Impact of an Epstein-Barr Virus Serology-Based Screening Program on Nasopharyngeal Carcinoma Mortality: A Cluster-Randomized Controlled Trial.

PURPOSE: Screening for nasopharyngeal carcinoma (NPC) has shown an improvement in early detection and survival rates of NPC in endemic regions. It is critical to evaluate whether NPC screening can reduce NPC-specific mortality in the population. METHODS: Sixteen towns in Sihui and Zhongshan cities, China, were selected; eight were randomly allocated to the screening group and eight to the control group. Residents age 30-69 years with no history of NPC were included from January 1, 2008, to December 31, 2015. Residents in the screening towns were invited to undergo serum Epstein-Barr virus (EBV) viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody tests; others received no intervention. The population was followed until December 31, 2019. Nonparametric tests and Poisson regression models were used to estimate the screening effect on NPC mortality, accounting for the cluster-randomized design. The trial is registered with ClinicalTrials.gov (identifier: NCT00941538). RESULTS: A total of 174,943 residents in the screening group and 186,263 residents in the control group were included. NPC incidence and overall mortality were similar between the two groups. A total of 52,498 (30.0% of 174,943) residents participated in the serum EBV antibody test. The overall compliance rate for endoscopic examination and/or biopsies among baseline and ever-classified high-risk participants was 65.9% (1,110 of 1,685) and 67.6% (1,703 of 2,518), respectively. A significant 30% reduction in NPC mortality was observed in the screening group compared with the control group (standardized NPC-specific mortality rate of 8.2 NPC deaths per 1,000 person-years versus 12.5; adjusted rate ratio [RR], 0.70 [95% CI, 0.49 to 0.997]; P = .048). This benefit was most evident among individuals age 50 years and older (RR, 0.56 [95% CI, 0.37 to 0.85]; P = .007) compared with those younger than 50 years (RR, 0.96 [95% CI, 0.64 to 1.46]; P = .856). CONCLUSION: In this 12-year trial, EBV antibody testing resulted in a significant reduction in NPC mortality.

Gypenosides alleviate oxidative stress in the hippocampus, promote mitophagy, and mitigate depressive-like behaviors induced by CUMS via SIRT1.

ETHNOPHARMACOLOGICAL RELEVANCE: The use and efficacy of Gynostemma [Gynostemma pentaphyllum (Thunb.) Makino], a versatile traditional Chinese herb, was first documented in the renowned pharmacopoeia, "Compendium of Materia Medica". Gypenosides (Gps), saponin components are the primary constituents responsible for its biological activities and clinical effects, which include antioxidant, immunoregulatory, antitumor, and neuroprotective properties. Pharmacological studies have shown that Gps has the potential to combat depression. However, the exact molecular mechanisms underlying its antidepressant effects remain unclear. AIM OF THE STUDY: This study aims to elucidate the mechanisms underlying the antidepressant effects of Gps through antioxidative stress, utilizing an integrated approach that includes network pharmacology, molecular simulations, and experimental validation. MATERIALS AND METHODS: Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) and were orally administered doses of Gps (50 and 100 mg/kg) and fluoxetine (10 mg/kg). The regulatory effects of Gps on depression-like behaviors in CUMS rats and their impact on oxidative stress levels in the hippocampus region were evaluated. Network pharmacology was used to investigate the mechanisms by which Gps affects oxidative stress in depression, and was accompanied by molecular docking and dynamics simulations. CUMS rats were treated orally with Gps (100 mg/kg) and injected with EX527 for rescue experiments to validate the role of SIRT1 in antioxidative stress and evaluate the impact of Gps on mitophagy. RESULTS: Gps ameliorated depression-like behaviors induced by CUMS in rats. The improvements observed included an increased sucrose preference, reduced immobility time in the tail suspension and forced swim tests, and an increased movement distance in the open-field test. Additionally, Gps effectively reduced reactive oxygen species, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine levels in the hippocampus, while increasing the contents of ATP, catalase, superoxide dismutase, and glutathione, indicating an increased capacity for antioxidative stress in the hippocampus. Furthermore, Gps increased the number of neuronal cells in the hippocampal CA1 region and the level of mitochondrial autophagy, with SIRT1 as a potential key target. Inhibition of SIRT1 expression by exposure to EX527 reversed the beneficial effects of Gps, further validating the critical role of SIRT1 in the regulation of oxidative stress and improving depression-like behavior. CONCLUSION: Gps improved the antioxidative stress capacity of the hippocampus and promoted mitophagy in CUMS rats through SIRT1, thus protecting hippocampal neurons and improving depression-like behavior.

