The identification of novel schizophrenia-related metabolites using untargeted lipidomics.

Human lipidome still remains largely unexplored among Chinese schizophrenia patients. We aimed to identify novel lipid molecules associated with schizophrenia and cognition among schizophrenia patients. The current study included 96 male schizophrenia patients and 96 gender-matched healthy controls. Untargeted lipidomics profiling was conducted among all participants. Logistic regression models were used to assess metabolite associations with schizophrenia. We further assessed the incremental predictive value of identified metabolites beyond conventional risk factors on schizophrenia status. In addition, identified metabolites were tested for association with cognitive function among schizophrenia patients using linear regression models. A total of 34 metabolites were associated with schizophrenia. Addition of these identified metabolites to age, body mass index, smoking, and education significantly increased the risk reclassification of schizophrenia. Among the schizophrenia-related metabolites, 10 were further associated with cognition in schizophrenia patients, including four metabolites associated with immediate memory, two metabolites associated with delayed memory, three metabolites associated with visuospatial, four metabolites associated with language, one metabolite associated with attention, and two metabolites associated with the total score. Our findings provide novel insights into the biological mechanisms of schizophrenia, suggesting that lipid metabolites may serve as potential diagnostic or therapeutic targets of schizophrenia.

Alcohol Consumption Among Adults With a Cancer Diagnosis in the All of Us Research Program.

Importance: Alcohol consumption is associated with adverse oncologic and treatment outcomes among individuals with a diagnosis of cancer. As a key modifiable behavioral factor, alcohol consumption patterns among cancer survivors, especially during treatment, remain underexplored in the United States. Objective: To comprehensively characterize alcohol consumption patterns among US cancer survivors. Design, Setting, and Participants: This cross-sectional study used data from May 6, 2018, to January 1, 2022, from the National Institutes of Health All of Us Research Program, a diverse US cohort with electronic health record (EHR) linkage, and included 15 199 participants who reported a cancer diagnosis and 1839 patients among a subset with EHR data who underwent treatment within the past year of the baseline survey. Data analysis was performed from October 1, 2022, to January 31, 2023. Main Outcomes and Measures: Prevalence of current drinking and of risky drinking behaviors, including exceeding moderate drinking (>2 drinks on a typical drinking day), binge drinking (≥6 drinks on 1 occasion), and hazardous drinking (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] score ≥3 for women or ≥4 for men). Results: This study included 15 199 adults (mean [SD] age at baseline, 63.1 [13.0] years; 9508 women [62.6%]) with a cancer diagnosis. Overall, 11 815 cancer survivors (77.7%) were current drinkers. Among current drinkers, 1541 (13.0%) exceeded moderate drinking, 2812 (23.8%) reported binge drinking, and 4527 (38.3%) engaged in hazardous drinking. After multivariable adjustment, survivors who were younger than 65 years, men, or of Hispanic ethnicity or who received a diagnosis before 18 years of age or ever smoked were more likely to exceed moderate drinking (aged <50 years: odds ratio [OR], 2.90 [95% CI, 2.41-3.48]; aged 50-64 years: OR, 1.84 [95% CI, 1.58-2.15]; men: OR, 2.38 [95% CI, 2.09-2.72]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.04-1.64]; aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.04-2.24]; former smokers: OR, 2.46 [95% CI, 2.16-2.79]; current smokers: OR, 4.14 [95% CI, 3.40-5.04]) or binge drink (aged <50 years: OR, 4.46 [95% CI, 3.85-5.15]; aged 50-64 years: OR, 2.15 [95% CI, 1.90-2.43]; men: OR, 2.10 [95% CI, 1.89-2.34]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.09-1.58]; aged <18 years at diagnosis: OR, 1.71 [95% CI, 1.24-2.35]; former smokers: OR, 1.69 [95% CI, 1.53-1.87]; current smokers: OR, 2.27 [95% CI, 1.91-2.71]). Survivors with cancer diagnosed before 18 years of age or who ever smoked were more likely to be hazardous drinkers (aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.11-2.08]; former smokers: OR, 1.83 [95% CI, 1.68-1.99]; current smokers: OR, 2.13 [95% CI, 1.79-2.53]). Of 1839 survivors receiving treatment as captured in the EHR, 1405 (76.4%) were current drinkers, and among these, 170 (12.1%) exceeded moderate drinking, 329 (23.4%) reported binge drinking, and 540 (38.4%) engaged in hazardous drinking, with similar prevalence across different types of cancer treatment. Conclusions and Relevance: This cross-sectional study of a diverse US cohort suggests that alcohol consumption and risky drinking behaviors were common among cancer survivors, even among individuals receiving treatment. Given the adverse treatment and oncologic outcomes associated with alcohol consumption, additional research and implementation studies are critical in addressing this emerging concern among cancer survivors.

