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Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER +ve ) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.

Significance Because obese people are at an increased risk of many age-related diseases, it is a plausible hypothesis that obesity increases the biological age of some tissues and cell types. However, it has been difficult to detect such an accelerated aging effect because it is unclear how to measure tissue age. Here we use a recently developed biomarker of aging (known as “epigenetic clock”) to study the relationship between epigenetic age and obesity in several human tissues. We report an unexpectedly strong correlation between high body mass index and the epigenetic age of liver tissue. This finding may explain why obese people suffer from the early onset of many age-related pathologies, including liver cancer. Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an “epigenetic clock”) to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver ( r = 0.42, P = 6.8 × 10 ⁻⁴ in dataset 1 and r = 0.42, P = 1.2 × 10 ⁻⁴ in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10 ⁻⁹) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2 . Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world 1 , 2 , 3 . We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 ( P = 1.03 × 10 −9 ) and TM6SF2 ( P = 7.89 × 10 −10 ) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis ( P = 1.54 × 10 −48 ) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients’ sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Background The group of colorectal cancer (CRC) survivors continues to grow worldwide. Understanding health-related quality of life (HRQOL) determinants and consequences of HRQOL impairments in long-term CRC survivors may help to individualize survivorship care plans. We aimed to i) examine the HRQOL status of CRC long-term survivors, ii) identify cross-sectional sociodemographic and clinical correlates of HRQOL, and iii) investigate the prospective association of HRQOL after CRC diagnosis with all-cause mortality. Methods We assessed HRQOL within a Northern German cohort of 1294 CRC survivors at a median of 6 years after CRC diagnosis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Cross-sectional correlates of different HRQOL dimensions were analyzed using multivariable-adjusted logistic regression models with HRQOL as a binary variable. With multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) of all-cause mortality were estimated per 10-point-increments of an HRQOL summary score, a global quality of life scale, and HRQOL functioning and symptom domains. Results The median HRQOL summary score was 87 (interquartile range: 75–94). Sex, age, education, tumor location, metastases, other cancers, type of therapy, and current stoma were identified as correlates of different HRQOL scales. After a median follow-up time of 7 years after HRQOL assessment, 175 participants had died. Nearly all HRQOL domains, except for cognitive functioning and diarrhea, were significantly associated with all-cause mortality. A 10-point-increment in the summary score decreased the risk of death by 24% (HR: 0.76; 95% CI: 0.70–0.82). Conclusions HRQOL in CRC survivors appeared to be relatively high in the long term. Various clinical and sociodemographic factors were cross-sectionally associated with HRQOL in long-term CRC survivors. Lower HRQOL was associated with increased all-cause mortality. Individualized healthcare programs for CRC survivors (including psychosocial screening and interventions) are needed to detect decreased HRQOL and to further improve long-term HRQOL and survival.

A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver. Spatial mapping of genomic programs in tissue cells is an important step in the understanding of organ function and disease. Here, the authors provide a spatially resolved epigenomic and transcriptomic map of human liver and show porto-central gradients in metabolic and morphogen networks and transcription factor binding sites as a basis to better understand liver regeneration and function.

Purpose: Aim of this study was to investigate the association between postdiagnosis body mass index (BMI) and all-cause mortality in colorectal cancer (CRC) survivors in a prospective study and meta-analysis. Methods: We conducted a prospective cohort study on 2,143 CRC survivors in Germany. Participants were recruited to the study on average 4 years after diagnosis, and postdiagnosis BMI was assessed at recruitment using a self-administered questionnaire. CRC survivors were followed up for a mean time of 3.5 years. The association between BMI and all-cause mortality was investigated using multivariable Cox proportional hazards models. Additionally, we performed a meta-analysis of studies on postdiagnosis BMI and all-cause mortality (n = 5, including this study) by applying random-effects models. Results: In the prospective analysis, 349 participants died. BMI was not statistically significantly associated with all-cause mortality. Compared to normal weight survivors, the hazard ratios (HRs) [95 % confidence interval (CI)] for all-cause mortality in underweight, overweight and obese survivors were 1.65 (0.79–3.45), 0.80 (0.62–1.03) and 0.84 (0.62–1.14), respectively. In the meta-analysis, individuals with underweight were at increased risk for all-cause mortality [HR (95 % CI) 1.72 (1.18–2.49)], whereas individuals with overweight had a lower risk [HR (95 % CI) 0.79 (0.71–0.88)], compared to normal weight subjects. For obesity, the risk of mortality was also reduced with only borderline significance [HR (95 % CI) 0.88 (0.77–1.00)]. Conclusions: While the present study as well as single previously published studies showed that overweight was associated with a non-significant reduced risk for all-cause mortality, our meta-analysis indicated a decreased mortality risk among overweight CRC survivors.

Background Anastomotic leakage after esophagectomy is a life-threatening complication. No comparative outcome analyses for the different treatment regimens are yet available. Methods In a single-center study, data from all esophagectomy patients from January 1995 to January 2012, including tumor characteristics, surgical procedure, postoperative anastomotic leakage, leakage therapy regimens, APACHE II scores, and mortality, were collected, and predictors of patient survival after anastomotic leakage were analyzed. Results Among 366 resected patients, 62 patients (16 %) developed an anastomotic leak, 16 (26 %) of whom died. Therapy regimens included surgical revision ( n  = 18), endoscopic endoluminal vacuum therapy ( n  = 17), endoscopic stent application ( n  = 12), and conservative management ( n  = 15). APACHE II score at the initiation of treatment for leakage was the strongest predictor of in-hospital mortality ( p  < 0.0017). Conservatively managed patients showed mild systemic illness (mean APACHE II score 5) and no mortality. In systemically ill patients matched for APACHE II scores (mean, 14.4), endoscopic endoluminal vacuum therapy patients had lower mortality (12 %) compared to surgically treated (50 %, p  = 0.01) cases and patients managed by stent placement (83 %, p  = 00014, log rank test). No other clinical or laboratory parameters significantly influenced patient survival. Conclusions Endoscopic endoluminal vacuum therapy was the best treatment of anastomotic leakage in systemically ill patients after esophagectomy in this retrospective analysis. It should therefore be considered an important instrument in the management of this disorder.