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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.

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone-related biomarkers-25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)-with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two-sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta-analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL-C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: -0.03; -0.05 to -0.01; p = 0.006 for T2DM_BBJ and -0.03; -0.05 to -0.01; p = 0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).

Sarcopenia is an age-dependent skeletal muscle disorder that is common in patients with heart failure. The current study aimed to investigate the associations of sarcopenia with carotid atherosclerosis, cardiovascular disease and cardiac arrhythmia in a middle-aged and elderly population without clinical heart failure.A total of 2432 participants (992 men and 1440 women) from Shanghai Changfeng Study were included for analysis. The degree of sarcopenia was measured using height-adjusted appendicular skeletal muscle mass (ASM/heightSarcopenia was associated with higher prevalence of carotid atherosclerosis (26.4% vs 20.4%, P = 0.027), myocardial infarction (4.0% vs 1.1%, P = 0.001), and premature ventricular contraction (4.0% vs 2.0%, P = 0.034) in the participants with normal body weight, and higher prevalence of carotid atherosclerosis (45.0% vs 31.2%, P = 0.016), myocardial infarction (10.0% vs 4.3%, P = 0.020) and atrial fibrillation (7.5% vs 1.3%, P 0.001) in those with overweight/obese status. After adjustment for age, gender, cigarette smoking, alcohol drinking, menopausal status in women and other metabolic and inflammatory confounding factors, sarcopenia was independently associated with the risk of myocardial infarction in the whole population, and the risk of atrial fibrillation in the overweight/obese participants (all P 0.05). Compared with nonsarcopenic lean participants, the risk of myocardial infarction was gradually increased in sarcopenic lean (OR 3.08 [1.28-7.45], P = 0.012) and sarcopenic overweight/obese participants (OR 4.07 [1.31-12.62], P = 0.015). For the atrial fibrillation, the participants with either sarcopenia or overweight/obesity alone showed no higher risk. However, concomitant sarcopenia and overweight/obesity was associated with approximately 5-fold risk of atrial fibrillation (OR 5.68 [1.34-24.12], P = 0.019) after multiple adjustment.Sarcopenia is associated with myocardial infarction and atrial fibrillation in middle-aged and elderly adults without clinical heart failure.

Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend

Objective To explore the effect of berberine (BBR) on skeletal muscle mass and metabolism and the possible mechanism. Methods Eight-week-old male C57BL/6 mice were fed with a high-fat diet (HFD) for 8 weeks to establish the insulin resistance obesity model. Then, mice were randomly divided into two groups (normal chow diet (NCD) and HFD), while NCD and HFD were further classified into two groups respectively, which were NCD+CS (Carmellose Sodium), NCD+BBR, HFD+CS and HFD+BBR. After the BBR intervention, insulin tolerance test (ITT) and glucose tolerance test (GTT) were carried out. Metabolic parameters and inflammatory biomarkers were detected. Various parts of adipose tissue and gastrocnemius were separated and measured. The gastrocnemius muscle was selected for tissue staining. The mRNA expression of myostatin (Mstn) was tested by quantitative real-time PCR (RT-PCR). Western blotting was performed to detect the expression of Mstn, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), small ribonucleoprotein particle protein 2 (Smd2), small ribonucleoprotein particle protein 3 (Smd3), and small ribonucleoprotein particle protein 4 (Smd4). Results Both body weights (P

Background Motoric cognitive risk syndrome (MCR) is a newly proposed predementia syndrome incorporating subjective cognitive complaints and slow gait. Previous studies have reported that subjective cognitive complaints and slow gait are associated with frailty in cognitively unimpaired older adults, but little is known about the link between MCR and frailty in older adults. Therefore, the aim of the study was to explore the associations of MCR and its components with frailty in older Chinese adults. Methods In an observational cross-sectional study, a total of 429 older adults aged 60 years and older were admitted to the geriatric department. According to MCR criteria, all participants were classified into 4 groups: 1) the MCR group; 2) the subjective cognitive complaints only group; 3) the slow gait only group; and 4) the healthy control group. Physical frailty was assessed by the Clinical Frailty Scale (CFS). Multivariate logistic regression analysis was used to examine the association between MCR and frailty in older adults. Results The prevalence rates of subjective cognitive complaints, slow gait and MCR were 15.9, 10.0 and 4.0%, respectively. After adjusting for confounding variables, the logistic regression analysis showed that slow gait (odds ratio [OR]: 3.40, 95% confidence interval [CI]: 1.40–8.23, P = 0.007) and MCR (OR: 5.53, 95% CI: 1.46–20.89, P = 0.012) were independently associated with frailty, but subjective cognitive complaints were not. Conclusions MCR and slow gait were significantly associated with frailty in older Chinese adults. Further studies should prospectively determine the causal relationship between MCR and frailty.

