The mediation effect of serum metabolites on the relationship between long-term smoking exposure and esophageal squamous cell carcinoma.

BACKGROUND: Long-term smoking exposure will increase the risk of esophageal squamous cell carcinoma (ESCC), whereas the mechanism is still unclear. We conducted a cross-sectional study to explore whether serum metabolites mediate the occurrence of ESCC caused by cigarette smoking. METHODS: Serum metabolic profiles and lifestyle information of 464 participants were analyzed. Multiple logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of smoking exposure to ESCC risk. High-dimensional mediation analysis and univariate mediation analysis were performed to screen potential intermediate metabolites of smoking exposure for ESCC. RESULTS: Ever smoking was associated with a 3.11-fold increase of ESCC risk (OR = 3.11, 95% CI 1.63-6.05), and for each cigarette-years increase in smoking index, ESCC risk increased by 56% (OR = 1.56, 95% CI 1.18-2.13). A total of 5 metabolites were screened as mediators by high-dimensional mediation analysis. In addition, glutamine, histidine, and cholic acid were further proved existing mediation effects according to univariate mediation analysis. And the proportions of mediation of histidine and glutamine were 40.47 and 30.00%, respectively. The mediation effect of cholic acid was 8.98% according to the analysis of smoking index. CONCLUSIONS: Our findings suggest that cigarette smoking contributed to incident ESCC, which may be mediated by glutamine, histidine and cholic acid.

Trajectories of Haemoglobin and incident stroke risk: a longitudinal cohort study.

BACKGROUND: Studies have demonstrated that high or low haemoglobin increases the risk of stroke. Previous studies, however, performed only a limited number of haemoglobin measurements, while there are dynamic haemoglobin changes over the course of a lifetime. This longitudinal cohort study aimed to classify the long-term trajectory of haemoglobin and examine its association with stroke incidence. METHODS: The cohort consisted of 11,431 participants (6549 men) aged 20 to 50 years whose haemoglobin was repeatedly measured 3-9 times during 2004-2015. A latent class growth mixture model (LCGMM) was used to classify the long-term trajectory of haemoglobin concentrations, and hazard ratios (HRs) and 95% confidence intervals (95% CI) according to the Cox proportional hazard model were used to investigate the association of haemoglobin trajectory types with the risk of stroke. RESULTS: Three distinct trajectory types, high-stable (n = 5395), normal-stable (n = 5310), and decreasing (n = 726), were identified, with stroke incidence rates of 2.7, 1.9 and 3.2 per 1000 person-years, respectively. Compared to the normal-stable group, after adjusting for the baseline covariates, the decreasing group had a 2.94-fold (95% CI 1.22 to 7.06) increased risk of developing stroke. Strong evidence was observed in men, with an HR (95% CI) of 4.12 (1.50, 11.28), but not in women (HR = 1.66, 95% CI 0.34, 8.19). Individuals in the high-stable group had increased values of baseline covariates, but the adjusted HR (95% CI), at 1.23 (0.77, 1.97), was not significant for the study cohort or for men and women separately. CONCLUSIONS: This study revealed that a decreasing haemoglobin trajectory was associated with an increased risk of stroke in men. These findings suggest that long-term decreasing haemoglobin levels might increase the risk of stroke.

Ring-Contraction Disproportionation/Spirocyclization Cascade Reaction of Isochromeno[4,3-b]indol-5(11H)-ones: Synthesis of N-Unsubstituted Spirocycles.

An efficient ring-contraction reaction of isochromeno[4,3-b]indol-5(11H)-ones via a nucleophile-induced disproportionation/spirocyclization cascade process has been developed under mild conditions. The process realized the conversion of isochromeno[4,3-b]indol-5(11H)-ones into N-unsubstituted spiro[indoline-2,1'-isobenzofuran]-3,3'-diones and spiro[indoline-2,1'-isoindoline]-3,3'-diones in the absence of a transition-metal catalyst or oxidant. Gram-scale reaction further demonstrated the practicability of the protocol.

Desulfitative Sonogashira cross-coupling of thiopyronin for the synthesis of NIR arylacetylene-containing rhodamines.

