AbstractBackground: Cancer-associated fibroblasts (CAFs) critically regulate colorectal cancer (CRC) progression, but the contribution of 5-fluorouracil (5-FU)-induced senescent CAFs to CRC malignancy and whether this stromal response can be pharmacologically restrained remain unclear. This study investigated whether Glabridin (Gla) attenuates the pro-tumorigenic activity of 5-FU-induced senescent CAFs.Methods: Primary human CRC-derived CAFs were exposed to 5-FU to establish a senescence model, which was validated by SA-β-Gal staining, EdU assay, cell-cycle analysis, γ-H2AX immunofluorescence, p53/p21 detection, and SASP marker analysis. Drug-free conditioned media (CM) collected from control, 5-FU-treated, and 5-FU plus Gla-treated CAFs after drug withdrawal and medium replacement were applied to RKO and SW480 cells to assess proliferation, migration, and invasion. Transcriptomic and integrative analyses were used to identify candidate SASP factors, followed by RT-qPCR and ELISA validation.Results: 5-FU induced a stable senescent phenotype in primary CAFs and enhanced SASP factor expression. CM from senescent CAFs promoted CRC cell proliferation, wound closure, and invasion. MMP1, MMP3, and MMP12 were identified as candidate senescence-associated secretory factors and were upregulated in 5-FU-induced senescent CAFs. Gla significantly suppressed 5-FU-induced MMP1/3/12 mRNA expression and reduced the cell number-normalized secretion of these MMPs in senescent CAF-CM. Functionally, CM from 5-FU plus Gla-treated CAFs exhibited weaker pro-tumorigenic effects than 5-FU-CM.Conclusions: Gla attenuates the pro-tumorigenic activity of 5-FU-induced senescent CAFs, at least in part by suppressing MMP1/3/12 expression and secretion. These findings suggest that Gla may help mitigate chemotherapy-associated stromal remodeling in CRC.

BackgroundProgrammed death-1 (PD-1) inhibitors plus tyrosine kinase inhibitors (TKIs) combination therapy are considered as a first-line treatment recommendation for advanced hepatocellular carcinoma (HCC). However, patients with hyperbilirubinemia are excluded from this therapeutic option due to limitations in indications. There is a notable absence of published studies evaluating the safety and efficacy of the PD-1 inhibitors plus TKIs combination therapy in patients with HCC combined with hyperbilirubinemia.MethodsPatients with HCC complicated with hyperbilirubinemia who received combination therapy with PD-1 inhibitors and TKIs were retrospectively analyzed. Adverse events, tumor response, and laboratory parameters were recorded to assess the safety and efficacy of the treatment, as well as to identify potential risk factors influencing survival.ResultsA total of 108 participants were included in the study, with 56 patients (51.9%) reporting at least one adverse event, the majority of which were mild. The objective response rate (ORR) for the enrolled participants was 11.9%, and the disease control rate(DCR) reached 61.2%. The median overall survival (OS) for the entire cohort was 5.03 months, while the median progression-free survival (PFS) was 3.63 months. Multifactorial analysis showed that MELD score >18 and increased total bilirubin (TBIL) levels within one week were significant risk factors for OS. Patients with a decrease in TBIL levels within one week had significantly prolonged median OS (not reached vs 3.3months, P =0.013) and median PFS (7.03 months vs 2.77 months, P =0.010).ConclusionCombination therapy demonstrated favorable safety and tolerability among patients with HCC combined with hyperbilirubinemia. Patients who experienced a rapid decline in TBIL levels during the early phase of treatment with PD-1 inhibitors and TKIs were observed to derive clinical benefits. Early initiation of aggressive interventions aimed at reducing TBIL levels is recommended to optimize treatment outcomes.