Pregnancy and neonatal outcomes among women with early-onset colorectal cancer: a nationwide case-control study.

Background: Early-onset colorectal cancer has risen worldwide, leaving more women with colorectal cancer at reproductive ages. We aimed to investigate the risk of adverse pregnancy and neonatal outcomes among women with early-onset colorectal cancer. Methods: We conducted a nationwide, matched case-control study of maternal/pregnancy outcomes including pre-eclampsia and Cesarean delivery (C-section) as well as neonatal outcomes including preterm birth among 207 births in women with early-onset colorectal cancer (ages 18-49) and 1019 births in women without colorectal cancer in Sweden (1992-2019). Early-onset colorectal cancer cases were identified through the Cancer Register, and outcome data were retrieved through linkage to Medical Birth Register and National Patient Register. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Findings: Between Jan 1, 1992, and Dec 31, 2019, women with early-onset colorectal cancer who gave birth had increased odds of pre-eclampsia (7.2% vs 3.2%; OR = 2.52, 95%CI = 1.25-5.08), any C-section (24.6% vs 19.4%; OR = 1.43, 95%CI = 1.00-2.06), particularly emergency C-section (17.4% vs 10.5%; OR = 1.79, 95%CI = 1.17-2.75), after adjustment for maternal education level, country of birth, body mass index and smoking in early pregnancy, and comorbidities. Maternal history of early-onset colorectal cancer was also associated with offspring preterm birth (12.1% vs 5.2%; OR = 2.31, 95%CI = 1.34-3.99), delineated as spontaneous (OR = 1.06, 95%CI = 0.47-2.39) or medically-indicated preterm birth (OR = 4.48, 95%CI = 2.05-9.79). There was no increased risk of congenital malformation or small for gestational age birth. Interpretation: In this population-based study, maternal history of early-onset colorectal cancer was associated with risk of both adverse pregnancy (pre-eclampsia, C-section) and neonatal outcomes (preterm birth). Funding: US National Institutes of Health, Swedish Society of Medicine, Swedish Cancer Foundation.

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: a prospective, nested case-control study in men.

BACKGROUND: Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. METHODS: We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). FINDINGS: Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR per standard deviation [SD] increase, 1.28; 95%CI 1.06-1.53; Ptrend = 0.01). This positive association remained similar after adjusting for C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor-2, and within strata of putative CRC risk factors. We also observed a suggestive inverse association between EndoCAb IgM and risk of CRC (OR per SD increase, 0.84; 95%CI 0.69-1.02; Ptrend = 0.09). INTERPRETATION: Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. FUNDING: US National Institutes of Health.

Association between human blood metabolome and the risk of breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women with limited treatment options. To identify promising drug targets for breast cancer, we conducted a systematical Mendelian randomization (MR) study to screen blood metabolome for potential causal mediators of breast cancer and further predict target-mediated side effects. METHODS: We selected 112 unique blood metabolites from 3 large-scale European ancestry-based genome-wide association studies (GWASs) with a total of 147,827 participants. Breast cancer data were obtained from a GWAS in the Breast Cancer Association Consortium (BCAC), involving 122,977 cases and 105,974 controls of European ancestry. We conducted MR analyses to systematically assess the associations of blood metabolites with breast cancer, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Two blood metabolites were identified as the potential causal mediators for breast cancer, including high-density lipoprotein cholesterol (HDL-C) (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06-1.12; P = 9.67 × 10-10) and acetate (OR, 1.24; 95% CI, 1.13-1.37; P = 1.35 × 10-5). In the phenome-wide MR analysis, lowering HDL-C might have deleterious effects on the risk of the circulatory system and foreign body injury, while lowering acetate had deleterious effects on mental disorders disease. CONCLUSIONS: The present systematic MR analysis revealed that HDL-C and acetate may be the causal mediators in the risk of developing breast cancer. Side-effect profiles were characterized to help inform drug target prioritization for breast cancer prevention. HDL-C and acetate might be promising drug targets for preventing breast cancer, but they should be applied under weighting advantages and disadvantages.