Apolipoprotein E E3/E4 genotype is associated with an increased risk of coronary atherosclerosis in patients with hypertension.

OBJECTIVE: Apolipoprotein E (APOE) gene polymorphisms were associated with coronary atherosclerosis and hypertension. However, the relationship between APOE polymorphisms and coronary atherosclerosis susceptibility in hypertensive patients is unclear. The aim of this study was to assess the relationship. METHODS: A total of 1713 patients with hypertension who were admitted to Meizhou People's Hospital from November 2019 to August 2023 were retrospectively analyzed, including 848 patients with coronary atherosclerosis and 865 patients without coronary atherosclerosis. The rs429358 and rs7412 polymorphisms of APOE were genotyped, and relationship between APOE polymorphisms and the risk of coronary atherosclerosis in hypertensive patients were analyzed. RESULTS: There were 10 (0.6%), 193 (11.3%), 30 (1.8%), 1234 (72.0%), 233 (13.6%), and 13 (0.8%) individuals with APOE ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4 genotype, respectively. The frequency of APOE ɛ3/ɛ4 was higher (16.4% vs. 10.9%, p = 0.001) in the patients with coronary atherosclerosis than controls. Logistic analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (24.0 kg/m2 vs. 18.5-23.9 kg/m2, odds ratio (OR): 1.361, 95% confidence interval (CI): 1.112-1.666, p = 0.003), advanced age (≥ 65/<65, OR:1.303, 95% CI: 1.060-1.602, p = 0.012), history of smoking (OR: 1.830, 95% CI: 1.379-2.428, p < 0.001), diabetes mellitus (OR: 1.380, 95% CI: 1.119-1.702, p = 0.003), hyperlipidemia (OR: 1.773, 95% CI: 1.392-2.258, p < 0.001), and APOE ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 1.514, 95% CI: 1.133-2.024, p = 0.005) were associated with coronary atherosclerosis in hypertensive patients. CONCLUSIONS: Overweight (BMI ≥ 24.0 kg/m2), advanced age, history of smoking, diabetes mellitus, and APOE ɛ3/ɛ4 genotype were independent risk factors for coronary atherosclerosis in hypertensive patients.

Aldehyde dehydrogenase 2 rs671 a/A Genotype is Associated with an Increased Risk of Early Onset Coronary Artery Stenosis.

Background: The role of aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases has been gradually studied. However, it is unclear whether ALDH2 polymorphism is associated with the risk of early onset (onset age ≤55 years old in men and ≤65 years old in women) coronary artery stenosis (CAS). The association between ALDH2 single nucleotide polymorphism (SNP) rs671 and risk in patients with early onset CAS was investigated in this study. Methods: The study included 213 early onset CAS patients and 352 individuals without CAS were set as controls. The ALDH2 rs671 polymorphism was genotyped by polymerase chain reaction (PCR) - microarray. Differences in ALDH2 rs671 genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for gender, body mass index (BMI), smoking history, drinking history, and diabetes mellitus to assess the relationship between ALDH2 rs671 genotypes and early onset CAS risk. Results: The frequency of the ALDH2 rs671 G/G genotype was lower in the early onset CAS patients (43.7% vs 55.3%, p=0.007) than that in the controls. The frequency of the ALDH2 rs671 A allele was higher (32.9% vs 25.0%) than that in the controls (p=0.005). After adjusting for other confounding factors, multivariate logistic regression showed that ALDH2 rs671 A/A genotype (A/A vs G/G: odds ratio (OR) 2.508, 95% confidence interval (CI): 1.130-5.569, p=0.024), overweight (BMI≥24.0 vs 18.5-23.9: OR 5.047, 95% CI: 3.275-7.777, p<0.001), history of smoking (yes vs no: OR 2.813, 95% CI: 1.595-4.961, p<0.001), and diabetes mellitus (yes vs no: OR 2.191, 95% CI: 1.397-3.437, p=0.001) were the independent risk factors of early onset CAS. Conclusion: In men ≤55 years old and women ≤65 years old, individuals with ALDH2 rs671 A/A genotype, overweight (BMI ≥24.0 kg/m2), smoking history, and diabetes mellitus increased risk of developing CAS.