Purpose The study aimed to investigate the association between body composition and frailty in elder inpatients. Patients and Methods This is a cross-sectional study including 656 elder inpatients (275 females and 381 males) aged ≥65 years, from department of geriatrics of Zhejiang Hospital between January 2018 and March 2019. Sociodemographic, health-related data and anthropometric measurements were evaluated. Body composition was assessed by bioimpedance analysis (BIA), mainly including skeletal muscle mass, body fat mass, total body water, fat-free mass,percent body fat, basal metabolic rate. Frailty was assessed by Clinical Frailty Scale (CFS). Univariate logistic regression was used to analyze the association between body composition and frailty. Results Frailty was present in 43.9% of the participants. Frail inpatients showed higher waist circumference, body fat mass and percent body fat, non-frail inpatients showed greater upper arm circumference, calf circumference, skeletal muscle mass, total body water, fat-free mass and basal metabolic rate. Subjects with underweight (body mass index (BMI)

Context: The relationship between resveratrol and histone acetylation in renal cell carcinoma (RCC) has not yet been reported. Objective: To explore the functional role of resveratrol in RCC. Materials and methods: Functional experiments were performed to determine proliferatio n of ACHN cells with treatment of resveratrol (0, 7.8125, 15.625, 31.25 and 62.5 μg/mL, for 12, 24 and 48 h of culture) or 0.1 μM SAHA. The enzyme activities of MMP-2/-9 were measured by gelatine zymography and histone acetylation by Western blot. Results: When the cells were treated with 15.625, 31.25 and 62.5 μg/mL resveratrol, ACHN cells viability was 73.2 ± 3.5%, 61.4 ± 3.1%, 50.2 ± 4.7% for 12 h, 62.7 ± 4.5%, 52.4 ± 5.5%, 40.2 ± 3.8% for 24 h, and 60.8 ± 3.7%, 39.4 ± 5.1%, 37.6 ± 2.7% for 48 h, and the wound closure (%) of migration was increased from 0.6 to 0.7, 0.85, 0.9 for 12 h and from 0.23 to 0.3, 0.48, 0.59 for 24 h. The invasion rate was 8.5 ± 0.9%, 7.4 ± 0.3% and 5.8 ± 0.6%, and cell cycle was arrested at G1 from 42.5 ± 2.9% to 55.3 ± 5.7%, 59.8 ± 3.4%, 68.7 ± 4.6%. MMP-2/-9 expression (p

Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank. MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62⋅10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.

Angiotensin-converting enzyme 2 (ACE2) is known as a host cell receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is identified to be dysregulated in multiple tumors. Although the characterization of abnormal ACE2 expression in malignancies has been preliminarily explored, in-depth analysis of ACE2 in breast cancer (BRCA) has not been elucidated. A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between ACE2 expression immunological characteristics in the BRCA tumor microenvironment (TME) were evaluated. Also, the role of ACE2 in predicting the clinical features and the response to therapeutic options in BRCA was estimated. These findings were subsequently validated in another public transcriptomic cohort as well as a recruited cohort. ACE2 was lowly expressed in most cancers compared with adjacent tissues. ACE2 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB). Besides, high ACE2 levels indicated the triple-negative breast cancer (TNBC) subtype of BRCA, lower response to endocrine therapy and higher response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. To sum up, ACE2 correlates with an inflamed TME and identifies immuno-hot tumors, which may be used as an auxiliary biomarker for the identification of immunological characteristics in BRCA.

Xiufang Hong,1,2 Jing Yan,1 Liyu Xu,1 Shanshan Shen,1 Xingkun Zeng,1 Lingyan Chen1 1Department of Geriatrics, Zhejiang Hospital, Hangzhou 310013, People’s Republic of China; 2The Second School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, People’s Republic of China Objective: The definition of frailty still lacks quantitative biomarkers. This study aimed to investigate the relationship between nutrition-related biomarkers and frailty in hospitalized older patients.Materials and methods: This is a cross-sectional study including 380 hospitalized older patients. The patients were categorized as nonfrail (n=140), prefrail (n=81), and frail (n=159) by the criteria of frailty phenotype. The nutritional status was assessed using the mini nutritional assessment-short form (MNA-SF), levels of serum transferrin (TNF), prealbumin (PA), total protein (TP), albumin (ALB), retinol-binding protein (RBP), and hemoglobin (Hb).Results: The grip strength, levels of serum TFN, TP, ALB, Hb, and MNA-SF scores all decreased significantly in the order of nonfrail, prefrail, and frail groups (P