Tumor- and metastasis-promoting roles of miR-488 inhibition via HULC enhancement and EZH2-mediated p53 repression in gastric cancer.

Dysregulation of microRNAs (miRNAs or miRs) is implicated in the development of gastric cancer (GC), which is possibly related to their roles in targeting tumor-suppressive or tumor-promoting genes. Herein, the current study was intended to ascertain the function of miR-488 and its modulatory mechanism in GC. Initially, human GC cells were assayed for their in vitro malignancy after miRNA gain- or loss-of-function and RNA interference or overexpression. Also, tumorigenesis and liver metastasis were evaluated in nude mouse models. Results demonstrated that miR-488 elevation suppressed GC (MKN-45 and OCUM-1) cell proliferation, migration, and invasiveness in vitro and reduced their tumorigenesis and liver metastasis in vivo. The luciferase assay identified that miR-488 bound to HULC and inhibited its expression. Furthermore, HULC could enhance EZH2-H3K27me3 enrichment at the p53 promoter region and epigenetically repress the p53 expression based on the data from RIP- and ChIP-qPCR assay. Additionally, HULC was validated to enhance GC growth and metastasis in vitro and in vivo. Overall, HULC re-expression elicited by miR-488 inhibition can enhance EZH2-H3K27me3 enrichment in the p53 promoter and repress the p53 expression, thus promoting the growth and metastasis of GC.

Osteoprotegerin and Ischemic Stroke Prognosis: A Prospective Multicenter Study and Mendelian Randomization Analysis.

BACKGROUND: Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis. METHODS: Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke. RESULTS: After adjustment for age, sex, admission National Institutes of Health Stroke Scale score, and other important covariates, elevated osteoprotegerin levels were associated with increased risks of primary outcome (odds ratio, 1.40 [95% CI, 1.05-1.88]), death (hazard ratio, 2.05 [95% CI, 1.04-4.08]), and composite outcome of death and vascular events (hazard ratio, 2.00 [95% CI, 1.15-3.48]) when 2 extreme quartiles were compared. Each 1-SD higher log-osteoprotegerin was associated with a 18% (95% CI, 6%-32%) increased risk of primary outcome, 69% (95% CI, 31%-118%) increased risk of death, and 53% (95% CI, 24%-89%) increased risk of composite outcome of death and vascular events, respectively. Multiple-adjusted spline regression model showed a linear association of osteoprotegerin with primary outcome (P for linearity <0.001). Adding osteoprotegerin to conventional risk factors did not significantly improve discriminatory power (C statistics, 0.817 versus 0.818; P=0.232) but did slightly improve the risk reclassification of primary outcome (net reclassification improvement: 13.68%, P<0.001; integrated discrimination improvement: 0.23%, P=0.039). In Mendelian randomization analysis, genetically determined high plasma osteoprotegerin was associated with increased risk of primary outcome (odds ratio, 5.74 [95% CI, 1.12-29.44]; P=0.036). CONCLUSIONS: Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

Risk of nonalcoholic fatty liver disease and associations with gastrointestinal cancers.

Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006-2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (<20%), intermediate (20%-49%), and high (≥50%). We also examined the associations by age of cancer diagnosis (earlier onset [<60] vs. ≥60). A total of 273 incident liver cancer and 4789 non-liver GI cancer cases were diagnosed. Compared with individuals at low risk for NAFLD, those at high risk had 2.41-fold risk of liver cancer (RR = 2.41, 95% CI: 1.73-3.35) and 23% increased risk of non-liver GI cancers (RR = 1.23, 95% CI: 1.14-1.32) (all ptrend < 0.001). Stronger associations were observed for men and individuals who were obese (all pinteraction < 0.05). NAFLD-associated elevated risk was stronger for earlier-onset cancers. For each 25% increase in NAFLD risk, the RRs for earlier-onset cancers were 1.32 (95% CI: 1.05-1.66) for esophageal cancer, 1.35 (95% CI: 1.06-1.72) for gastric cancer, 1.34 (95% CI: 1.09-1.65) for pancreatic cancer, and 1.10 (95% CI: 1.01-1.20) for colorectal cancer. Conclusion: NAFLD risk was associated with an increased risk of liver and most GI cancers, especially those of earlier onset.

