Exogenous chemical exposures are a global health concern due to their hepatotoxic potential, yet the extent to which endogenous metabolic disruption bridges these exposures to long-term liver cancer risk remains unclear. In a nested case-control study within a prospective Chinese cohort (n = 200), we conducted a metabolome-wide association analysis integrating 254 serum exogenous chemical residues with 478 endogenous metabolites to characterize pre-diagnostic metabolic disorders occurring up to 10 years before liver cancer onset and to delineate exposure-risk relationships. Individuals who later developed liver cancer exhibited pronounced metabolic perturbations, particularly involving bile acid metabolism, acylcarnitine pathways, glycerophospholipid turnover, sphingomyelin composition, and acylglycerol metabolism. A candidate early-warning panel comprising Phe/Tyr, FFA 24:1, PC (16:0_20:5), TG (18:1_18:1_21:0), and TG (18:3_17:1_18:2) was identified for liver cancer risk stratification. Exposure to salmeterol, diethylstilbestrol, and dibutyl phosphate showed positive associations with liver cancer risk, and mediation analysis highlighted tyrosine, PC (19:0_18:2), and SM (d18:1/24:1) as significant intermediators, suggesting hepatocarcinogenesis arises from the combined impact of exogenous chemical exposure and endogenous metabolic disorders. Overall, these findings indicate that early disturbances in bile acid, lipid, and amino acid metabolism precede clinical diagnosis by years and may serve as mechanistic links and early-warning biomarkers for exposure-related liver carcinogenesis.

Background:Early screening and detection is essential to reduce morbidity and mortality in esophageal cancer (EC), particularly for individuals at high risk. To reduce the burden and high costs of whole-population screening, we developed a risk score model for individualized risk assessment of esophageal squamous cell carcinoma (ESCC) incidence. Methods:The study was conducted using the Linxian Nutrition Intervention Trial cohort. Cox regression and the points system method were used to build a score-based model for ESCC risk prediction. The receiver operating characteristic (ROC) curve and calibration curve were used to examine the distinction and calibration of the models. Results:A total of 29,408 participants were included in final analysis. During the 10-year follow-up period, 1386 ESCC new cases were identified. Cox regression showed that increasing age, smoking, family history of esophageal cancer, dysphagia, fresh vegetable consumption (≤ 1 time/day), low body mass index (BMI < 18.5kg/m2), not drinking tap water (versus untreated natural water), and tooth loss were independent risk factors of ESCC incidence. The risk score based on 8 risk factors ranged from 0 to 59 points. Compared to subjects with a risk score < 20 points, the ESCC incidence risk increased by 201% for 20 to 39 points and 615% for score of over 39 points. The area under the curve (AUC) value of the risk score estimating ESCC incidence within 3 years was 0.70 (95% CI: 0.67-0.72). Conclusions:Our model effectively stratified the risk of ESCC, demonstrating a potential application in high-risk population identification and ESCC prevention.

BACKGROUND:The survival rate of pancreatic cancer is low, and there is a lack of effective treatment. AIM:To explore the epidemiological characteristics of patients with pancreatic cancer in China and compare multiple chemotherapy regimens at different stages. METHODS:This was a retrospective study conducted from 2005 to 2014, involving six cancer hospitals and eight general hospitals across seven geographical regions of China (East, South, North, Central, Southwest, Northwest, and Northeast). Stratified sampling was used based on the population distribution of each region. Efficacy assessments were conducted by Cox proportional hazards regression models. When assessing the effectiveness of various chemotherapy regimens, traditional drugs such as gemcitabine used as monotherapy served as the reference. RESULTS:A total of 3256 patients were included. The median follow-up time was 407 days, and the median overall survival was 183 days. At diagnosis, 56% of patients were already in stage IV. Chemotherapy was administered to 39.73% of patients. In the adjuvant therapy phase, gemcitabine + fluorouracil was superior to gemcitabine monotherapy [hazard ratio (HR) = 0.35, 95% confidence interval (CI): 0.14-0.89]. In fluorouracil-based regimens, other combination regimens did not show effectiveness relative to monotherapy. For first-line treatment in patients with advanced disease, tegafur alone (HR = 0.20, 95%CI: 0.06-0.66), gemcitabine plus cisplatin (HR = 0.16, 95%CI: 0.04-0.70), and tegafur, gemcitabine plus platinum-based agents (HR = 0.32, 95%CI: 0.11-0.91) were associated with a lower risk of death compared to gemcitabine alone. In second-line treatment, there were no significant differences in efficacy among various drugs, but FOLFIRINOX (irinotecan + oxaliplatin + leucovorin + 5-fluorouracil) had an outstanding point estimate (HR = 0.10, 95%CI: 0.01-1.27). CONCLUSION:In China, pancreatic cancer is often diagnosed at advanced stages, emphasizing the need for early diagnosis and treatment. Combined therapies in adjuvant and first-line settings may reduce the risk of death compared with monotherapy, and FOLFIRINOX might offer more significant benefits in second-line treatment.