A classical, safe and efficient red-shift strategy contributing to NIR arylacetylene-containing rhodamines has been developed via the desulfitative Sonogashira cross-coupling reaction of thiopyronin for the first time, exhibiting a broad substrate scope with good yields. In addition, compound 3m shows great potential for application as a singlet oxygen probe, demonstrating the practicality of the method.

An Anthracene Carboxamide-Based Fluorescent Probe for Rapid and Sensitive Detection of Mitochondrial Hypochlorite in Living Cells.

Mitochondrial hypochlorite (ClO-) plays important and often contradictory roles in maintaining the redox balance of mitochondria. Abnormal ClO- levels can induce mitochondrial inactivation and further cause cell apoptosis. Herein, we have developed an anthracene carboxyimide-based fluorescent probe mito-ACS for imaging mitochondrial ClO- in living cells. This probe exhibits some distinctive features as excellent resistance to photobleaching, high selectivity and sensitivity, as well as good water solubility. Mito-ACS showed a noticeable fluorescence response toward ClO- with a fast response (within 6 s) and a low detection limit (23 nM). Moreover, the introduction of triphenylphosphonium makes the probe soluble in water and selectively localizes to mitochondria. Furthermore, mito-ACS was successfully applied to image mitochondria ClO- in living cells with low toxicity. Remarkably. the less used fluorophore anthracene carboxyimide exhibiting excellent photostability and desirable optical properties provides a promising application prospect in biological systems.

Remnant cholesterol, stronger than triglycerides, is associated with incident non-alcoholic fatty liver disease.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals. Methods: All subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status. Results: In multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p<0.001), high-density lipoprotein cholesterol (HDL-C) (HR, 95% CI: 0.571,0.487-0.670; p<0.001), and remnant-C (HR, 95% CI: 1.143,1.052-1.242; p=0.002), but not total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), were associated with incident NAFLD. Atherogenic dyslipidemia (triglycerides>1.69 mmol/L, HDL-C<1.03 mmol/L in men or<1.29 mmol/L in women) was also associated with NAFLD (HR, 95% CI: 1.343,1.177-1.533; p<0.001). Remnant-C levels were higher in females than in males and increased with increasing BMI and in participants with diabetes and CVD compared with those without diabetes or CVD. After adjusting for other factors in the Cox regression models, we found that serum levels of TG and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes in women group, non-cardiovascular disease status, non-diabetes status and middle BMI categories (24 to 28 kg/m2). Discussion: In the middle aged and elderly subset of the Chinese population, especially those who were women, non-CVD status, non-diabetes status and middle BMI status (24 to 28 kg/m2), levels of triglycerides and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes independent of other risk factors.

Temporal sequence of blood lipids and insulin resistance in perimenopausal women: the study of women's health across the nation.

INTRODUCTION: To explore the temporal relationship between blood lipids and insulin resistance in perimenopausal women. RESEARCH DESIGN AND METHODS: The longitudinal cohort consisted of 1386 women (mean age 46.4 years at baseline) in the Study of Women's Health Across the Nation. Exploratory factor analysis was used to identify appropriate latent factors of lipids (total cholesterol (TC); triglyceride (TG); high-density lipoprotein cholesterol (HDL-C); low-density lipoprotein cholesterol (LDL-C); lipoprotein A-I (LpA-I); apolipoprotein A-I (ApoA-I); apolipoprotein B (ApoB)). Cross-lagged path analysis was used to explore the temporal sequence of blood lipids and homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Three latent lipid factors were defined as: the TG factor, the cholesterol transport factor (CT), including TC, LDL-C, and ApoB; the reverse cholesterol transport factor (RCT), including HDL-C, LpA-I, and ApoA-I. The cumulative variance contribution rate of the three factors was 86.3%. The synchronous correlations between baseline TG, RCT, CT, and baseline HOMA-IR were 0.284, -0.174, and 0.112 (p<0.05 for all). After adjusting for age, race, smoking, drinking, body mass index, and follow-up years, the path coefficients of TG→HOMA-IR (0.073, p=0.004), and HOMA-IR→TG (0.057, p=0.006) suggested a bidirectional relationship between TG and HOMA-IR. The path coefficients of RCT→HOMA-IR (-0.091, P < 0.001) and HOMA-IR→RCT (-0.058, p=0.002) were also significant, but the path coefficients of CT→HOMA-IR (0.031, p=0.206) and HOMA-IR→CT (-0.028, p=0.113) were not. The sensitivity analyses showed consistent results. CONCLUSIONS: These findings provide evidence that TG and the reverse cholesterol transport-related lipids are related with insulin resistance bidirectionally, while there is no temporal relationship between the cholesterol transport factor and insulin resistance.