Association of Lifestyle With Incidence of Heart Failure According to Metabolic and Genetic Risk Status: A Population-Based Prospective Study.

BACKGROUND: Whether lifestyle factors are similarly associated with risk of heart failure (HF) for individuals with different metabolic or genetic risk status remains unclear. METHODS: We included 464 483 participants from UK Biobank who were free of major cardiovascular disease or HF during baseline recruitment. Healthy lifestyle factors included avoidance of smoking, no obesity, regular physical activity, and healthy diet. Lifestyle was categorized as favorable (3 or 4 healthy lifestyle factors), intermediate (2 healthy lifestyle factors), and unfavorable (0 or 1 healthy lifestyle factor) lifestyles. Metabolic status was defined by the presence of hypertension, high total cholesterol, or diabetes at baseline. A weighted genetic risk score was created based on 12 single-nucleotide polymorphisms associated with HF. RESULTS: Compared with favorable lifestyle, the multivariable-adjusted hazard ratios of HF were 1.79 (95% CI, 1.68-1.90) and 2.90 (95% CI, 2.70-3.11) for intermediate lifestyle and unfavorable lifestyle, respectively (Ptrend <0.0001). This association was largely consistent regardless of the presence of any single metabolic risk factor or the number of metabolic risk factors (Pinteraction ≥0.21). The association was also similar across different genetic risk categories (Pinteraction=0.92). In a joint analysis, the hazard ratio of HF was 4.05 (95% CI, 3.43-4.77) comparing participants who had both higher genetic risk and an unfavorable lifestyle with those having lower genetic risk and a favorable lifestyle. CONCLUSIONS: Combined lifestyle was associated with incident HF regardless of metabolic or genetic risk status, supporting the recommendation of healthy lifestyles for HF prevention across the entire population.

Diet, Lifestyle Behaviours and Other Risk Factors Associated With Type 2 Diabetes Beyond Body Mass Index: A Mendelian Randomization Study.

OBJECTIVES: Our aim in this study was to identify promising targets for the prevention of type 2 diabetes in addition to weight loss. We conducted a Mendelian randomization (MR) study to investigate the body mass index (BMI)-independent associations of 16 risk factors, including diet, lifestyle behaviours and others, with type 2 diabetes. METHODS: We selected genetic variants as instrumental variables for diet, sleep traits, smoking, physical activity, education and blood pressure (BP) from European-descent genome-wide association studies (GWASs). Summary statistics for type 2 diabetes were derived from a recent GWAS with 74,124 European cases and 824,006 European controls. The inverse-variance weighted MR method was used to assess the associations of the risk factors with type 2 diabetes, followed by validation of robustness using different MR methods in sensitivity analyses. RESULTS: Genetically predicted insomnia (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.06 to 1.15), smoking initiation (OR, 1.14; 95% CI, 1.06 to 1.21), educational level (OR, 0.69; 95% CI, 0.65 to 0.74), hypertension (OR, 6.50; 95% CI, 3.13 to 13.50), systolic BP (OR, 1.02; 95% CI, 1.02 to 1.03) and diastolic BP (OR, 1.03; 95% CI, 1.02 to 1.03) had BMI-independent effects on type 2 diabetes risk. In addition, alcohol dependence (OR, 1.10; 95% CI, 1.05 to 1.16; BMI-adjusted OR, 1.04; 95% CI, 0.98 to 1.09) and vegetarian diet (OR, 0.50; 95% CI, 0.33 to 0.74; BMI-adjusted OR, 0.78; 95% CI, 0.57 to 1.06) appeared to be correlated with type 2 diabetes via a BMI-mediated pathway. Sensitivity analyses further confirmed the relationship between these factors and type 2 diabetes. CONCLUSIONS: In this systematic MR study, insomnia, smoking, education and BP had BMI-independent causal effects on the risk of type 2 diabetes, whereas alcohol dependence and vegetarian diet were associated with type 2 diabetes through BMI.

