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BACKGROUND: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined. METHODS: A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia. FINDINGS: The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases. CONCLUSIONS: This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD. FUNDING: X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).
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Large prospective studies are required to better elucidate the associations of physical activity, sedentary behaviors (SBs), and sleep with overall cancer and site-specific cancer risk, accounting for the interactions with genetic predisposition. The study included 360,271 individuals in UK Biobank. After a median follow-up of 12.52 years, we found higher total physical activity (TPA) level and higher sleep scores were related to reduced risk of cancer while higher SB level showed a positive association with cancer. Compared with high TPA-healthy sleep group and low SB-healthy sleep group, low TPA-poor sleep group and high SB-poor sleep group had the highest risk for overall cancer, breast cancer, and lung cancer. Adherence to a more active exercise pattern was associated with a lower risk of cancer irrespective of genetic risk. Our study suggests that improving the quality of sleep and developing physical activity habits might yield benefits in mitigating the cancer risk.
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OBJECTIVE: To investigate the associations across genetic and lifestyle factors with lifespan. DESIGN: A longitudinal cohort study. SETTING: UK Biobank. PARTICIPANTS: 353 742 adults of European ancestry, who were recruited from 2006 to 2010 and were followed up until 2021. EXPOSURES: A polygenic risk score for lifespan with long (
Subject(s)
Genetic Predisposition to Disease , Life Style , Longevity , Humans , Female , Male , Middle Aged , Longevity/genetics , Aged , Longitudinal Studies , Adult , United Kingdom , Cohort Studies , Healthy Lifestyle , ExerciseABSTRACT
Lifestyle factors after a cancer diagnosis could influence the survival of cancer 60 survivors. To examine the independent and joint associations of healthy lifestyle factors with mortality outcomes among cancer survivors, four prospective cohorts (National Health and Nutrition Examination Survey [NHANES], National Health Interview Survey [NHIS], UK Biobank [UKB] and Kailuan study) across three countries. A healthy lifestyle score (HLS) was defined based on five common lifestyle factors (smoking, alcohol drinking, diet, physical activity and body mass index) that related to cancer survival. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of individual lifestyle factors and HLS with all-cause and cancer mortality among cancer survivors. During the follow-up period of 37,095 cancer survivors, 8927 all-cause mortality events were accrued in four cohorts and 4449 cancer death events were documented in the UK and US cohorts. Never smoking (adjusted HR = 0.77, 95% CI: 0.69-0.86), light alcohol consumption (adjusted HR = 0.86, 95% CI: 0.82-0.90), adequate physical activity (adjusted HR = 0.90, 95% CI: 0.85-0.94), a healthy diet (adjusted HR = 0.69, 95% CI: 0.61-0.78) and optimal BMI (adjusted HR = 0.89, 95% CI: 0.85-0.93) were significantly associated with a lower risk of all-cause mortality. In the joint analyses of HLS, the HR of all-cause and cancer mortality for cancer survivors with a favorable HLS (4 and 5 healthy lifestyle factors) were 0.55 (95% CI 0.42-0.64) and 0.57 (95% CI 0.44-0.72), respectively. This multicohort study of cancer survivors from the United States, the United Kingdom and China found that greater adherence to a healthy lifestyle might be beneficial in improving cancer prognosis.
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Healthy Lifestyle , Neoplasms , Humans , United States , Cohort Studies , Nutrition Surveys , Prospective Studies , Life Style , Risk FactorsABSTRACT
Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; Pinteraction = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted.