Development of a Risk Scoring System for Predicting Anastomotic Leakage Following Laparoscopic Rectal Cancer Surgery.

PURPOSE: To develop a risk scoring system that can predict the incidence of anastomotic leakage after laparoscopic rectal cancer surgery. PATIENTS AND METHODS: The clinical data of 387 patients with rectal cancer who underwent laparoscopic low anterior resection were retrospectively collected. Univariable and multivariable logistic regression analyses were used to evaluate independent risk factors for postoperative anastomotic leakage. A simplified points system was then developed based on the corresponding regression coefficient ß of each risk factor. Receiver operating characteristic (ROC) analysis was used to evaluate the performance and the optimal cut-off value in predicting anastomotic leakage. The performance of the points system was then externally validated in an independent cohort of 192 patients based in another institution. RESULTS: Anastomotic leakage occurred in 36 of 387 patients with rectal cancer (9.30%). Logistic multivariable regression analysis showed that males, maximum tumor diameter (≥5cm), operation time (≥180min), preoperative chemoradiation, intraoperative blood transfusion and the anastomosis level from the anal verge (≤5cm) were independent risk factors for the incidence of anastomotic leakage. According to the scoring standard, the risk points of each patient were calculated. ROC analysis based on the risk points showed that the area under the curve (AUC) was 0.795 (95% CI:0.752-0.834) and the optimal cut-off value was 6, yielding a sensitivity of 88.89% and a specificity of 62.96%. Using this risk points system, the AUC of another cohort of 192 patients from another institution who underwent laparoscopic low anterior resection for rectal cancer was 0.853 (95% CI:0.794-0.900, p<0.001) and patients with risk points ≥6 had a 21.05% chance of developing anastomotic leakage. CONCLUSION: This risk points system for predicting anastomotic leakage following laparoscopic rectal cancer surgery may be useful for surgeons in their decisions to perform intraoperative diversion stoma, which can reduce the incidence of postoperative anastomotic leakage.

Bidirectional temporal relationship between obesity and hyperinsulinemia: longitudinal observation from a Chinese cohort.

INTRODUCTION: Although obesity and hyperinsulinemia are closely intercorrelated, their temporal sequence is still uncertain. This study aims to investigate the temporal relationship patterns between obesity measures and hyperinsulinemia in Chinese adults. RESEARCH DESIGN AND METHODS: The longitudinal cohort consisted of 2493 participants (860 males and 1633 female, mean age 56.71 years at follow-up) for whom measurements of obesity and hyperinsulinemia measures were collected twice between 2011 and 2014, with an average follow-up time of 3 years. Cross-lagged panel analysis was used to examine the temporal relationship between obesity measures (body mass index (BMI); waist circumference (WC); hip circumference (HC); waist-to-hip ratio (WHR)) and hyperinsulinemia (insulin, homeostasis model assessment of insulin resistance (HOMA-IR), or homeostasis model assessment of beta cell function (HOMA-%ß)). RESULTS: After the adjustment of age, sex, smoking, drinking and follow-up years, in the BMI-insulin model, the path coefficient (ß2=0.229; p<0.001) of baseline BMI to follow-up insulin was significantly greater than the path coefficient (ß1=0.073; p<0.001) of baseline insulin to follow-up BMI (p<0.001 for ß2>ß1). In the WHR-insulin model, the path coefficient (ß1=0.152; p<0.001) of baseline insulin to follow-up WHR was significantly greater than the path coefficient (ß2=0.077; p<0.001) of baseline WHR to follow-up insulin (p=0.007 for ß1>ß2). In the WC/HC-insulin model, the path coefficients of baseline insulin to follow-up WC or HC (ß1s) were also greater than the path coefficients of baseline WC or HC to follow-up insulin (ß2s), but the difference between ß1s and ß2s were not significant. The similar temporal patterns were founded between obesity measures with HOMA-IR or HOMA-%ß. CONCLUSIONS: These findings indicate that there is a bidirectional relationship between obesity and hyperinsulinemia, and abdominal obesity measures are more sensitive to hyperinsulinemia measures than BMI.