Comparative Study of Pyloromyotomy and H-M Pyloroplasty in Proximal Gastrectomy for Adenocarcinoma of Esophageal-Gastric Junction.

INTRODUCTION: The incidence of adenocarcinoma of esophageal-gastric junction (AEJ) has been increasing in recent years. Esophagogastrostomy after proximal gastrectomy (PG-EG) is the most commonly used surgical method for this disease which causes a constant spasm of the pyloric sphincter by cutting the vagus nerve around the esophagus, so H-M pyloroplasty (Heineke-Mikulicz pyloroplasty) is often operated after PG-EG to prevent delayed gastric emptying. However, H-M pyloroplasty destroys anti-reflux structure of pylorus and leads to serious bile reflux. The present study was designed to compare pyloromyotomy and H-M pyloroplasty in proximal subtotal gastrectomy through clinical studies and animal experiments. METHODS: We retrospectively evaluated the outcomes of 73 AEJ patients (39 underwent PG-EG with an H-M pyloroplasty and 34 underwent PG-EG with a pyloromyotomy) between January 2016 and August 2020, and perioperative variables were compared. In the animal experiment, 48 rats were randomly divided into four groups (n = 12): vagotomy group (V group), H-M pyloroplasty group (HM group), pyloromyotomy group (PM group), and control group (O group). Gastric emptying and bile reflux were evaluated in each group. RESULTS: In the retrospective clinic study, pyloromyotomy and H-M pyloroplasty could all prevent delayed gastric emptying effectively, and the incidence of bile reflux found by electronic gastroscopy in the PM group was significantly lower than that in the HM group (HM, 14/39; PM, 4/34; P = 0.028). In the animal experiment, there was no significant between-group difference of gastric emptying rate (%) in the HM group and PM group (HM, 70.6 ± 16; PM, 72.3 ± 12; P = 0.68) while the gastric emptying rate (%) was significantly lower in the V group than in the HM, PM, and control group (P values were 0.037, 0.021, and 0.001 respectively). The gastric mucosa bile acid concentration was significantly higher in the HM group than other group (P values were all less than 0.001). CONCLUSIONS: The pyloromyotomy could prevent delayed gastric emptying effectively after PG-EG for types II and III AEJ and reduce bile reflux compared to Heineke-Mikulicz pyloroplasty.

Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study.

BACKGROUND AND AIMS: Etiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method. METHODS AND RESULTS: Previously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21-6.41]; ischemic stroke: OR, 4.92 [4.12-5.86]), systolic BP (CAD: OR, 1.03 [1.03-1.04]; ischemic stroke: OR, 1.03 [1.03-1.03]), diastolic BP (CAD: OR, 1.05 [1.05-1.06]; ischemic stroke: OR, 1.05 [1.04-1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08-1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18-1.35]; ischemic stroke: OR, 1.24 [1.16-1.33]), educational attainment (CAD: OR, 0.62 [0.58-0.66]; ischemic stroke: OR, 0.68 [0.63-0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41-1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74-0.91]), triglycerides (CAD: OR, 1.29 [1.14-1.45]), body mass index (CAD: OR, 1.25 [1.19-1.32]), and alcohol dependence (OR, 1.04 [1.03-1.06]) were causally related to CVD. CONCLUSION: This systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD.

Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer.