Background Previous studies have presented skeletal muscle loss was associated with diabetes mellitus (DM) and non-alcoholic fatty liver disease (NAFLD). However, whether the presence of NAFLD could influence the association between skeletal muscle mass and DM was still unknown. The aim of the present study was to investigate the relationship of skeletal muscle mass with diabetes in Chinese middle-aged and older community population, and whether the association could be effected by NAFLD. Methods A cross-sectional study of 5,626 residents aged 45 and above in Changfeng community in Shanghai were conducted. Skeletal muscle mass (SMM) was detected by dual-energy X ray absorption (DXA) and calculated as ASM% [appendicular skeletal muscle mass (ASM) (kg) /body weight*100%]. Liver fat content (LFC) was measured using a quantitative ultrasound method. Multivariate logistic regression analyses were conducted to investigate the association between ASM% quartiles with DM. Results With ASM% decreasing, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2hBG) and Homeostasis model assessment for insulin resistance (HOMA-IR) as well as LFC increased in both genders, and the prevalence of diabetes and NAFLD also increased. Spearman analysis showed ASM% was negatively correlated with FBG, 2hBG and LFC. Stepwise logistic regression analysis showed after multiple adjustments, ASM% quartile was negatively associated with the risk of diabetes only in male, but not in female. Subgroup analysis found the ASM% quartiles remained negatively correlated with the risk of diabetes in male non-NAFLD population, but not in NAFLD population. When stratified by LFC quartiles, the results was similar. After multivariate adjustments, low ASM% was negatively correlated with the risk of diabetes only in the first and second LFC quartile in male, and the association remained insignificant in each LFC quartile in female. Conclusions Skeletal muscle mass was negatively associated with the risk of diabetes in male population but not in female. The presence of NAFLD weakened this association. The results suggested stratified management of diabetes should be considered according to skeletal muscle mass and the presence of NAFLD.

Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.

BackgroundThe frequently discovered incidental findings (IFs) from imaging observations are increasing. The IFs show the potential clues of structural abnormalities underlying cognitive decline in elders. Detecting brain IFs and their relationship with cognitive and behavioral functions helps provide the information for clinical strategies.MethodsFive hundred and seventy-nine participants were recruited in the Shanghai Changfeng Study. All participants performed the demographic, biochemical, and cognitive functions and gait speed assessment and underwent the high-resolution multimodal magnetic resonance imaging scans. We calculated the detection rate of brain IFs. The association between cardiovascular risk factors and IFs and the associations between IFs and cognitive and motor functions were assessed using regression models. The relationships among gray matter volume, cognitive function, and gait speed were assessed with/without adjusting the IFs to evaluate the effects of potential IFs confounders.ResultsIFs were found in a total of 578 subjects with a detection rate of 99.8%. Age and blood pressure were the most significant cardiovascular risk factors correlated with IFs. IFs were found to be negatively associated with Montreal Cognitive Assessment, Mini-Mental State Examination, and gait speed. The gray matter volume was found to be positively correlated with the cognitive function without adjusting the white matter hyperintensity but not if adjusted.ConclusionIFs are commonly found in the elderly population and related to brain functions. The adequate intervention of IFs related cardiovascular risk factors that may slow down the progression of brain function decline. We also suggest that IFs should be considered as confounding factors that may affect cognitive issues on the structural neuroimaging researches in aging or diseases.