BACKGROUND:Ursodeoxycholic acid (UDCA) is the first-line therapeutic agent for primary biliary cholangitis (PBC). However, a subset of patients exhibit a suboptimal response to UDCA, and reliable predictive biomarkers remain elusive. Studies have implicated plasma microRNAs (miRNAs) in the pathophysiological progression of PBC, with certain miRNAs demonstrating potential as diagnostic and disease progression biomarkers. However, biomarkers capable of predicting the therapeutic efficacy of UDCA have not yet been identified. AIM:To investigate differentially expressed miRNAs in PBC patients with divergent UDCA treatment responses and to explore potential biomarkers that predict treatment response in PBC. METHODS:Plasma samples from treatment-naive PBC patients receiving ≥ 1 year of standard UDCA treatment were collected. Efficacy was evaluated using the Paris I criteria. Patient samples were divided into discovery group (n = 10) and validation group (n = 30), with further stratification of patients into drug-resistant and drug-sensitive (DS) cohorts. Next-generation sequencing and quantitative real-time polymerase chain reaction were used to screen, functionally analyze, and validate the pre-treatment miRNA profiles of the treatment groups. RESULTS:Forty-nine miRNAs were differentially expressed between the two groups before UDCA treatment (N = 40). MiR-22-5p and miR-126-3p were highly expressed in the DS group before treatment (P < 0.001), whereas miR-7706 exhibited a low expression (P = 0.017). Post-treatment, miR-126-3p maintained low expression in the drug-resistant group (P = 0.003), but showed elevated levels in the DS group (P < 0.001). Logistic regression analysis identified miR-126-3p expression (odds ratio = 34.32, 95% confidence interval: 1.95-605.40, P = 0.016) as a significant factor influencing UDCA treatment response, while miR-22-5p (P = 0.990) and miR-7706 (P = 0.157) showed no significant association. MiR-126-3p levels were negatively correlated with total bilirubin (r = -0.356, P = 0.005) and immunoglobulin G levels (r = -0.311, P = 0.015). The area under the receiver operating characteristic curve was 0.891 (P = 0.0003, 95% confidence interval: 0.772-1.000) with a sensitivity of 82.4% and a specificity of 84.6%. CONCLUSION:Plasma miRNA expression profiles are heterogenous in patients with PBC with differential responses to UDCA therapy. MiR-126-3p demonstrates predictive potential for a suboptimal response to UDCA in patients with PBC.

This study retrospectively evaluated the safety and efficacy of cadonilimab combined with tyrosine kinase inhibitors (TKI) for the treatment of unresectable hepatocellular carcinoma (uHCC). Seventy-eight patients who received cadonilimab + TKI were included; 42 and 36 received it as first-line (1 L) and second-line and above (≥ 2 L) systemic treatment, respectively. Besides, ninety-five patients who received PD-1 inhibitor + TKI as first-line treatments were included. Safety was the primary endpoint; secondary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Treatment-related adverse events (TRAEs) of any grade occurred in 84.6

Addressing the enduring challenge of evaluating traditional Chinese medicines (TCMs), the integrated evidence chain-based effectiveness evaluation of TCMs (Eff-iEC) has emerged. This paper explored its capacity through a demonstration study that evaluated the effectiveness evidence of six commonly used anti-hepatic fibrosis Chinese patent medicines (CPMs), including Biejiajian Pill (BP), Dahuang Zhechong Pill (DZP), Biejia Ruangan Compound (BRC), Fuzheng Huayu Capsule (FHC), Anluo Huaxian Pill (AHP), and Heluo Shugan Capsule (HSC), using both Eff-iEC and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The recognition of these CPMs within the TCM academic community was also assessed through their inclusion in relevant medical documents. Results showed that the evidence of BRC and FHC received higher assessments in both Eff-iEC and GRADE system, while the assessments for others varied. Analysis of community recognition revealed that Eff-iEC more accurately reflects the clinical value of these CPMs, exhibiting superior evaluative capabilities. By breaking through the conventional pattern of TCMs effectiveness evaluation, Eff-iEC offers a novel epistemology that better aligns with the clinical realities and reasoning of TCMs, providing a coherent methodology for clinical decision-making, new drug evaluations, and health policy formulation.

Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven’t been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ − 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child–Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child–Pugh classification.

Background: The outbreak and prevalence of the Omicron variant have threatened human health since March 2022 in mainland China. In this study, we aimed to investigate the clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) in the Beijing region. Methods: In this retrospective study, we enrolled inpatients admitted for COVID-19 in the Fifth Medical Center of Chinese PLA General Hospital in Beijing between November 10, 2022, and January 30, 2023. Demographic and clinical features and treatment outcomes were comprehensively analyzed. We used logistic regression and linear regression analyses to explore the risk factors associated with disease severity and time of nucleic acid conversion, respectively. Results: A total of 1010 hospitalized patients with COVID-19 were enrolled. The median age was 43.0 years (interquartile range, 28.0-63.0), and patients aged <60 years and >= 60 years comprised 71.2% and 28.8% of total included patients, respectively. The clinical classification of mild (74.6%, 753/1010), moderate (21.0%, 212/1010), severe (2.7%, 27/1010), and unidentified (1.8%, 18/1010) was separately recorded; 1005 patients were discharged, and 5 patients died in the hospital. The outbreak of the emerging epidemic witnessed an evident increase in the proportion of moderate (42.9% vs. 16.4%) and severe (10.3% vs. 1.1%) cases after December 7, 2022. Patients with a moderate/severe classification had higher levels of procalcitonin, IL-6, serum ferritin, C-reactive protein, lactic dehydrogenase, serum urea nitrogen, and d-dimer and lower counts of CD4(+) T, CD8(+) T, and B cells (all P < 0.001). Multivariable regression analysis revealed that increased odds of disease severity were associated with the following factors: age >= 60 years, IL-6 > 7 pg/mL, lactic dehydrogenase level >245 U/L, cough, and fever at admission. Age >= 80 years and chronic lung disease were independent risk factors in the nonmild group in elderly patients. In addition, the duration for nucleic acid to turn negative was approximately 5.0 d (interquartile range, 3.0-7.0). Prolonged time of nucleic acid conversion was associated with age >= 60 years, serum urea nitrogen level >8.2 mmol/L, neutrophil count >7 x10(9)/L, and the presence of a chronic lung disease or carcinoma. Finally, unvaccinated patients accounted for 37.3% of enrolled patients; children and the elder people accounted for approximately half of that. The univariable analysis found that booster doses reduced disease severity and shortened the time of nucleic acid conversion in elderly patients. Conclusions: The outbreak of Omicron rapidly increased the number of patients with COVID-19 in Beijing. In elderly patients, booster doses may reduce disease severity and shorten the time of nucleic acid conversion. Healthcare systems should be optimized before an emerging epidemic outbreak.