BACKGROUND: Preclinical and epidemiological studies indicate a potential chemopreventive role of low-density lipoprotein cholesterol (LDL-C) -lowering drugs in the risks of breast cancer and prostate cancer, but the causality remains unclear. We aimed to evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) with risks of breast cancer and prostate cancer using a two-sample Mendelian randomization (MR) method. METHODS: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study (GWAS) meta-analysis from the Global Lipids Genetics Consortium (GLGC; up to 188,577 European individuals) were used to proxy inhibition of HMG-CoA reductase, NPC1L1, and PCSK9. Summary statistics with outcomes were obtained from a GWAS meta-analysis of the Breast Cancer Association Consortium (BCAC; 228,951 European females) and a Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL; 140,254 European males) consortium. SNPs were combined into multiallelic models and MR estimates representing lifelong inhibition of targets were generated using the inverse-variance weighted method. RESULTS: Genetically proxied inhibition of HMG-CoA reductase (OR: 0.84; 95% CI 0.74-0.95; P = 0.005) and NPC1L1 (OR: 0.72; 95% CI 0.58-0.90; P = 0.005) equivalent to a 1-mmol/L (38.7 mg/dL) reduction in LDL-C was associated with reduced breast cancer risk. There were no significant associations of genetically proxied inhibition of PCSK9 with breast cancer. In contrast, genetically proxied inhibition of PCSK9 (OR: 0.81; 95% CI 0.73-0.90; P < 0.001) but not HMG-CoA reductase and NPC1L1 was negatively associated with prostate cancer. In the secondary analysis, genetically proxied inhibition of HMG-CoA reductase (OR: 0.82; 95% CI 0.71-0.95; P = 0.008) and NPC1L1 (OR: 0.66; 95% CI 0.50-0.86; P = 0.002) was associated with estrogen receptor-positive breast cancer, whereas there was no association of HMG-CoA reductase and NPC1L1 with estrogen receptor-negative breast cancer. CONCLUSIONS: Genetically proxied inhibition of HMG-CoA reductase and NPC1L1 was significantly associated with lower odds of breast cancer, while genetically proxied inhibition of PCSK9 was associated with reduced risk of prostate cancer. Further randomized controlled trials are needed to confirm the respective roles of these LDL-C-lowering drugs in breast cancer and prostate cancer.

Association Between Baseline Buccal Telomere Length and Progression of Kidney Function: The Health and Retirement Study.

We aimed to evaluate associations of baseline telomere length with overall and annual change in estimated glomerular filtration rate (eGFR) and trajectory of kidney function during an 8-year follow-up. A total of 3 964 participants of the Health and Retirement Study were included. We identified 3 trajectory groups of kidney function: consistently normal (n = 1 163 or 29.3%), normal to impaired (n = 2 306 or 58.2%), and consistently impaired groups (n = 495 or 12.5%). After controlling for age, sex, race, education, smoking, drinking, diabetes, heart disease, blood pressure, body mass index, total cholesterol, and hemoglobin A1c, participants with longer telomere length were 20% less likely (odds ratio = 0.80, 95% confidence interval: 0.69-0.93, p = .003) to have a normal to impaired kidney function trajectory than a consistently normal function trajectory. Telomere length was not associated with changing rate of eGFR over 8 years (p = .45). Participants with longer telomere length were more likely to have consistently normal kidney function.

The Relationship between Physical Activity, Mobile Phone Addiction, and Irrational Procrastination in Chinese College Students.

The aim of the current study was to examine the associations between physical activity, mobile phone addiction, and irrational procrastination after adjustment for potential confounding variables. The participants were 6294 first- and second-year students recruited as a cluster sample from three public universities in Shanghai, China. Physical activity, mobile phone use, and irrational procrastination were assessed using the International Physical Activity Questionnaire-Short Form (IPAQ-SF), the mobile phone addiction index scale (MPAI), and the irrational procrastination scale (IPS). The participants were divided into four groups according to their mobile phone usage status and physical activity level. The binary logistic regression model was used to predict the probability of serious irrational procrastination among different groups. The emergence of serious of irrational procrastination under physical activity of different intensity and different mobile phone addiction statuses was predicted by a multiple linear regression model. In this study, the combination of insufficient physical activity and mobile phone addiction is positively associated with high levels of irrational procrastination. Furthermore, students who exhibited both mobile phone addiction behaviors and insufficient physical activity tended to have significantly higher odds of reporting high levels of irrational procrastination than those students who exhibited one behavior or neither behavior. After adjusting for the effects of age, BMI, tobacco, alcohol use, and sedentary time, the result is consistent with previous outcomes. These findings suggest that intervention efforts should focus on the promotion of physical activity and reduction of mobile phone addiction.