Background: Intrinsic capacity (IC) is a novel view focusing on healthy aging. The effect of IC on adverse outcomes in older hospitalized Chinese adults is rarely studied. Objectives: This study focused on investigating the impact of IC domains on the adverse health outcomes including new activities of daily living (ADL) dependency, new instrumental activities of daily living (IADL) dependency, and mortality over a 1-year follow-up. Methods: In a retrospective observational population-based study, a total of 329 older hospitalized patients from Zhejiang Hospital in China were enrolled and completed 1-year follow-up. The 5 domains of IC including cognition, locomotion, sensory, vitality, and psychological capacity were assessed at admission. The IC composite score was calculated based on these domains, and the higher IC composite score indicated the greater amount of functional capacities reserved. Multivariate logistic regression models were used to explore the association between IC at baseline and 1-year adverse outcomes. Results: During the 1-year follow-up, 69 patients (22.5%) experienced new ADL dependency, 103 patients (33.6%) suffered from new IADL dependency, and 22 patients (6.7%) died. After adjusting for age, sex, education level, comorbidities, and polypharmacy, low Mini-Mental State Examination (MMSE) scores at admission predicted 1-year new ADL dependency (odds ratio [OR] = 2.31, 95% confidence interval [CI]: 1.12–4.78) and new IADL dependency (OR = 2.15, 95% CI: 1.14–4.04) among older hospitalized patients, but no significance was obtained between IC domains and mortality. Higher IC composite score at admission was associated with decreased risks of 1-year new ADL dependency (OR = 0.53, 95% CI: 0.40–0.70) and new IADL dependency (OR = 0.76, 95% CI: 0.61–0.95), and 1-year mortality (OR = 0.48, 95% CI: 0.31–0.74) after adjustment for the possible confounders. Conclusions: Loss of ICs at admission predicted adverse health outcomes including new ADL and IADL dependency and mortality 1 year after discharge among older hospitalized patients.

Background Herbal remedies are becoming increasingly popular for the treatment of depression. Recently, accumulating evidences reveal a positive effect of saffron (Crocus sativus L.) in relieving depressive symptoms. The objective of this meta-analysis was to assess the safety and efficacy of saffron in treating mild to moderate depression by synthesizing all available data. Materials and methods Relevant studies were retrieved from electronic databases and cross-checking of reference lists. Eligible trials were carefully reviewed, and necessary data were extracted. The Hamilton Rating Scale for Depression or Beck Depression Inventory scores, response rate, remission rate, and adverse effects were compared between saffron and placebo or saffron and antidepressants to assess the efficacy of saffron for depression. Results Twelve studies were included in the meta-analysis. Overall results showed that saffron possessed better efficacy in the improvement of depressive symptoms when compared with placebo, whereas saffron was as effective as synthetic antidepressants. No significant difference was detected in the incidence of adverse effects between saffron and placebo or between saffron and antidepressants. Conclusions Saffron could be considered as an alternative to synthetic antidepressants in the treatment of mild to moderate depression. However, multicenter trials with larger sample size, longer treatment duration, and different ethnic groups are required to verify our results.

Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in thePROCRgene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found thatPROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte–endothelial cell adhesion, a marker for vascular inflammation. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting thatPROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations.

ObjectiveUsing three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRS) for predicting the susceptibility and severity of Systemic lupus erythematosus (SLE), using renal disease as a proxy for severity.MethodsWe used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by Receiver Operating Characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group.ResultsWe found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of PP-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1=2.44e-08; Pcohort2=0.00205) and a significant negative correlation with age of SLE onset (Pcohort1=1.76e-12; Pcohort2=0.00384). We found that the GRS performed better in prediction of renal disease in the ‘later onset’ compared to the ‘earlier onset’ group.ConclusionThe GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age of onset and lupus nephritis.

Epilepsy is a common neurological disorder with a core feature of cognitive impairments. Previous studies showed that patients with focal epilepsy have deficits in both theory of mind (ToM) and executive function (EF). However, there are few studies of ToM in patients with idiopathic generalized epilepsy (IGE), especially in populations with pediatric epilepsy. The aim of this study was to examine the characteristics of ToM and EF, including some of their subcomponents, and explore the relationship between them in Chinese children with IGE.We recruited 54 children and adolescents with IGE as the experimental subjects and 37 typically developing children and adolescents as control subjects. Both groups completed ToM tests, namely, second-order false belief tasks (FBTs) and faux pas tasks (FPTs). Their caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF) at the same time.Children and adolescents with IGE displayed worse performance on some of the FBTs and FPTs than healthy controls (p0.01). They also exhibited widespread EF deficits, comprising eight subcomponents (p0.05). Pearson's correlation analysis revealed that several subcomponents of EF (inhibition, emotional control, initiation, working memory, and monitoring) were unequally correlated with FBT and FPT. Regression analysis showed that ToM had associations with inhibition, working memory, and duration of seizures. Analysis of variance (ANOVA) indicated that children with newly diagnosed epilepsy displayed significant deficits in FBT, FPT, and distinct subscales of EF.Our results revealed significant impairments in ToM and EF in children and adolescents with IGE compared with healthy controls. We found significant correlations between ToM and two subcomponents of EF (inhibition and working memory) in children with IGE. Additionally, the duration of seizures affected ToM in patients but was a less powerful predictor than the two subcomponents of EF. Even for children with new-onset seizures and without medication, the deficits in ToM and some distinct subscales of EF were apparent. This result has clinical implications for both nonpharmaceutical therapies and cognitive rehabilitation.

