Sex steroid and cognitive function among community-dwelling older men with or without vascular risk factors: a cross-sectional study.

BACKGROUND: The relationship of testosterone and estradiol concentrations with cognitive function among community-dwelling older men was inconclusive. To examine the association of serum testosterone and estradiol concentrations with cognitive function in older men with or without vascular risk factors (VRFs). METHODS: This cross-sectional study consisted of 224 community-dwelling men aged 65-90 years in the Songjiang District of Shanghai, China. Serum testosterone and estradiol were measured by electrochemiluminescence immunoassay. The following five factors were defined as VRFs in this study: obesity, history of hypertension, diabetes, stroke, and coronary heart disease. Multivariable linear regression was used to examine the association of testosterone and estradiol with the Mini-Mental State Examination (MMSE) in participants with or without VRF. Restricted cubic spline (RCS) regression was performed to account for the nonlinearity of these associations. RESULTS: An inverted "U" shaped non-linear relationship was found between testosterone concentration and MMSE score in men with one VRF (P overall =.003, non-linear P =.002). Estradiol showed an inverted "U" shaped non-linear relationship with MMSE score independent of VRFs (men without VRF, P overall =.049, non-linear P =.015; men with one VRF, overall P =.007, non-linear P =.003; men with two or more VRFs, overall P =.009, non-linear P =.005). CONCLUSION: In older men, an optimal level of sex steroid concentration may be beneficial to cognitive function and the VRFs should be considered when interpreting the relationship between sex steroid and cognitive function.

Joint effect of testosterone and neurofilament light chain on cognitive decline in men: The Shanghai Aging Study.

INTRODUCTION: The association of testosterone and cognitive decline is inconclusive, and its joint effect with neurofilaments light chain (NfL) remains largely unknown. METHODS: A total of 581 non-demented older men in the Shanghai Aging Study were included. Blood total testosterone (TT), free testosterone (FT), and NfL were measured at baseline. The relationships between TT, FT, TT/FT-NfL, and cognitive decline were explored by Cox regression models. RESULTS: During a median follow-up of 6.7 years, there was an inverse association between TT/FT and cognitive decline (TT, trend p = .004, Q1 vs Q4, hazard ratio [HR] = 4.39, 95% confidence interval [CI] = 1.60 to 12.04; FT, trend p = .002, Q1 vs Q4, HR = 5.29, 95% CI = 1.50 to 16.89). Compared to participants with high TT/FT-low NfL, those with low TT/FT-high NfL had significantly higher risks of cognitive decline (TT, HR = 5.10, 95% CI = 1.11 to 23.40; FT, HR = 6.14, 95% CI = 1.34 to 28.06). DISCUSSION: Our findings suggest that the combination of testosterone and neurodegenerative markers may provide reliable predictive insights into future cognitive decline. HIGHLIGHTS: Testosterone is inversely associated with cognitive decline in older men. There is a joint effect of testosterone and NfL on cognitive decline. Sex hormone and neurodegeneration may synergistically contribute to cognitive deterioration.

Life expectancy among older adults with or without frailty in China: multistate modelling of a national longitudinal cohort study.

BACKGROUND: Little is known about life expectancy (LE) with or without frailty. We aimed to estimate the total LE and duration of the state of frailty in China. METHODS: This study included older adults aged 65 years and older from the Chinese Longitudinal Healthy Longevity Study (CLHLS). Frailty status was classified into robust, pre-frailty and frailty based on a cumulative deficit model. Total and specific frailty state LEs at 65 years of age were estimated and stratified by demographic characteristics, behaviours, and psychosocial factors using continuous-time multistate modelling. RESULTS: The total LE of older adults aged 65 years in China was 14.74 years on average (95% CI: 14.52-14.94), of which 4.18 years (95% CI: 4.05-4.30) were robust, 7.46 years (95% CI: 7.31-7.61) pre-frail and 3.10 years (95% CI: 3.01-3.20) frail. Older adults with higher robust LE included men (4.71 years, 95% CI: 4.56-4.88), married older adults (4.41 years, 95% CI: 4.27-4.56), those engaging in physical activity (4.41 years, 95% CI: 4.23-4.59), those consuming fruits daily (4.48 years, 95% CI: 4.22-4.77) and those with high social participation (4.39 years, 95% CI: 4.26-4.53). Increased educational attainment were gradually associated with increased robust LE. CONCLUSIONS: Frailty may lead to a reduced total LE and robust LE of older adults in China. In addition to finding inequalities in total and robust LEs by socioeconomic status, our findings also highlight that healthy behaviours and social participation may ease frailty-related reductions in total and robust LE. Our findings imply that national life-course strategies aimed at frailty screening and psychosocial and behavioural interventions could be important for health aging in China.