Triclosan (TCS) and triclocarban (TCC), widely used estrogen-mimicking antimicrobials in personal care products, raise health concerns due to their long-term environmental persistence. However, epidemiological evidence remains sparse. This prospective nested case-control study evaluated associations between serum TCS/TCC concentrations and esophageal squamous cell carcinoma (ESCC) incidence. We enrolled 400 age- and sex-matched participants, collecting baseline epidemiological data and measuring serum TCS/TCC via high-resolution liquid chromatography-mass spectrometry. Multivariable logistic regression, followed by subgroup and sensitivity analyses, assessed associations. A significant non-linear relationship emerged for TCC: participants with serum levels of 1.73-7.21 ng/L had a fully adjusted odds ratio (OR) of 3.46 (95 % CI: 1.48-8.07) for ESCC compared to those with levels < 1.73 ng/L. In contrast, TCS exposure showed no significant association, suggesting divergent biological mechanisms despite structural similarity. This study identifies TCC as a novel ESCC risk factor, highlighting potential health risks and supporting stricter regulation of TCC in consumer products.

With the development of precision medicine and single-cell analysis, spatial metabolomics has become a hotspot in the biomedical field. However, current spatial metabolomics methods are still unable to meet the demand for the integration of spatial omics in terms of metabolite coverage, isomer differentiation, and applicability of clinical samples. Therefore, this study developed an analytical strategy based on laser capture microdissection-assisted gas chromatography-triple-quadruple mass spectrometry to characterize metabolic profile differences in clinical tissue sections. The extraction and derivatization methods were optimized separately. Analytical characteristics evaluation showed intra- and inter-day precision within 20 %, with most metabolites exhibiting linear ranges spanning three orders of magnitude. Using this method, metabolic profiles of five morphologies in esophageal squamous cell carcinoma (ESCC) and adjacent normal tissue (ANT) sections were characterized, identifying 88 metabolites across multiple categories. ANT tissues exhibited metabolic diversity across different morphologies, with cancer nest metabolic profiles in ANT being closer to those of ESCC. Squamous epithelial hyperplasia tissues showed dramatically lower levels of amino-containing compounds than other morphologies. This study presents a spatial metabolomics analysis method with good robustness and clinical applicability, offering valuable methodological support for clinical spatial omics applications.

Esophageal squamous cell carcinoma (ESCC) is the primary histological subtype of esophageal carcinoma, yet research on environmental exposure risks and associated metabolic alterations preceding ESCC is limited. In a nested case-control cohort of 396 adults (199 diagnosed with ESCC and 197 healthy controls (HC)), we combined exposomics and metabolomics to assess circulating chemical residues and early serum metabolic changes linked to ESCC risk. A cell experiment further evaluated the proliferative impact of 1H,1H,2H,2H-perfluorooctanesulfonic acid (6:2 FTS), identifying it as a risk factor for ESCC, primarily through lipid metabolism-related chronic inflammation. Significant metabolic disruptions were observed in ESCC cases, characterized by increased carnitines, phosphatidylcholines (PCs), and triglycerides (TGs) alongside reduced lysophosphatidylcholines (LPCs) and ether lysophosphatidylcholines (LPC-Os). An early-warning biomarker panel, including glutamic acid, methionine, choline, LPC-O 18:0, TG (14:0_18:2_20:5), and PC (18:0_20:4)/LPC 18:0, showed improved predictive capacity when combined with 6:2 FTS. Metabolome-exposome-wide association studies largely confirmed 6:2 FTS as a potential ESCC risk factor through lipid mediation. This study offers novel insights for ESCC prevention and early diagnosis through a combined biomarker panel integrating metabolic and environmental risk indicators.