Diagnostic value of circulating tumor cells in patients with thyroid cancer: a retrospective study of 1478 patients.

BACKGROUND: Circulating tumor cell (CTC) detection is one form of liquid biopsy. It is a novel technique that is beginning to be applied in the field of thyroid cancer. The present study was designed to evaluate the diagnostic value of CTCs in patients with thyroid cancer. METHODS: A total of 1478 patients were retrospectively analyzed and divided into malignant group (n = 747) and benign group (n = 731). Peripheral blood was collected, and CTCs were enriched and quantified before surgery. The baseline data of the two groups were matched by Propensity Score Matching (PSM). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficiency of different indicators for thyroid cancer. The malignant group before PSM was further divided into subgroups according to the BRAF V600E mutation and lymphatic metastasis (N stage), and the number of CTCs in different subgroups was compared. RESULTS: After 1:1 PSM, baseline characteristics of the malignant group and benign group were matched and assigned 315 cases in each group. The number of CTCs and the TPOAb values were comparable in the two groups (p > 0.05). The TgAb values [1.890 (1.110 - 16.010) vs 1.645 (1.030 - 7.073) IU/mL, p = 0.049] were significantly higher in the malignant group than in the benign group. After PSM, ROC analyses showed that the areas under the curve (AUCs) of CTC, TgAb and ultrasound were 0.537 (sensitivity 65.6%, specificity 45.8%), 0.546 (sensitivity 40.0%, specificity 70.8%) and 0.705 (sensitivity 77.1%, specificity 63.2%), respectively. The AUCs of the combined detection of 'CTC + ultrasound' (combine 1) and the combined detection of 'CTC + TgAb + ultrasound' (combine 2) were 0.718 (sensitivity 79.3%, specificity 61.7%) and 0.724 (sensitivity 78.0%, specificity 63.3%), respectively. The AUC of ultrasound was significantly higher than CTC (p < 0.001). There was no statistically significant difference in AUC between combination 1 and ultrasound, and between combination 2 and ultrasound (p > 0.05). The number of CTCs between the N0 and N1 subgroups, and between the BRAF mutant and BRAF wild subgroups was comparable (p > 0.05). CONCLUSIONS: As an emerging and noninvasive testing tool, the efficacy of CTCs in diagnosing thyroid cancer is limited.

Association Between Germline BRCA1/2 Gene Variants and Clinicopathological Features of Ovarian Cancer.

