2 germline mutations in Chinese NSCLC patients and compared them with those from Chinese HBOC.

Information on BRCA1/2 germline mutations from 9010 Chinese NSCLC patients were collected from available studies and analyzed, and compared with the BRCA1/2 germline mutations from Chinese HBOC BRCA1/2 database (LOVD database, 20,523 patients).

19 (20 carriers, 0.22 %) pathogenic BRCA1 and 60 (66 carriers, 0.73 %) pathogenic BRCA2 germline mutations from NSCLC were identified. The carrier frequency of BRCA1/2in Chinese NSCLC patients (86/9010 = 0.95 %) was significantly lower than that in Chinese breast and ovary cancer patients (1481/20,523 = 7.2 %) (P < 0.001). We found that frameshift an HBOC, higher ratio of nonsense mutations and carriers than HBOC, and novel BRCA1/2 germline mutations never found in HBOC.

tRNA-derived small RNAs (tDRs), which are widely distributed in human tissues including blood and urine, play an important role in the progression of cancer. However, the expression of tDRs in colorectal cancer (CRC) plasma and their potential diagnostic values have not been systematically explored.

The expression profiles of tDRs in plasma of CRC and health controls (HCs) are investigated by small RNA sequencing. The level and diagnostic value of 5′-tRF-GlyGCC are evaluated by quantitative PCR in plasma samples from 105 CRC patients and 90 HCs. The mechanisms responsible for biogenesis of 5′-tRF-GlyGCC are checked by in vitro and in vivo models.

5′-tRF-GlyGCC is dramatically increased in plasma of CRC patients compared to that of HCs. The area under curve (AUC) for 5′-tRF-GlyGCC in CRC group is 0.882. The combination of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) with 5′-tRF-GlyGCC improves the AUC to 0.926. Consistently, the expression levelsof 5′-tRF-GlyGCC in CRC cells and xenograft tissues are significantly greater than that in their corresponding controls. Blood cells co-cultured with CRC cells or mice xenografted with CRC tumors show increased levels of 5′-tRF-GlyGCC. In addition, we find that the increased expression of 5′-tRF-GlyGCC is dependent onthe upregulation of AlkB homolog 3 (ALKBH3), a tRNA demethylase which can promote tRNA cleaving to generate tDRs.

The level of 5′-tRF-GlyGCC in plasma is a promising diagnostic biomarker for CRC diagnosis.

The level of 5′-tRF-GlyGCC in plasma is a promising diagnostic biomarker for CRC diagnosis.Intelligence predicts important life and health outcomes, but the biological mechanisms underlying differences in intelligence are not yet understood. The use of genetically determined metabotypes (GDMs) to understand the role of genetic and environmental factors, and their interactions, in human complex traits has been recently proposed. However, this strategy has not been applied to human intelligence. Here we implemented a two-sample Mendelian randomization (MR) analysis using GDMs to assess the causal relationships between genetically determined metabolites and human intelligence. The standard inverse-variance weighted (IVW) method was used for the primary MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Using 25 genetic variants as instrumental variables (IVs), our study found that 5-oxoproline was associated with better performance in human intelligence tests (PIVW = 9.25 × 10-5). The causal relationship was robust when sensitivity analyses were applied (PMR-Egger = 0.0001, PWeighted median = 6.29 × 10-6, PMR-PRESSO = 0.0007), and repeated analysis yielded consistent result (PIVW = 0.0087). Similarly, also dihomo-linoleate (202n6) and p-acetamidophenylglucuronide showed robust association with intelligence. Our study provides novel insight by integrating genomics and metabolomics to estimate causal effects of genetically determined metabolites on human intelligence, which help to understanding of the biological mechanisms related to human intelligence.