Biocompatible zinc gallogermanate persistent luminescent nanoparticles for fast tumor drainage lymph node imaging in vivo.

Tumor drainage lymph node identification and dissection are crucial for the oncological surgery to prevent/delay the recurrence. However, commercial imaging reagents distinguish the lymph nodes by staining them dark, which would be seriously interfered by blood and surrounding tissues. In this study, we reported the Cr3+/Pr3+-doped zinc gallogermanate persistent luminescent nanoparticles (PLNPs) for fast tumor drainage lymph node imaging with high contrast. PLNPs were synthesized by citrate sol-gel method and dispersed in Tween 80 for in vivo applications. PLNPs were well dispersed in water with hydrodynamic radii of 5 nm and emitted strong persistent luminescence at 696 nm upon the irradiation of UV light. The advantage of afterglow imaging over fluorescent imaging of PLNPs was first established after subcutaneous injection to mice with much higher contrast and less interference of autofluorescence. PLNPs quickly migrated to sentinel lymph nodes after the interdermal injection to extremity of mice. The tumor drainage lymph node imaging was achieved within 5 min upon the intratumoral injection to H460 tumor bearing mice and the signal to noise ratio was 462. Due to the lack of targeting moieties, the intravenous injected PLNPs mainly accumulated in liver. There were no statistical changes in serum biochemistry and abnormal histopathological characteristic, indicating the low toxicity of PLNPs. These findings highlighted the great potential of PLNPs as high-performance imaging reagent for lymph node identification.

Kaempferol inhibits benign prostatic hyperplasia by resisting the action of androgen.

Kaempferol is a natural compound that inhibits tumor development in androgenic related prostate cancer. However, it is still not clear about its phyto-androgenic activity and whether it suppresses testosterone-induced benign prostatic hyperplasia (BPH) development. In this study, molecular docking, cellular immunofluorescence staining, chromatin immunoprecipitation and dual luciferase reporter assay were performed to investigate the androgenic activity of kaempferol. Dihydrotestosterone-induced gene expression and cell proliferation were further analyzed upon treatment with kaempferol. Testosterone-induced BPH was established in rats and the effect and mechanism of action of kaempferol on BPH development was then assessed. Docking data showed that kaempferol could bind to ASN705 and THR877 residues of androgen receptor which were also the binding sites of dihydrotestosterone. The nuclear translocation of androgen receptor was promoted directly by kaempferol in androgen-dependent prostate cancer LNCaP cells. In addition, the in vivo interaction of androgen receptor with PSA promoter region and the transcriptional activity of androgen receptor were both significantly enhanced after kaempferol stimulation. However, kaempferol pretreatment suppressed dihydrotestosterone-induced effects including the transcriptional activity of androgen receptor, the expressions of PSA and AR genes and cell proliferation of LNCaP, BPH-1 and WPMY-1 cells. Consistently, kaempferol declined the prostate index and improved the pathological properties in BPH rats, and the up-regulated T level in serum from BPH rats was highly decreased after kaempferol administration. Kaempferol exhibited its androgenic-like activity and served as a selective androgen receptor modulator that contributes to androgen-related BPH development.

Mediating Effect of Perceived Stress on the Association between Physical Activity and Sleep Quality among Chinese College Students.

BACKGROUND: While physical activity has been reported to positively affect stress and sleep quality, less is known about the potential relationships among them. The present study aimed to investigate the mediating effect of stress on the association between physical activity and sleep quality in Chinese college students, after controlling for age, nationality, and tobacco and alcohol use. PARTICIPANTS: The sample comprised 6973 college students representing three Chinese universities. METHODS: Physical activity, perceived stress, and sleep quality were respectively measured using the International Physical Activity Questionnaire-Short Form (IPAQ-SF), Perceived Stress Scale-10 Items (PSS-10), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: Mediating effects of perceived stress on the association between physical activity and sleep quality were observed in males and females, with 42.4% (partial mediating effect) and 306.3% (complete mediating effect) as percentages of mediation, respectively. CONCLUSION: The results of this study may provide some suggestions that physical activity could improve sleep by aiding individuals in coping with stress and indicate that stress management might be an effective non-pharmaceutical therapy for sleep improvement.