Objective: To investigate the relationship between BRCA1/2 gene mutation and clinicopathological features in ovarian cancer patients, so as to develop precise individualized treatment plan for patients. Methods: Patients diagnosed with ovarian cancer between January 2018 and July 2023 who underwent BRCA1/2 genetic testing were retrospectively analyzed. The clinicopathological characteristics (age, body mass index (BMI), family history of ovarian cancer, pregnancy history, menopause status, tumor size, histopathology, Federation of Gynecology and Obstetrics (FIGO) staging, and ascites) of non-carriers and BRCA1/2 variant carriers were compared. Logistic regression analysis was used to explore the relationship between BRCA1/2 variants and clinicopathological characteristics of ovarian cancer. Results: A total of 284 ovarian cancer patients were collected, and the subjects were divided into two groups, 197 non-carriers and 87 BRCA1/2 variants carriers. The proportion of serous ovarian carcinoma in BRCA1/2 variant carriers is higher than that in non-BRCA variant carriers (78.2% vs 60.9%, p=0.015). There were 51 patients with BRCA pathogenic or likely pathogenic variant, 22 patients with BRCA likely benign variant, and 14 patients with BRCA variants of uncertain significance (VUS). The proportion of serous ovarian carcinoma in patients with BRCA pathogenic/likely pathogenic variant is higher than that in patients with BRCA likely benign variant and BRCA VUS (94.1% vs 50.0% and 64.3%. p<0.001). There were no statistically significant differences in BMI, family history of ovarian cancer, pregnancy history, menopause status, maximum diameter of the tumor lesion, FIGO stage, and ascites among patients with different grades of variants. Multivariate logistic regression analysis showed that serous ovarian carcinoma was related to BRCA mutation (Serous carcinoma vs non-serous carcinoma: OR 2.145, 95% CI: 1.044-4.407) (p=0.038). Conclusion: Patients with BRCA1 variant develop ovarian cancer at a younger age than those with the BRCA2 variant. The proportion of FIGO stage III-IV in patients with BRCA pathogenic + likely pathogenic variant was significantly higher than those in patients with other variants. Germline BRCA1/2 variants were most frequently identified in serous ovarian carcinoma patients.

BRCA1 and BRCA2 germline mutations in Chinese Hakka breast cancer patients.

OBJECTIVE: To investigate the prevalence of BRCA1/2 gene variants and evaluate the clinical and pathological characteristics associated with these variants in Chinese Hakka breast cancer patients. METHODS: A total of 409 breast cancer patients were analyzed based on next-generation sequencing results, with 337 categorized as non-carriers and 72 as carriers of BRCA1/2 variants. Data on the patients' BRCA1/2 gene mutation status, clinical and pathological characteristics, as well as menstrual and reproductive information, were collected, analyzed, compared, and tabulated. Logistic regression analysis was performed to explore the relationship between clinical characteristics and pathogenic variants. RESULTS: Among the patients, 72 were identified as carriers of pathogenic or likely pathogenic variants in BRCA1/2, while 337 had likely benign or benign mutations. The BRCA1 c.2635G > T (p. Glu879*) variant was detected at a high frequency, accounting for 12.5% (4/32) of the BRCA1 mutations, while the c.5164_5165del (p.Ser1722Tyrfs*4) variant was common among the BRCA2 mutations, accounting for 17.5% (7/40). It was observed that a higher proportion of BRCA1 carriers had the triple-negative breast cancer subtype, whereas more BRCA2 carriers exhibited estrogen receptor (ER) + and progesterone receptor (PR) + subtypes. Multivariate logistic regression analysis revealed that a family history of cancer (OR = 2.36, 95% CI = 1.00-5.54), bilateral cancer (OR = 4.78, 95% CI 1.61-14.20), human epidermal growth factor receptor 2 (HER2)- (OR = 8.23, 95% CI 3.25-20.84), and Ki67 ≥ 15% (OR = 3.88, 95% CI 1.41-10.65) were associated with BRCA1/2 mutations, with the age at diagnosis, age at menarche, and premenopausal status serving as covariates. CONCLUSIONS: The most common pathogenic variant of the BRCA1 and BRCA2 in breast cancer patients was c.2635G > T and c.5164_5165del, respectively. Additionally, a family history of cancer, bilateral cancer, HER2-, and Ki67 ≥ 15% were identified as independent predictors of BRCA1/2 pathogenic variants.

Analysis of the prognostic value of uric acid on the efficacy of immunotherapy in patients with primary liver cancer.