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Adenoma , Colorectal Neoplasms , Humans , Genotype , Colorectal Neoplasms/genetics , Risk Factors , Adenoma/genetics , Carcinogenesis , Galactoside 2-alpha-L-fucosyltransferaseABSTRACT
PURPOSE: Pathological complete response(pCR) during neoadjuvant chemotherapy(NAC) has been proposed as a predictor for better prognosis in breast cancer. However, few studies compare the outcomes of patients receiving NAC and adjuvant chemotherapy(AC). METHODS: We retrospectively matched the patients who received NAC(N = 462) and AC(N = 462) by age, time of diagnosis, and primary clinical stage using the propensity score match in breast cancer patients treated in Sir Run Run Shaw Hospital with the median follow up of 67 months. Death from breast cancer and recurrence were used as endpoints. A multivariable Cox models were used to estimate the hazard ratios for breast-cancer specific survival (BCSS) and DFS. A multivariable logistic regression model was simulated to predict pCR. RESULTS: In patients who received NAC, 18.0%(83/462) patients achieved pCR, while the rest of the patients did not. pCR subgroup demonstrated significant better BCSS and DFS than patients receiving AC(BCSS: HR = 0.39, 95% CI:0.12-0.93, P = 0.03; DFS: HR = 0.16, 95%CI 0.009-0.73, P = 0.013) and non-pCR patients(BCSS: HR = 0.32, 95%CI 0.10-0.77, P = 0.008; DFS: HR = 0.12, 95%CI 0.007-0.55, P = 0.002). Patients who received AC demonstrated insignificant survival compared to non-pCR patients(BCSS: HR= 0.82, 95%CI 0.62-1.10, P = 0.19; DFS: HR = 0.75, 95%CI 0.53-1.07, P = 0.12). Patients with AC had significant better DFS than non-pCR patients(HR = 0.33, 95% CI 0.10-0.94, P = 0.04) in luminal B Her2+ patients. More NAC cycles(>2), TNBC, lower cT stage, and mixed histology indicate higher possibility of pCR(AUC = 0.89). CONCLUSION: pCR patients with NAC indicated better prognosis than patients receiving AC or non-pCR patients from NAC. The timing of chemotherapy may need carefully pondering in luminal B Her2+ patients.
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Breast Neoplasms , Humans , Child, Preschool , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Neoadjuvant Therapy , Retrospective Studies , Prognosis , Chemotherapy, AdjuvantABSTRACT
BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.
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Colorectal Neoplasms , Genome-Wide Association Study , Humans , Colorectal Neoplasms/genetics , Risk , Genetic Loci , Alcohol Drinking , Quantitative Trait Loci/genetics , Polymorphism, Single Nucleotide/genetics , Genetic Predisposition to Disease , Phosphotransferases (Alcohol Group Acceptor)ABSTRACT
Background: Immune checkpoint inhibition therapy has been achieved significant success in the treatment of non-small cell lung cancer (NSCLC). However, the role of soluble immune checkpoint- related proteins in NSCLC remains obscure. Methods: We evaluated the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, LAG-3, GITR, IDO, PD-L2, PD-L1, PD-1, HVEM, Tim-3, CD28, CD27, CD80, CD137 and CTLA-4) and their associations with the risk of invasive disease and the risk of NSCLC in 43 pre-invasive (AIS), 81 invasive NSCLC (IAC) patients and matched 35 healthy donors using a multiplex Luminex assay. Gene expression in tumors from TCGA were analyzed to elucidate potential mechanisms. The multivariate logistic regression model was applied in the study. ROC(receiver operator characteristic) curve and calibration curve were used in the performance evaluation. Results: We found that sCD27, sCD80, CD137 and sPDL2 levels were significantly increased in IAC cases compared to AIS cases (P= 1.05E-06, 4.44E-05, 2.30E-05 and 1.16E-06, respectively), whereas sPDL1 and sPDL2 levels were significantly increased in NSCLC cases compared to healthy controls (P=3.25E-05 and 1.49E-05, respectively). Unconditional univariate logistic regression analysis indicated that increased sCD27, sCD80, sCD137, and sPDL2 were significantly correlated with the risk of invasive diseases. The model with clinical variables, sCD27 and sPDL2 demonstrated the best performance (AUC=0.845) in predicting the risk of IAC. CD27 and PDCD1LG2 (PDL2) showed significant association with cancer invasion signature in TCGA dataset. Conclusion: Our study provides evidence that soluble immune checkpoint-related proteins may associate with the risk of IAC, and we further established an optimized multivariate predictive model, which highlights their potential application in the treatment of NSCLC patients. Future studies may apply these biomarkers to test their predictive value of survival and treatment outcome during immunotherapy in NSCLC patients.