Sleep characteristic profiles and the correlation with spectrum of metabolic syndrome among older adult: a cross-sectional study.

BACKGROUND: Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS. OBJECTIVES: This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults. METHODS: This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration. RESULTS: Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17-2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P < 0.001). Furthermore, significant associations also included the associations of subjective sleep quality and daytime dysfunction with hypertension, the associations of sleep efficiency and rise time with hyperglycemia, the associations of rise time with TG levels, and the association of bedtime with waist circumference. CONCLUSIONS: The different sleep characteristics were associated with different MetS components.

Disturbed microbial ecology in Alzheimer's disease: evidence from the gut microbiota and fecal metabolome.

BACKGROUND: Gut microbiota (GMB) alteration has been reported to influence the Alzheimer's disease (AD) pathogenesis through immune, endocrine, and metabolic pathways. This study aims to investigate metabolic output of the dysbiosis of GMB in AD pathogenesis. In this study, the fecal microbiota and metabolome from 21 AD participants and 44 cognitively normal control participants were measured. Untargeted GMB taxa was analyzed through 16S ribosomal RNA gene profiling based on next-generation sequencing and fecal metabolites were quantified by using ultrahigh performance liquid chromatography-mass spectrometry (UPLC-MS). RESULTS: Our analysis revealed that AD was characterized by 15 altered gut bacterial genera, of which 46.7% (7/15 general) was significantly associated with a series of metabolite markers. The predicted metabolic profile of altered gut microbial composition included steroid hormone biosynthesis, N-Acyl amino acid metabolism and piperidine metabolism. Moreover, a combination of 2 gut bacterial genera (Faecalibacterium and Pseudomonas) and 4 metabolites (N-Docosahexaenoyl GABA, 19-Oxoandrost-4-ene-3,17-dione, Trigofoenoside F and 22-Angeloylbarringtogenol C) was able to discriminate AD from NC with AUC of 0.955 in these 65 subjects. CONCLUSIONS: These findings demonstrate that gut microbial alterations and related metabolic output changes may be associated with pathogenesis of AD, and suggest that fecal markers might be used as a non-invasive examination to assist screening and diagnosis of AD.

Cognitive leisure activity and all-cause mortality in older adults: a 4-year community-based cohort.

BACKGROUND: Cognitive leisure activity, such as reading, playing mahjong or cards and computer use, is common among older adults in China. Previous studies suggest a negative correlation between cognitive leisure activity and cognitive impairment. However, the relationship between cognitive leisure activity and all-cause mortality has rarely been reported. OBJECTIVES: This study aims to explore the relationships between cognitive leisure activity and all-cause mortality in a community-based older people cohort in China. METHODS: The current study sample comprised 4003 community residents aged ≥60 y who were enrolled in June 2015, and were followed up every year from 2015 to 2018. Reading, playing mahjong or cards and computer use were measured by questionnaires and summed into a cognitive leisure activity index (CLAI) score. Time-Dependent Cox Regression Model and Kaplan-Meier survival analysis were used to examine the association of cognitive leisure activity with all-cause mortality. RESULTS: During the 4-year follow-up of 4003 participants, 208 (5.2%) deaths were registered. Of all participants, 66.8, 26.7, 6.1 and 0.35% reported CLAI scores of 0, 1, 2 and 3, respectively. A strong association was noted between the CLA score and all-cause mortality (adjusted hazard ratio [HR] = 0.72, 95% confidence intervals [CI]: 0.54-0.97, P = 0.028). Stratified analysis suggested that a higher CLAI score was significantly associated with a decreased risk of all-cause mortality mainly among those who were male, aged ≥80 y, cognitively impaired, and not diagnosed with cancer (P < 0.05). CONCLUSION: Cognitive leisure activity was positively associated with reduced risk of death from all cause among the older people in major city of China, which helped promote a comprehensive understanding of health characteristics at advanced ages.