Background: Canine parvovirus (CPV) emerged in 1970s as a highly infectious disease. CPV modified live vaccines have been widely used to control the disease. It is urgent to develop specific monoclonal antibodies to differentiate field virus from vaccine virus in vaccinated dogs.

To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30, CYP2C19*2, CYP2B6*6, or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4-hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3. CYP2C19*2, CYP2B6*6, CYP2B6*29, and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene-gene interactions for treatment response contained CYP2C19*2, CYP2B6 785A>G, and CYP3A5*3 (cross-validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2-4 toxicities had CYP2C19*2, CYP2B6 785A>G, and 516 G>T (CVC, 10/10; P T, or CYP2B6 785A>G had higher tolerance to treatment.

INTRODUCTION Thyroid dysfunction is closely associated with skeletal muscle weakness. However, data on the optimal serum range of thyroid hormones for maintaining muscle strength in the elderly is lacking. METHODS We conducted a cross-sectional analysis in male elderly inpatients from the Geriatric Department of Zhongshan Hospital (affiliated to Fudan University, Shanghai, China). Serum biochemical parameters and thyroid hormones were detected for each participant. Hand grip (HG) was measured, with low hand grip defined as HG

Single nucleotide polymorphisms (SNPs) of p53 rs1042522, MDM2 rs2279744 and p21 rs1801270, all in the p53 pathway, which plays a crucial role in DNA damage and genomic instability, were reported to be associated with cancer risk and pathologic characteristics. This case-control study was designed to analyse the association between these SNPs and retinoblastoma (RB) in a Chinese Han population. These SNPs in 168 RB patients and 185 adult controls were genotyped using genomic DNA from venous blood. No significant difference was observed in allele or genotypic frequencies of these SNPs between Chinese RB patients and controls (all P > 0.05). However, the rs1042522 GC genotype showed a protective effect against RB invasion, as demonstrated by event-free survival (HR = 0.53, P = 0.007 for GC versus GG/CC). This effect was significant for patients with a lag time >1 month and no pre-enucleation treatment (P = 0.007 and P = 0.010, respectively), indicating an interaction between p53 rs1042522 and clinical characteristics, including lag time and pre-enucleation treatment status. Thus, the rs1042522 SNP may be associated with RB invasion in the Han Chinese population; however, further large and functional studies are needed to assess the validity of this association.

Aim: Aspirin resistance has an incidence of 5%–65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A 2 receptor (TXA 2 receptor, encoded by TBXA2R ), lipoprotein-associated phospholipase A 2 (Lp-PLA 2 , encoded by PLA2G7 ) and platelet endothelial aggregation receptor-1 ( PEAR1 , encoded by PEAR1 ) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1 ) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1 , TBXA2R , PLA2G7 , PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Methods: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB 2 ELISA kit. Results: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233–0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080–6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590–42.638). Conclusion: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931–rs7756935) polymorphisms.

The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4 year changes in body weight on liver steatosis and glucose metabolism. The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2 h post-load blood glucose (PBG) in relation to 4 year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.

Objective A Chinese visceral adiposity index (CVAI) was recently established to estimate the visceral fat area in Chinese adults. This study aimed to investigate the risk of incident prediabetes and diabetes in relation to visceral adiposity calculated by CVAI. Methods A total of 2558 subjects with normal plasma glucose levels from the Shanghai Changfeng Study were enrolled in a prospective cohort study. The independent associations of basal visceral fat area by CVAI and its longitudinal change with incident prediabetes and diabetes were identified using Cox regression analyses. Results During an average of 4.4 years of follow-up, 546 (21.3%) and 99 (3.9%) of 2558 nondiabetic subjects developed prediabetes and diabetes, respectively. Visceral fat area by CVAI and its longitudinal increase were independently associated with incident prediabetes and diabetes in Chinese adults. In a multivariable-adjusted regression model, CVAI, as well as its annual change, was the strongest independent predictor of incident prediabetes (HR, 1.383 [1.162-1.647]) and diabetes (HR, 1.607 [1.092-2.364]) compared with other estimates of obesity (BMI and waist circumference). Receiver operating characteristic curve analyses showed that CVAI had better performance than BMI and waist circumference for the prediction of prediabetes and diabetes in Chinese adults. Conclusions Visceral adiposity plays a pivotal role in the pathogenesis of diabetes, and the visceral adiposity estimated by CVAI is superior to the traditional estimates of obesity for the prediction of incident prediabetes and diabetes in Chinese adults.