PURPOSE: Uric acid (UA) plays a dual role as an antioxidant and a prooxidant in patients with malignant tumors; however, the relationship between serum UA and malignancy is currently unclear. This study aims to investigate the prognostic value of serum uric acid level before immunotherapy on the efficacy of primary liver cancer (PLC) immunotherapy, which might provide a basis for optimizing the comprehensive treatment scheme. METHODS: Patients with PLC who were admitted to the First Affiliated Hospital of Gannan Medical College from January 2019 to June 2022 and underwent immunotherapy were collected retrospectively. The difference between serum UA levels in patients with PLC, the correlation between serum UA levels, and the clinical characteristics of patients with PLC were analyzed using the chi-square test, and the survival was estimated using the Kaplan-Meier analysis. To further assess the prognostic significance of UA concentrations, univariate and multivariate Cox regression analyses were performed. RESULTS: Ninety-nine patients were included in this study cohort. The median follow-up was 7 months (range: 1-29 months), and 76 (76.8%) of the 99 patients with PLC died as of December 31, 2022. Serum UA concentrations ranged from 105 to 670 µmol/l, with a median of 269 µmol/l. The results showed that the serum UA level of patients with PLC was higher than that of healthy subjects (P < 0.001). After subgroup analyses, only male patients with liver cancer had higher serum UA levels than healthy men (P = 0.001). The results of the Kaplan-Meier analysis showed that higher UA levels were associated with poor overall survival (OS) (P = 0.005). In univariate analysis, the OS rate of patients with elevated serum UA levels was significantly lower than the cut-off value (hazard ratio [HR]: 3.191, 95% confidence interval [CI]: 1.456-6.993, P = 0.004), with a median survival time of 151 and 312 days in the high and low serum UA groups, respectively. The results of multivariate analysis showed that the UA level was an independent prognostic factor for immunotherapy in patients with PLC (HR: 3.131, 95% CI: 1.766-5.553, P < 0.001). CONCLUSIONS: The serum UA level is a reliable biomarker for predicting the prognosis of patients undergoing immunotherapy for PLC, and might provide a basis for the individualized treatment of these patients. Dynamic monitoring of the serum UA level may compensate for the deficiency of the current liver cancer staging system.

Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients.

OBJECTIVE: The traditional treatment of rheumatoid arthritis (RA) has some side effects. We aimed to explore the effect of metformin treatment on the expression of HMGB1, cytokines, T cell subtypes and the clinical outcomes in RA patients. METHODS: The present prospective cohort study recruited 124 RA patients (metformin group) who were treated with metformin and conventional therapy (methotrexate, hydroxychloroquine sulfate and sulfasalazine) and 98 RA patients (conventional therapy group) who were only treated with conventional therapy. All subjects were admitted from December 2018 to December 2021 and continuous medication for 90 days. The serum high mobility group box 1 (HMGB1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1ß and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometric were used to analyze the expression of CD4+ and CD8+. Demographic and clinical statistics including age, body mass index (BMI), sex, course of disease, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), visual analogue score (VAS)and disease activity score (DAS)-28 were collected. RESULTS: The serum levels of HMGB1, CRP, IL-6, CD4+ expression and CD4+/CD8+ ratio were significantly increased in patients with DAS-28 score ≥ 2.6. The serum HMGB1 and cytokines levels of metformin group declined more quickly during the study time. Pearson's analysis supported that a positive correlation existed between the HMGB1 and IL-6, TNF-α, CRP, CD4+, CD4+/CD8+ ratio, and VAS scores. HMGB1 could be a potential diagnostic biomarker for RA patients in active phase. Serum HMGB1 (95% CI 1.133-1.397, P < 0.001) was a factor associated with active RA. CONCLUSION: The serum HMGB1 levels were significantly increased in RA patients in active phase. The serum levels of HMGB1 and inflammatory factors and VAS scores were decreased gradually with metformin treatment. HMGB1 might act as a novel therapeutic target for RA.

Collagen co-localized with macrovesicular steatosis better differentiates fibrosis progression in non-alcoholic fatty liver disease mouse models.