Generalized anxiety disorder and resilience during the COVID-19 pandemic: evidence from China during the early rapid outbreak.

BACKGROUND: Generalized Anxiety Disorder (GAD) is a common but urgent mental health problem during disease outbreaks. Resilience buffers against the negative impacts of life stressors on common internalizing psychopathology such as GAD. This study assesses the prevalence of GAD and examines the protective or compensatory effect of resilience against worry factors during the COVID-19 outbreak. METHODS: A cross-sectional online survey was conducted among Chinese citizens aged ≥18 years from January 31 to February 2, 2020. A total of 4827 participants across 31 provinces and autonomous regions of the mainland of China participated in this study. The Generalized Anxiety Disorder scale (GAD-7), the Connor-Davidson Resilience Scale (CD-RISC), and a self-designed worry questionnaire were used to asses anxiety disorder prevalence, resilience level, and anxiety risk factors. Multivariable logistic regression was used to identify the associations of resilience and worry factors with GAD prevalence after controlling for other covariates. RESULTS: The prevalence of anxiety disorder was 22.6% across the 31 areas, and the highest prevalence was 35.4% in Hubei province. After controlling for covariates, the results suggested a higher GAD prevalence among participants who were worried about themselves or family members being infected with COVID-19 (adjusted odds ratio, AOR 3.40, 95%CI 2.43-4.75), worried about difficulty obtaining masks (AOR 1.92, 95%CI 1.47-2.50), worried about difficulty of distinguishing true information (AOR 1.65, 95%CI 1.36-2.02), worried about the prognosis of COVID-19 (AOR 2.41, 95%CI 1.75-3.33), worried about delays in working (AOR 1.71, 95%CI 1.27-.31), or worried about decreased income (AOR 1.45, 95%CI 1.14-1.85) compared with those without such worries. Additionally, those with a higher resilience level had a lower prevalence of GAD (AOR 0.59, 95%CI 0.51-0.70). Resilience also showed a mediating effect, with a negative influence on worry factors and thereby a negative association with GAD prevalence. CONCLUSION: It may be beneficial to promote public mental health during the COVID-19 outbreak through enhancing resilience, which may buffer against adverse psychological effects from worry factors.

Health Belief Model Perspective on the Control of COVID-19 Vaccine Hesitancy and the Promotion of Vaccination in China: Web-Based Cross-sectional Study.

BACKGROUND: The control of vaccine hesitancy and the promotion of vaccination are key protective measures against COVID-19. OBJECTIVE: This study assesses the prevalence of vaccine hesitancy and the vaccination rate and examines the association between factors of the health belief model (HBM) and vaccination. METHODS: A convenience sample of 2531 valid participants from 31 provinces and autonomous regions of mainland China were enrolled in this online survey study from January 1 to 24, 2021. Multivariable logistic regression was used to identify the associations of the vaccination rate and HBM factors with the prevalence of vaccine hesitancy after other covariates were controlled. RESULTS: The prevalence of vaccine hesitancy was 44.3% (95% CI 42.3%-46.2%), and the vaccination rate was 10.4% (9.2%-11.6%). The factors that directly promoted vaccination behavior were a lack of vaccine hesitancy (odds ratio [OR] 7.75, 95% CI 5.03-11.93), agreement with recommendations from friends or family for vaccination (OR 3.11, 95% CI 1.75-5.52), and absence of perceived barriers to COVID-19 vaccination (OR 0.51, 95% CI 0.35-0.75). The factors that were directly associated with a higher vaccine hesitancy rate were a high level of perceived barriers (OR 1.63, 95% CI 1.36-1.95) and perceived benefits (OR 0.51, 95% CI 0.32-0.79). A mediating effect of self-efficacy, influenced by perceived barriers (standardized structure coefficient [SSC]=-0.71, P<.001), perceived benefits (SSC=0.58, P<.001), agreement with recommendations from authorities (SSC=0.27, P<.001), and agreement with recommendations from friends or family (SSC=0.31, P<.001), was negatively associated with vaccination (SSC=-0.45, P<.001) via vaccine hesitancy (SSC=-0.32, P<.001). CONCLUSIONS: It may be possible to increase the vaccination rate by reducing vaccine hesitancy and perceived barriers to vaccination and by encouraging volunteers to advocate for vaccination to their friends and family members. It is also important to reduce vaccine hesitancy by enhancing self-efficacy for vaccination, due to its crucial mediating function.

Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma.

BACKGROUND: Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. METHODS: We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. RESULTS: The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. CONCLUSIONS: This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.

TP53 R249S mutation detected in circulating tumour DNA is associated with Prognosis of hepatocellular carcinoma patients with or without hepatectomy.

BACKGROUND AND AIMS: Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC. METHODS: We analysed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N = 260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression-free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumour DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analysed in HCC patients with (Cohort 2, N = 275) or without (Cohort 3, N = 360) hepatectomy. RESULTS: In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P = .006) and PFS (P = .01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohorts 2 and 3 with R249S had worse OS (P = 8.291 × 10-7 and 2.608 × 10-7 in Cohorts 2 and 3, respectively) and PFS (P = 5.115 × 10-7 and 5.900 × 10-13 in Cohorts 2 and 3, respectively) compared to those without this mutation. CONCLUSIONS: TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy.

MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma.

Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.

miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients.

Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients ≤50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor.

HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas.

OBJECTIVE: Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP-3), another member of the HRP family in hepatocellular carcinoma (HCC). DESIGN: HRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo. RESULTS: Expression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal-regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs. CONCLUSION: These findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC.

Stock trend prediction using sentiment analysis.

These days, the vast amount of data generated on the Internet is a new treasure trove for investors. They can utilize text mining and sentiment analysis techniques to reflect investors' confidence in specific stocks in order to make the most accurate decision. Most previous research just sums up the text sentiment score on each natural day and uses such aggregated score to predict various stock trends. However, the natural day aggregated score may not be useful in predicting different stock trends. Therefore, in this research, we designed two different time divisions: 0:00t∼0:00t+1 and 9:30t∼9:30t+1 to study how tweets and news from the different periods can predict the next-day stock trend. 260,000 tweets and 6,000 news from Service stocks (Amazon, Netflix) and Technology stocks (Apple, Microsoft) were selected to conduct the research. The experimental result shows that opening hours division (9:30t∼9:30t+1) outperformed natural hours division (0:00t∼0:00t+1).

Education level modifies parental hesitancy about COVID-19 vaccinations for their children.

It is important to encourage parental acceptance of children's vaccination against COVID-19 to ensure population immunity and mitigate morbidity and mortality. This study drew upon protection motivation theory (PMT) to explore the factors of parental hesitancy about vaccinating their children. A national online survey was performed in China. A total of 2054 Chinese parents of children aged 6-12 years were included in this study. They reported on measures that assessed hesitancy about children's vaccination against COVID-19, PMT constructs (susceptibility, severity, response efficacy, self-efficacy, and response costs) and sociodemographic characteristics. Chinese parents reported a hesitancy rate of 29.4% for children's vaccination. Parents with higher level education were more likely to hesitate to vaccinate their children against COVID-19. After controlling for parents' and children's demographic variables, logistic regression showed that parents' hesitancy about their children's vaccination increased if parents had lower levels of susceptibility, response efficacy or self-efficacy, as well as higher levels of response costs. In addition, a high educational level can significantly increase the promotive effect of response cost and the protective effect of response efficacy on vaccine hesitancy. In conclusion, our findings suggested that PMT can explain parents' vaccine hesitancy and that education level can modify the effect of copying appraisal, but not threat appraisal, on parental hesitancy. This study will help public health officials send targeted messages to parents to improve the rate of COVID-19 vaccination in children aged 6-12 years and thus reach a higher level of immunity in the population.

Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas.

Members of the metallothionein (MT) family are short, cysteine-rich proteins involved in metal metabolism and detoxification, suggesting that MT proteins protect cells from damage caused by electrophilic carcinogens and thereby constitute a critical surveillance system against carcinogenesis. However, the roles of MT proteins in human hepatocellular carcinoma (HCC) are not fully understood. We identified a member of the MT family, termed MT1M. MT1M is expressed in various normal tissues with the highest level in the liver. MT1M expression can be induced by heavy metals and protect Escherichia coli from heavy metal toxicity. However, MT1M expression markedly decreased in human HCC specimens. A methylation profiling analysis indicated that the MT1M promoter is methylated in the majority of HCC tumors examined. Moreover, restored expression of MT1M in the HCC cell line Hep3B, which lacks endogenous MT1M expression, suppressed cell growth in vitro and in vivo and augmented apoptosis induced by tumor necrosis factor α. Furthermore, stable expression of MT1M in Hep3B cells blocked tumor necrosis factor α-induced degradation of IκBα and transactivation of NF-κB. We conclude that MT1M is a novel member of the MT family. Frequent downregulation of MT1M in human HCC may contribute to liver tumorigenesis by increasing cellular NF-κB activity.