Porcine circovirus type 3 (PCV3) was initially reported in 2016 in the United States of America. Since then, the virus has been detected on swine farms in Poland, South Korea, and China using PCR. However, a serological survey of PCV3 in pig populations has never been conducted. In this study, for the first time, we established an indirect enzyme-linked immunosorbent (ELISA) assay and performed a national retrospective serological survey for PCV3. Our results showed that the PCV3-postive rate increased from 22.35% to 51.88% between 2015 and 2017. The above results suggest PCV3 has spread widely in China with increased positive rates since 2015.

PURPOSE OF REVIEW: More than 80 susceptibility loci are now reported to show robust genetic association with systemic lupus erythematosus (SLE). The differential functional effects of the risk alleles for the majority of these loci remain to be defined. Here, we review current SLE association findings and the recent progress in the annotation of noncoding regions of the human genome as well as the new technologies and statistical methods that can be applied to further the understanding of SLE genetics.RECENT FINDINGS: Genome-wide association studies (GWAS) have markedly expanded the catalogue of genetic signals contributing to SLE development; we can now explain more than 50% of the disease's heritability. Expression quantitative trait loci mapping with colocalization analysis of GWAS results help to identify the underlying causal genes. The Encyclopedia of DNA elements, Roadmap Epigenome, and the Blueprint Epigenome projects have jointly annotated more than 80% of the noncoding genome, providing a wealth of information (from healthy individuals) to define the functional elements within the risk loci. Technologies, such as next-generation sequencing, chromatin structure determination, and genome editing, will help elucidate the actual mechanisms that underpin SLE risk alleles.SUMMARY: Gene expression and epigenetic databases provide a valuable resource to interpret genetic association in SLE. Expansion of such resources to include disease status and multiple ancestries will further aid the exploration of the biology underlying the genetics.

Xiufang Hong,1,2 Xujiao Chen,2 Jiaojiao Chu,2 Shanshan Shen,2 Qichen Chai,2 Gaobo Lou,2 Lingyan Chen2 1Zhejiang Chinese Medical University, 2Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China Objective: To investigate whether there is a difference in balance function between older persons with and without diabetes mellitus (DM), and to identify whether mediating factors, such as diabetic complications, Instrumental Activities of Daily Living (IADL) score, Mini-Mental State Examination (MMSE) score, as well as hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), are associated with balance function in older persons with DM.Methods: In this cross-sectional study, a total of 208 older persons were divided into a DM group (n=80) and a control group who did not have DM (n=128). Balance function was evaluated with the Tinetti performance-oriented mobility assessment (POMA), which includes balance and gait subscales. Activities of daily living (ADL), IADL, and the MMSE were also measured. Fall incidents in last 12 months, the use of walking aids, fear of falling, comorbidities, and polypharmacy were recorded. Diabetic complications were recorded, and HbA1c, FPG, TC, TG, and LDL were measured in the patients of the DM group.Results: Fall incidents in last 12 months were higher in the DM group than in the control group (P

© 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients.A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d).Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers.The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.

In applications of solar physics, extreme ultraviolet imaging of solar corona by selecting the He-II (λ = 30.4 nm) emission line requires high reflectivity multilayer mirrors. Some material combinations were studied to design the mirrors working at a wavelength of 30.4 nm, including SiC/Mg, B4C/Mg, C/Mg, C/Al, Mo/Si, B4C/Si, SiC/Si, C/Si, and Sc/Si. Based on optimization of the largest reflectivity and the narrowest width for the multilayer mirror, a SiC/Mg material combination was selected as the mirror and fabricated by a magnetron sputtering system. The layer thicknesses of the SiC/Mg multilayer were measured by an X-ray diffractometer.

© 2015 Nature America, Inc. All rights reserved.Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. Ctrough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of Ctrough was 173.9 ng/ml (P25–P75, 130.5–231.2 ng/ml) and cutoff value 200 ng/ml was determined by X-Tile. The PFS between Ctrough trough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). Ctrough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.

e13533 Background: Some studies postulated that the plasma concentration of gefitinib may have great influence on its efficacy; meanwhile, it is well-known that polymorphisms in metabolic enzymes a...