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Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Immune Checkpoint Proteins/genetics , Immunotherapy , Lung Neoplasms/pathologyABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, which is characterized by metabolic reprogramming. Cuproptosis, a novel form of cell death, is highly linked to mitochondrial metabolism and mediated by protein lipoylation. However, the clinical impacts of cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In the current study, we systematically evaluated the genetic alterations of cuproptosis-related genes in ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 and PDHB exhibited differential expression between ccRCC and normal tissues (|log2(fold change)| > 2/3 and p < 0.05). Utilizing an iterative sure independence screening (SIS) method, we separately constructed the prognostic signature of CRGs for predicting the overall survival (OS) and progression-free survival (PFS) in ccRCC patients. The prognostic score of CRGs yielded an area under the curve (AUC) of 0.658 and 0.682 for the prediction of 5-year OS and PFS, respectively. In the Kaplan−Meier survival analysis of OS, a higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01−3.68), log-rank p = 1.76 × 10−7). Patients with a higher risk had a significantly shorter PFS (HR = 2.83 (2.08−3.85), log-rank p = 3.66 × 10−7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, suggesting that CDKN2A (log2(fold change) = 1.46, 95%CI: 1.75−2.35) showed significantly higher expression in ccRCC tissues while DLAT (log2(fold change) = −0.54, 95%CI: −0.93−−0.15) and FDX1 (log2(fold change) = −1.01, 95%CI: −1.61−−0.42) were lowly expressed. The expression of CDKN2A and FDX1 in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 × 10−8; FDX1: r = −0.17, p = 1.37 × 10−4). In conclusion, the cuproptosis-related gene signature could serve as a potential prognostic predictor for ccRCC patients and may offer novel insights into the cancer treatment.
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Apoptosis , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Prognosis , CopperABSTRACT
This study aimed to quantitatively assess the effectiveness of the Wuhan lockdown measure on controlling the spread of coronavirus diesase 2019 (COVID-19). : Firstlyï¼estimate the daily new infection rate in Wuhan before January 23ï¼2020 when the city went into lockdown by consulting the data of Wuhan population mobility and the number of cases imported from Wuhan in 217 cities of Mainland China. Then estimate what the daily new infection rate would have been in Wuhan from January 24 to January 30th if the lockdown measure had been delayed for 7 daysï¼assuming that the daily new infection in Wuhan after January 23 increased in a highï¼moderate and low trend respectively (using exponential, linear and logarithm growth models). Based on thatï¼calculate the number of infection cases imported from Wuhan during this period. Finallyï¼predict the possible impact of 7-day delayed lockdown in Wuhan on the epidemic situation in China using the susceptible-exposed-infectious-removed (SEIR) model. : The daily new infection rate in Wuhan was estimated to be 0.021%ï¼0.026%ï¼0.029%ï¼0.033% and 0.070% respectively from January 19 to January 23. And there were at least 20 066 infection cases in Wuhan by January 23ï¼2020. If Wuhan lockdown measure had been delayed for 7 daysï¼the daily new infection rate on January 30 would have been 0.335% in the exponential growth modelï¼0.129% in the linear growth modelï¼and 0.070% in the logarithm growth model. Correspondinglyï¼there would have been 32 075ï¼24 819 and 20 334 infection cases travelling from Wuhan to other areas of Mainland Chinaï¼and the number of cumulative confirmed cases as of March 19 in Mainland China would have been 3.3-3.9 times of the officially reported number. Conclusions: Timely taking city-level lockdown measure in Wuhan in the early stage of COVID-19 outbreak is essential in containing the spread of the disease in China.
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COVID-19 , Communicable Disease Control , China/epidemiology , Cities , Humans , SARS-CoV-2ABSTRACT
A simple and efficient synthetic protocol for the preparation of acridinium esters and amides through the cyclization and esterification or amidation of isatins with alcohols or amines as nucleophiles in the presence of CF3SO3H is established. A series of polycyclic acridine derivatives bearing large π-conjugated systems were obtained in high yields, including some key intermediates for the synthesis of biologically active molecules. The photophysical properties of these synthesized acridines were investigated, demonstrating that the sulfur heterocyclic acridine 9w was obtained in a high quantum yield.
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This study aims to describe the characteristics and trends of pneumoconiosis in the Jiangsu Province, China, and provide information for the occupational diseases control. We collected and analyzed the data of pneumoconiosis cases reported annually from 2006 to 2017. The information of the cases mainly includes case distributions, clinical types and stages, enterprise types and scales, as well as diagnosis age and exposure duration. A total of 9243 pneumoconiosis cases were reported between 2006 and 2017, among which silicosis and coal workers' pneumoconiosis accounted for the vast majority (87.5%). The incidence of pneumoconiosis was relatively higher in Wuxi, Yancheng, Suzhou and Xuzhou, compared to the other district. Most pneumoconiosis cases occurred in the state-owned (58.4%) and collective enterprises (23.8%). Most cases worked in industries related to geology and coal production. The median exposure duration and diagnosis age of the total pneumoconiosis cases was 13.2 and 61.0 years, respectively. Therefore, more measurements are needed to control pneumoconiosis in the Jiangsu Province.