Background: Whether the dynamic weight change is an independent risk factor for mortality remains controversial. This study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial (NIT) cohort. Methods: Body weight of 21,028 healthy residents of Linxian, Henan province, aged 40-69 years was measured two times from 1986 to 1991. Outcome events were prospectively collected up to 2016. Weight maintenance group (weight change <2 kg) or stable normal weight group was treated as the reference. Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the risk of mortality. Results: A total of 21,028 subjects were included in the final analysis. Compared with the weight maintenance group, subjects with weight loss >= 2 kg had an increased risk of death from all-cause (HRAll-cause = 1.14, 95% CI: 1.09-1.19, P <0.001), cancer (HRCancer = 1.12, 95% CI: 1.03-1.21, P = 0.009), and heart disease (HRHeart diseases = 1.21, 95% CI: 1.11-1.31, P <0.001), whereas subjects with weight gain >= 5 kg had 11% (HRCancer = 0.89, 95% CI: 0.79-0.99, P = 0.033) lower risk of cancer mortality and 23% higher risk of stroke mortality (HRStroke = 1.23,95% CI: 1.12-1.34, P <0.001). For the change of weight status, both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death (HROverweight to normal = 1.18, 95% CI: 1.09-1.27; HRBecoming underweight = 1.35, 95% CI: 1.25-1.46) and cancer death (HROverweight to normal = 1.20, 95% CI: 1.04-1.39; HRBecoming underweight = 1.44, 95% CI: 1.24-1.67), while stable overweight could increase the risk of total death (HRStable overweight = 1.11, 95% CI: 1.05-1.17) and death from stroke (HRStable overweight = 1.44, 95% CI: 1.33-1.56). Interaction effects were observed between age and weight change on cancer mortality, as well as between baseline BMI and weight change on all-cause, heart disease, and stroke mortality (all P-interaction <0.01). Conclusions: Weight loss was associated with an increased risk of all-cause, cancer, and heart disease mortality, whereas excessive weight gain and stable overweight were associated with a higher risk of stroke mortality. Efforts of weight management should be taken to improve health status. Trial registration:https://classic.clinicaltrials.gov/, NCT00342654.

Background To evaluate the associations between pre-diagnostic levels of serum insulin, glucose and insulin resistance (HOMA-IR) and future risk of incident primary liver cancer (PLC) or chronic liver disease (CLD)-related mortality. Methods We used a nested case-control design to evaluate subjects over 22 years of follow-up. Glucose, insulin, and three markers of hepatitis B virus (HBV) and hepatitis C virus were measured in fasting baseline serum from 119 incident PLCs, 157 CLD-death cases and 512 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression to estimate the associations between insulin, glucose, HOMA-IR and the risk of PLC or CLD death. Results Compared with the lowest quartile of insulin, multivariable adjusted models showed that subjects in the highest quartile had elevated odds of developing PLC (OR Q4/Q1 = 2.42, 95% CI = 1.26–4.75, P trend = 0.007), particularly in HBV-positive subjects ( P interaction = 0.040), and of CLD death (OR Q4/Q1 = 1.80, 95% CI = 1.02–3.21, P trend = 0.018). For glucose, in the HBV-positive group, subjects in the fourth quartile had an increased risk of PLC (OR Q4/Q1 = 2.18, 95% CI = 1.07–4.60, P trend = 0.009), and of CLD mortality (OR Q4/Q1 = 1.75, 95% CI = 0.95–3.28, P trend = 0.019). Subjects with the highest HOMA-IR values had a threefold risk of developing PLC (OR Q4/Q1 = 2.94, 95% CI = 1.54–5.87, P trend = 0.001), and a twofold risk of CLD death (OR Q4/Q1 = 2.20, 95% CI = 1.25–3.94, P trend = 0.005). Conclusions We found that serum insulin and HOMA-IR could potentially be risk factors for PLC or CLD death.

BackgroundThe objective of this study was to determine the short-term and long-term effects of a nutrition intervention in using 37 years of follow-up data. MethodsThe Linxian Dysplasia Population Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial with 7 years of intervention and 30 years of follow-up. The Cox proportional hazard model was used for analyses. Subgroup analyses were conducted in age and sex subgroups, and the 30 years of follow-up were divided into two 15-year early and late periods. ResultsThe results at 37 years did not indicate any effects on mortality from cancers or other diseases. In the first 15 years, the intervention decreased the overall risk of gastric cancer deaths in all participants (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.58-1.00) and in the subgroup participants younger than 55 years (HR, 0.64; 95% CI, 0.43-0.96). In addition, in the group younger than 55 years (HR, 0.58; 95% CI, 0.35-0.96), the intervention decreased the risk of death from other diseases; and, in the group aged 55 years and older (HR, 0.75; 95% CI, 0.58-0.98), the intervention reduced the risk of death from heart disease. There were no significant results in the later 15 years, which indicated the disappearance of the intervention effect. Comparing demographic characteristics between those who died during the two periods, the participants who died later included more women, had a higher education level, had a lower smoking rate, were younger, and also more had a mild degree of esophageal dysplasia, representing a better lifestyle and health condition. ConclusionsLong-term follow-up indicated no effect of nutrition on deaths in a population with esophageal squamous dysplasia, further supporting the significance of continuous nutritional intervention for cancer protection. The pattern of protective effect of a nutrition intervention on gastric cancer in patients with esophageal squamous dysplasia was similar to that in the general population. Participants who died in the later period had more protective factors than those who died in the earlier period, contributing to the obvious effect of the intervention in early stage disease.