Gene locus polymorphisms and expression levels of interleukin-1 in lumbar disc disease: A MOOSE-compliant meta-analysis and immunohistochemical study.

OBJECTIVE: To investigate the association between interleukin (IL)-1α (rs1800587), IL-1ß (rs1143634) and IL-1 receptor antagonist (RN) variable number tandem repeat polymorphisms, expression levels and lumbar disc disease (LDD). METHODS: All relevant articles were searched from 4 databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the association between IL-1 gene locus polymorphisms (rs1800587 in IL-1α, rs1143634 in IL-1ß, variable number tandem repeat in interleukin-1 receptor antagonist) and LDD susceptibility. Statistical analysis was conducted by Review Manager (Revman) 5.31 software (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Furthermore, qRT-PCR and immunohistochemistry were performed to evaluate IL-1α, IL-1ß and interleukin-1 receptor antagonist expressions in the normal and degenerated disc. RESULTS: A total of 15 case-control studies (1455 cases and 2362 controls) were included in our meta-analysis. The pooled results suggested that IL-1α rs1800587 polymorphism was associated with an increased risk of LDD in overall population (T vs. C, OR = 1.21, 95% CI = 1.04-1.40, P = .01). The subgroup analysis found a significant association between IL-1ß rs1143634 polymorphism and LDD in Asian population (T vs. C, OR = 0.61, 95% CI = 0.39-0.96, P = .03). Results of qRT-PCR and immunohistochemistry demonstrated that expressions of IL-1α and IL-1ß were significantly increased in the degenerated disc. (all P < .05). CONCLUSION: IL-1α rs1800587 and IL-1ß rs1143634 polymorphisms were significantly associated with LDD in overall population and in Asian population, respectively. The increased expression levels of IL-1α and IL-1ß may be the important risk factors for LDD.

The Relationship Between Low-Density Lipoprotein Cholesterol and Progression of Mild Cognitive Impairment: The Influence of rs6859 in PVRL2.

Background: Genome-wide association studies have identified many Alzheimer's disease (AD) genetic-risk single nucleotide polymorphisms (SNPs) and indicated the important role of the cholesterol/lipid metabolism pathway in AD pathogenesis. This study aims to investigate the effects of cholesterol and genetic risk factors on progression of mild cognitive impairment (MCI) to AD. Methods: We prospectively followed 316 MCI participants aged ≥50 years with a baseline cholesterol profile and SNP genotyping data for 4.5 years on average in a sub-cohort of the Shanghai Aging Study. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol in serum were measured at baseline. SNP genotyping was performed using a MassARRAY system. At follow-up, consensus diagnosis of incident dementia and AD were established based on medical, neurological, and neuropsychological examinations. Cox regression models were used to assess the association of cholesterol and SNP with incident AD. Results: The AG/AA genotypes of PVRL2 rs6859 were significantly associated with increased incident AD in MCI participants, compared with GG genotype (adjusted hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.32-5.76, p = .007, false discovery rate-adjusted p = .030). In PVRL2 rs6859 AG/AA carriers, each-1 mmol/L higher level of LDL-C was significantly associated with a 48% decreased risk of AD (adjusted HR 0.52, 95%CI 0.33-0.84, p = .007). Consistent results were obtained when using LDL-C as the categorical variable (P for trend = 0.016). Conclusion: The relationship between LDL-C and progression of MCI may be influenced by genetic variants.

An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression.

Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10-10). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment.

Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese.

INTRODUCTION: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive. METHODS: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed. RESULTS: We identified two variants, rs114401688 (P = 1.05 × 10-6, PFDR = 2.43 × 10-3) and rs115126566 (P = 9.04 × 10-5, PFDR = 1.77 × 10-1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03). DISCUSSION: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.