Background: Non-alcoholic fatty liver disease (NAFLD) is a global commonly occurring liver disease. However, its exact pathogenesis is not fully understood. The purpose of this study was to quantitatively evaluate the progression of steatosis and fibrosis by examining their distribution, morphology, and co-localization in NAFLD animal models. Methods: Six mouse NAFLD groups were established: (1) western diet (WD) group; (2) WD with fructose in drinking water (WDF) group; (3) WDF + carbon tetrachloride (CCl4) group, WDF plus intraperitoneal injection of CCl4; (4) high-fat diet (HFD) group, (5) HFD with fructose (HFDF) group; and (6) HFDF + CCl4 group, HFDF plus intraperitoneal injection of CCl4. Liver tissue specimens from NAFLD model mice were collected at different time points. All the tissues were serially sectioned for histological staining and second-harmonic generation (SHG)/two-photon excitation fluorescence imaging (TPEF) imaging. The progression of steatosis and fibrosis was analyzed using SHG/TPEF quantitative parameters with respect to the non-alcoholic steatohepatitis Clinical Research Network scoring system. Results: qSteatosis showed a good correlation with steatosis grade (R: 0.823-0.953, p < 0.05) and demonstrated high performance (area under the curve [AUC]: 0.617-1) in six mouse models. Based on their high correlation with histological scoring, qFibrosis containing four shared parameters (#LongStrPS, #ThinStrPS, #ThinStrPSAgg, and #LongStrPSDis) were selected to create a linear model that could accurately identify differences among fibrosis stages (AUC: 0.725-1). qFibrosis co-localized with macrosteatosis generally correlated better with histological scoring and had a higher AUC in six animal models (AUC: 0.846-1). Conclusion: Quantitative assessment using SHG/TPEF technology can be used to monitor different types of steatosis and fibrosis progression in NAFLD models. The collagen co-localized with macrosteatosis could better differentiate fibrosis progression and might aid in developing a more reliable and translatable fibrosis evaluation tool for animal models of NAFLD.

The burden of hepatitis C virus in the world, China, India, and the United States from 1990 to 2019.

Background and aim: Hepatitis C virus infection can lead to an enormous health burden worldwide. Investigating the changes in HCV-related burden between different countries could provide inferences for disease management. Hence, we aim to explore the temporal tendency of the disease burden associated with HCV infection in China, India, the United States, and the world. Methods: Detailed data on the total burden of disease related to HCV infection were collected from the Global Burden of Disease (GBD) 2019 database. Joinpoint regression models were used to simulate the optimal joinpoints of annual percent changes (APCs). Further analysis of the age composition of each index over time and the relationship between ASRs and the socio-demographic Index (SDI) were explored. Finally, three factors (population growth, population aging, and age-specific changes) were deconstructed for the changes in the number of incidences, deaths, and DALYs. Results: It was estimated that 6.2 million new HCV infections, 0.54 million HCV-related deaths, and 15.3 million DALYs worldwide in 2019, with an increase of 25.4, 59.1, and 43.6%, respectively, from 1990, are mainly due to population growth and aging. China experienced a sharp drop in age-standardized rates in 2019, the United States showed an upward trend, and India exhibited a fluctuating tendency in the burden of disease. The incidence was increasing in all locations recently. Conclusion: HCV remains a global health concern despite tremendous progress being made. The disease burden in China improved significantly, while the burden in the United States was deteriorating, with new infections increasing recently, suggesting more targeted interventions to be established to realize the 2030 elimination goals.

Diagnostic performance and prognostic value of circulating tumor DNA methylation marker in extranodal natural killer/T cell lymphoma.

Circulating tumor DNA (ctDNA) carries tumor-specific genetic and epigenetic variations. To identify extranodal natural killer/T cell lymphoma (ENKTL)-specific methylation markers and establish a diagnostic and prognosis prediction model for ENKTL, we describe the ENKTL-specific ctDNA methylation patterns by analyzing the methylation profiles of ENKTL plasma samples. We construct a diagnostic prediction model based on ctDNA methylation markers with both high specificity and sensitivity and close relevance to tumor staging and therapeutic response. Subsequently, we built a prognostic prediction model showing excellent performance, and its predictive accuracy is significantly better than the Ann Arbor staging and prognostic index of natural killer lymphoma (PINK) risk system. Notably, we further establish a PINK-C risk grading system to select individualized treatment for patients with different prognostic risks. In conclusion, these results suggest that ctDNA methylation markers are of great value in diagnosis, monitoring, and prognosis, which might have implications for clinical decision-making of patients with ENKTL.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma.

BACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

ALDH2 gene rs671 G > a polymorphism and the risk of colorectal cancer: A hospital-based study.

BACKGROUND: The susceptibility to some cancers is linked to genetic factors, such as aldehyde dehydrogenase 2 (ALDH2) polymorphisms. The relationship between ALDH2 rs671 and colorectal cancer (CRC) is not clear in Hakka population. METHODS: Between October 2015 and December 2020, a total of 178 CRC patients and 261 controls were recruited. ALDH2 rs671 was genotyped in these subjects, medical records (smoking history, drinking history and blood cell parameters) were collected, and the relationship between these information and CRC was analyzed. RESULTS: The proportion of the ALDH2 rs671 G/G, G/A, and A/A genotype was 48.3%, 44.4%, and 7.3% in patients; 62.1%, 34.1%, and 3.8% in controls, respectively. The difference of ALDH2 genotypes distribution between cases and controls was statistically significant (p = 0.011). The higher percentage of smokers and alcoholics, higher level of neutrophil to lymphocyte ratio (NLR), platelet count, and platelet to lymphocyte ratio (PLR), and lower level of lymphocyte count, lymphocyte to monocyte ratio (LMR), and mean hemoglobin concentration were observed in patients. Logistic regression analysis indicated that ALDH2 rs671 G/A genotype (G/A vs. G/G) (adjusted OR 1.801, 95% CI 1.160-2.794, p = 0.009) and A/A genotype (A/A vs. G/G) (adjusted OR 2.630, 95% CI 1.041-6.645, p = 0.041) in the co-dominant model, while G/A + A/A genotypes (G/A + A/A vs. G/G) (adjusted OR 1.883, 95% CI 1.230-2.881, p = 0.004) in the dominant model were risk factors for CRC. CONCLUSIONS: Individuals carrying ALDH2 rs671 A allele (G/A, A/A genotypes) may be at increased risk of colorectal cancer.

APOE Genetic Polymorphism rs7412 T/T Genotype May Be a Risk Factor for Essential Hypertension among Hakka People in Southern China.

Objective: One of the causes of hypertension is a genetic factor. The purpose of this study was to look at the relationship between apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms and essential hypertension in the Hakka population. Methods: The study included 2,850 patients with hypertension and 2,034 controls. APOE rs429358, rs7412, and MTHFR rs1801133 were genotyped by polymerase chain reaction (PCR)-microarray. The differences in these polymorphisms between the two groups were analyzed. Results: The genotype and allele frequency of APOE and MTHFR polymorphisms did not differ significantly between hypertensive patients and controls. Patients with hypertension who were APOE rs429358C/C homozygous had higher TG, TC, LDL-C, and Apo-B levels, whereas patients with the T/T genotype had higher HDL-C levels. Patients with hypertension who were APOE rs7412T/T homozygous had higher TG and TC levels and lower LDL-C and Apo-B levels. Homocysteine (Hcy) levels in patients with MTHFR CC, CT, and TT genotypes were increased, while patients with the TT genotype and T allele had higher Hcy levels than those of patients with other genotypes and the C allele. The APOE rs7412T/T genotype in the co-dominant model (APOE rs7412T/T vs. C/C) (gender-, age-, smoking-, and drinking-adjusted OR 2.682, 95% CI, 1.072-6.710, P=0.035) was a significant risk factor for hypertension. The APOE rs429358 and MTHFR rs1801133 genotypes in co-dominant, dominant, and recessive models were not significant risk factors for hypertension. Conclusions: It supports that APOE polymorphisms are related to hypertension in the Hakka population. Specifically, the APOE rs7412T/T genotype may be a risk factor for hypertension.

Developing a New qFIBS Model Assessing Histological Features in Pediatric Patients With Non-alcoholic Steatohepatitis.