[目的]开展巢式病例对照研究,通过代谢组学的手段分析得到差异代谢物,探索食管鳞癌发病前可能的代谢标志物.[方法]本研究基于1985年开展的林县营养干预试验随访队列,选择2001年及之后确诊为食管鳞癌者30例,并根据年龄(±3岁)、性别匹配至今仍存活的健康对照30名.1999年秋季至2000年春季的随访调查中获得了上述研究对象的血浆标本,使用LC-MS的方法进行代谢组学检测,对获得的代谢组特征进行分析.[结果]食管鳞癌组和对照组的基线人口学信息差异无统计学意义,但饮食偏好存在一定差异.代谢组检测数据稳定,代谢分析发现两组在代谢物分布上有明显差异,确定了包括谷氨酸、胆碱、溶血卵磷脂类、鸟氨酸在内的9种重要差异代谢物.[结论]食管鳞癌患者体内代谢物表达存在明显改变,某些含量波动的物质或可以成为食管鳞癌识别和诊断的潜在生物标志.

ObjectiveThis study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC).Methods3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrence/metastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites.ResultsA total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI: 1.04-9.07).ConclusionMolecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

The optimal treatment regimen for breast cancer patients with gBRCA mutations remains controversial given the availability of numerous options, such as platinum-based agents, polymerase inhibitors (PARPis), and other agents. We included phase II or III RCTs and estimated the HR with 95% CI for OS, PFS, and DFS, in addition to the OR with 95% CI for ORR and pCR. We determined the treatment arm rankings by P-scores. Furthermore, we carried out a subgroup analysis in TNBC and HR-positive patients. We conducted this network meta-analysis using R 4.2.0 and a random-effects model. A total of 22 RCTs were eligible, involving 4253 patients. In the pairwise comparisons, PARPi + Platinum + Chemo was better than PARPi + Chemo for OS (in whole study group and in both subgroups) as well as PFS. The ranking tests demonstrated that PARPi + Platinum + Chemo ranked first in PFS, DFS, and ORR. Platinum + Chemo showed higher OS than PARPi + Chemo. The ranking tests for PFS, DFS, and pCR indicated that, except for the best treatment (PARPi + Platinum + Chemo) containing PARPi, the second and third treatments were platinum monotherapy or platinum-based chemotherapy. In conclusion, PARPi + Platinum + Chemo might be the best regime for gBRCA-mutated BC. Platinum drugs showed more favorable efficacy than PARPi in both combination and monotherapy.

Background This study aimed to explore the association between drinking water source and risk of upper gastrointestinal (UGI) cancer, including esophageal cancer (EC) and gastric cancer (GC), in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. Methods In this study, we used data from the Linxian NIT cohort, which included 29,584 healthy adults aged 40 to 69 years. Subjects were enrolled in April 1986 and followed up until March 2016. Tap water drinking status and demographic characteristics were collected at baseline. Subjects who drank tap water were treated as the exposed group. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model. Results A total of 5,463 cases of UGI cancer were identified during the 30-year follow-up period. After adjusting for multiple factors, the incidence rate of UGI cancer in participants who drank tap water was significantly lower compared with individuals in the control (HR = 0.91, 95% CI: 0.86–0.97). A similar association was observed between tap water drinking and EC incidence (HR = 0.89, 95% CI: 0.82–0.97). The association between drinking tap water and risk of UGI cancer and EC incidence did not vary across the subgroup by age and gender (All P interaction > 0.05). For EC incidence, an interaction effect was observed for riboflavin/niacin supplements and drinking water source ( P interaction = 0.03). No association was observed between drinking water source and GC incidence. Conclusions In this prospective cohort study in Linxian, participants who drank tap water had a lower risk of EC incidence. As a source of drinking water, use of tap water may reduce the risk of EC by avoiding exposure to nitrate/nitrite. Measures should be taken to improve the quality of drinking water in high-incidence areas of EC. Trial registration The trial is registered with ClinicalTrials.gov (NCT00342654, 21/06/2006), and the trial name is Nutrition Intervention Trials in Linxian Follow-up Study.