Trajectories of early to mid-life adulthood BMI and incident diabetes: the China Health and Nutrition Survey.

INTRODUCTION: This longitudinal study aims to characterize distinct body mass index (BMI) trajectories during early to mid-life adulthood and to explore the association between BMI change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS: This study included 7289 adults who had repeatedly measured BMI 3-9 times during 1989-2011 and information on incident diabetes. Latent class growth mixed model (LCGMM) was used to identify different BMI trajectories. Cox proportional hazard models were used to investigate the association between the trajectory group membership and incident hyperglycemia, adjusting for covariates. The hyperglycemia group included individuals with prediabetes or diabetes. The model-estimated BMI levels and slopes were calculated at each age point in 1-year intervals according to the model parameters and their first derivatives, respectively. Logistic regression analyses were used to examine the association of model-estimated levels and slopes of BMI at each age point with incident hyperglycemia. The area under the curve (AUC) was computed from longitudinal growth curve models during the follow-up for each individual. Prior to the logistic regression analyses, quartiles of total, baseline, and incremental AUC values were calculated. RESULTS: Three distinct trajectories were characterized by LCGMM, comprising of low-increasing group (n=5136), medium-increasing group (n=1914), and high-increasing group (n=239). Compared with the low-increasing group, adjusted HRs and 95% CIs were 1.21 (0.99 to 1.48) and 1.56 (1.06 to 2.30) for the medium-increasing and the high-increasing group, respectively. The adjusted standardized ORs of model-estimated BMI levels increased among 20-50 years, ranging from 0.98 (0.87 to 1.10) to 1.19 (1.08 to 1.32). The standardized ORs of level-adjusted linear slopes increased gradually from 1.30 (1.16 to 1.45) to 1.42 (1.21 to 1.67) during 20-29 years, then decreased from 1.41 (1.20 to 1.66) to 1.20 (1.08 to 1.33) during 30-43 years, and finally increased to 1.20 (1.04 to 1.38) until 50 years. The fourth quartile of incremental AUC (OR=1.31, 95% CI 1.03 to 1.66) was significant compared with the first quartile, after adjustment for covariates. CONCLUSIONS: These findings indicate that the BMI trajectories during early adulthood were significantly associated with later-life diabetes. Young adulthood is a crucial period for the development of diabetes, which has implications for early prevention.

Body Mass Index Trajectories During Young Adulthood and Incident Hypertension: A Longitudinal Cohort in Chinese Population.

Background This longitudinal study aims to characterize longitudinal body mass index ( BMI ) trajectories during young adulthood (20-40 years) and examine the impact of level-independent BMI trajectories on hypertension risk. Methods and Results The cohort consisted of 3271 participants (1712 males and 1559 females) who had BMI and blood pressure ( BP ) repeatedly measured 4 to 11 times during 2004 to 2015 and information on incident hypertension. Four distinct trajectory groups were identified using latent class growth mixture model: low-stable (n=1497), medium-increasing (n=1421), high-increasing (n=291), sharp-increasing (n=62). Model-estimated levels and linear slopes of BMI at each age point between ages 20 and 40 were calculated in 1-year intervals using the latent class growth mixture model parameters and their first derivatives, respectively. Compared with the low-stable group, the hazard ratios and 95% CI were 2.42 (1.88, 3.11), 4.25 (3.08, 5.87), 11.17 (7.60, 16.41) for the 3 increasing groups, respectively. After adjusting for covariates, the standardized odds ratios and 95% CI of model-estimated BMI level for incident hypertension increased in 20 to 35 years, ranging from 0.80 (0.72-0.90) to 1.59 (1.44-1.75); then decreased gradually to 1.54 (1.42-1.68). The standardized odds ratio s of level-adjusted linear slopes increased from 1.22 (1.09-1.37) to 1.79 (1.59-2.01) at 20 to 24 years; then decreased rapidly to 1.12 (0.95-1.32). Conclusions These results indicate that the level-independent BMI trajectories during young adulthood have significant impact on hypertension risk. Age between 20 and 30 years is a crucial period for incident hypertension, which has implications for early prevention.