Background: The evolution of pediatric non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is associated with unique histological features. Pathological evaluation of liver specimen is often hindered by observer variability and diagnostic consensus is not always attainable. We investigated whether the qFIBS technique derived from adult NASH could be applied to pediatric NASH. Materials and Methods: 102 pediatric patients (<18 years old) with liver biopsy-proven NASH were included. The liver biopsies were serially sectioned for hematoxylin-eosin and Masson trichrome staining for histological scoring, and for second harmonic generation (SHG) imaging. qFIBS-automated measure of fibrosis, inflammation, hepatocyte ballooning, and steatosis was estabilshed by using the NASH CRN scoring system as the reference standard. Results: qFIBS showed the best correlation with steatosis (r = 0.84, P < 0.001); with ability to distinguish different grades of steatosis (AUROCs 0.90 and 0.98, sensitivity 0.71 and 0.93, and specificity 0.90 and 0.90). qFIBS correlation with fibrosis (r = 0.72, P < 0.001) was good with high AUROC values [qFibrosis (AUC) > 0.85 (0.85-0.95)] and ability to distinguish different stages of fibrosis. qFIBS showed weak correlation with ballooning (r = 0.38, P = 0.028) and inflammation (r = 0.46, P = 0.005); however, it could distinguish different grades of ballooning (AUROCs 0.73, sensitivity 0.36, and specificity 0.92) and inflammation (AUROCs 0.77, sensitivity 0.83, and specificity 0.53). Conclusion: It was demonstrated that when qFIBS derived from adult NASH was performed on pediatric NASH, it could best distinguish the various histological grades of steatosis and fibrosis.

Correlation between thrombopoietin and inflammatory factors, platelet indices, and thrombosis in patients with sepsis: A retrospective study.

BACKGROUND: Thrombopoietin (TPO) is a primary regulator of thrombopoiesis in physiological conditions. TPO, in combination with its specific cytokine receptor c-Mpl, drives platelet production by inducing the proliferation and differentiation of megakaryocytes. However, the role of TPO in sepsis is not well determined. The elevated levels of TPO are often accompanied by a decrease of platelet count (PLT) in systemic infected conditions, which is contrary to the view that TPO promotes platelet production under physiological conditions. In addition, whether TPO mediates organ damage in sepsis remains controversial. AIM: To explore the relationships between TPO and inflammatory factors, platelet indices, and thrombotic indicators in sepsis. METHODS: A total of 90 patients with sepsis diagnosed and treated at the emergency medicine department of The First People's Hospital of Foshan between January 2020 and March 2021 were enrolled in this study. In addition, 110 patients without sepsis who came to the emergency medicine department were included as controls. Clinical and laboratory parameters including age, gender, TPO, blood cell count in peripheral blood, platelet indices, inflammatory factors such as high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-21, and IL-6, organ damage indicators, and thrombotic indicators were collected and analyzed by using various statistical approaches. RESULTS: The results showed that the TPO levels were higher in the sepsis group than in controls [86.45 (30.55, 193.1) vs 12.45 (0.64, 46.09) pg/mL, P < 0.001], but PLT was lower (P < 0.001). Multivariable analysis showed that white blood cell count (WBC) [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.01-1.722; P = 0.044], TPO (OR = 1.02; 95%CI: 1.01-1.04; P = 0.009), IL-21 (OR = 1.02; 95%CI: 1.00-1.03; P = 0.019), troponin I (OR = 55.20; 95%CI: 5.69-535.90; P = 0.001), and prothrombin time (PT) (OR = 2.24; 95%CI: 1.10-4.55; P = 0.027) were independent risk factors associated with sepsis. TPO levels were positively correlated with IL-21, IL-6, hs-CRP, creatinine, D-dimer, PT, activated prothrombin time, international normalized ratio, fibrinogen, WBC count, and neutrophil count, and negatively correlated with PLT, thrombin time, red blood cell count, and hemoglobin concentration (P < 0.05). Receiver operating characteristic analysis showed that TPO had fair predictive value in distinguishing septic patients and non-septic patients (the area under the curve: 0.788; 95%CI: 0.723-0.852; P < 0.001). With an optimized cutoff value (28.51 pg/mL), TPO had the highest sensitivity (79%) and specificity (65%). CONCLUSION: TPO levels are independently associated with sepsis. High TPO levels and low PLT suggest that TPO might be an acute-phase response protein in patients with infection.