Table S1 shows the information of Linxian Nutrition Intervention Trials; Table S2 shows the correlation between sex hormones and SHBG; Table S3-S6 show the ORs by age, alcohol drinking, smoking, follow-up time subgroups; Table S7 shows that the ORs in General Population Trial.

Objective:To summarize the trend of disease burden of esophageal cancer in 4 countries with high incidence of esophageal cancer and analyse the proportion of death attribution of three common risk factors, which helps to provide reference for the prevention and control of esophageal cancer.Methods:Based on the 2019 Global Burden of Disease Study (GBD2019) database and visualization platform, the absolute number and age-standardized rates of incidence, mortality and disability adjusted life years (DALY) of esophageal cancer in 4 countries with high incidence of esophageal cancer (China, Iran, Russia and South Africa) from 1990 to 2019 were described. The Joinpoint regression model was used for time trend analysis, and the annual percentage change (APC) and average annual percentage change (AAPC) of age-standardized incidence, age-standardized mortality, and age-standardized DALY rate of esophageal cancer were calculated. The proportion of death attribution of three common risk factors (smoking, alcohol consumption and low fruit intake) in 2019 was compared, and the differences in the population attributable fraction (PAF) for risk factors globally and in 4 countries were analyzed. The incidence and mortality of esophageal cancer under different socio-demographic index (SDI) were analyzed by drawing fitting curves.Results:From 1990 to 2019, the age-standardized incidence, mortality and DALY rates of esophageal cancer showed an overall decreasing trend globally and in 4 countries with high incidence of esophageal cancer. The age-standardized incidence rate of esophageal cancer in China decreased from 21.0/100 000 to 13.9/100 000 (AAPC = -1.4%, 95% CI -1.3% - -1.1%), the age-standardized mortality rate decreased from 22.1/100 000 to 13.1/100 000 (AAPC = -1.8%, 95% CI -1.9% - -1.7%), and the age-standardized DALY rate decreased from 507.0/100 000 to 227.5/100 000 (AAPC = -2.1%, 95% CI -2.2% - -1.9%). These rates in China had been decreasing at a much faster rate than the other 3 countries. Both Chinese men and Russian men had higher rates of esophageal cancer deaths due to smoking and alcohol consumption than the global average (PAF smoking: 59.2%, 56.7% vs. 51.2%; PAF alcohol consumption: 29.7%, 38.3% vs. 28.4%). The proportion of alcohol-related esophageal cancer deaths in Russian women was higher than the global average for women (PAF: 14.9% vs. 7.3%). Attributing low fruit intake to esophageal cancer deaths in South African men and women were higher than the global average for men and women (PAF men: 20.8% vs. 9.8%; PAF women: 21.3% vs. 11.7%). The age-standardized incidence and mortality rates in China and South Africa were consistently higher than would be expected for the same level of SDI, while those in Iran were consistently lower than would be expected, and Russia was broadly in line with expectation. Conclusions:Although the disease burden of countries with high incidence of esophageal cancer in the world has been effectively controlled, the disease burden of esophageal cancer in China is still higher than that in other countries. Targeted prevention measures should be made according to the epidemiological characteristics of esophageal cancer in Chinese population.

Odds ratio and 95% confidence intervals for the associations between presence/absence of individual strain/species and PGI/II ratio

This study aims to evaluate deep learning (DL) performance in differentiating low -and high-grade glioma. Search online database for studies continuously published from 1st January 2015 until 16th August 2022. The random-effects model was used for synthesis, based on pooled sensitivity (SE), specificity (SP), and area under the curve (AUC). Heterogeneity was estimated using the Higgins inconsis-tency index (I2). 33 were ultimately included in the meta-analysis. The overall pooled SE and SP were 94% and 93%, with an AUC of 0.98. There was great heterogeneity in this field. Our evidence-based study shows DL achieves high accuracy in glioma grading. Subgroup analysis reveals several limitations in this field: 1) Diagnostic trials require standard method for data merging for AI; 2) small sample size; 3) poor-quality image preprocessing; 4) not standard algorithm development; 5) not standard data report; 6) different definition of HGG and LGG; and 7) poor extrapolation.

Odds ratio and 95% confidence intervals for the associations between presence of individual strain/species and Esophageal Squamous Dysplasia (ESD) status