Background:The most common type of primary liver cancer is hepatocellular carcinoma (HCC), and hepatitis B virus (HBV)-related HCC accounts for many HCC cases and has a high mortality rate. The goal of our study was to investigate the efficacy and safety of lenvatinib plus sintilimab therapy in real-world practice and identify factors affecting long-term prognosis.Methods:A retrospective study was conducted with 139 consecutive patients with unresectable HCC treated with lenvatinib or lenvatinib plus sintilimab at the Fifth Medical Center of PLA General Hospital from June 2018 to June 2021. The 139 patients were divided into the control group (85 patients) and the combined treatment group (54 patients) according to the antitumour drugs used for treatment. Efficacy was determined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the HCC-specific modified RECIST (mRECIST) for 139 patients who completed the 1st and second tumour assessments. Safety was evaluated in 60 patients in the combined treatment group and 90 patients in the control group using the Common Terminology Criteria for Adverse Events version 5.0.Results:A total of 139 male Chinese patients (49.6% ≥ 55 years old) were included in the efficacy analysis. The median overall survival in the combined treatment group was 21.7 months, and the median progression-free survival was 11.3 months. According to the mRECIST criteria, the objective response rate was 38.9%, and the disease control rate was 92.6%. The median overall survival (mOS), median progression-free survival (mPFS), overall response rate (ORR) and disease control rate (DCR) in the lenvatinib monotherapy group were 12.8 months, 6.6 months, 24.7%, and 74.1%, respectively. Hypertension was the most common adverse event in both groups. Some immune-related adverse events, such as hypothyroidism (n = 5), elevated blood creatinine (n = 3), elevated cardiac enzymes (n = 1), elevated amylase (n = 1) and increased fasting glucose (n = 1), occurred only in the combined therapy group. Five patients in the lenvatinib monotherapy group and six patients in the lenvatinib plus sintilimab group discontinued therapy due to severe adverse events (AEs) (grade 3). No ≥ 4-grade AEs occurred in any patients.Conclusion:The TKI lenvatinib combined with PD-1-targeted immunotherapy sintilimab is efficacious and safe in real-world practice and may lead to better long-term outcomes than lenvatinib alone.

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09538.].

Objective:To study the curative efficacy of Chinese and Western medicine treatment the virus hepatitis B virus associated acute-on-chronic liver failure and chronic hepatic failure.Methods:The perspective multicenter randomized control clinical trial was used.The patients who were liver failure and chronic hepatic failure had the ratio of 2:1 access to treatment group and control group.Study the fatality rate between two groups in 8weeks,12 weeks,24 weeks,and 48 weeks.Results:Patients' fatality rates about the hepatitis B virus associated acute-on-chronic liver failure had a significant difference between the two groups in 8 weeks,12 weeks,24weeks and 48weeks(P ＜ 0.05).The case fatalities were reduced obviously in treatment group.For the advanced stage patients suggested that traditional Chinese medicine may improve the prognosis,according the variance homogeneity(P =0.0525).For patients of the hepatitis B virus associated chronic hepatic failure,there was no statistical difference (P ＞ 0.05)between the two groups in in 8 weeks,12 weeks,24weeks and 48weeks.Conclusion:The treatment prescription with the method of integrated traditional and western medicine in the virus hepatitis B virus associated acute-on-chronic liver failure can reduce the mortality,especially in the advanced stage that cannot have liver transplantation and other means.

一、前言 药源性肝损伤,亦称药物性肝损伤(Druginduced liver injury,DILI),是指由药物本身及/或其代谢产物等所导致的肝脏损伤,为临床常见的药物不良反应之一[1-4],严重者可致急性肝衰竭甚至死亡[5].药源性肝损伤已成为药物研发包括中药研发失败、增加警示和撤市的重要原因,受到医药界、制药业、管理部门及公众的高度重视[6-8].

1. Introduction Drug-induced liver injury （DILI）, defined as liver injury caused by a drug and/or its metabolites, is a common clinical adverse drug reaction 1–4 . This type of injury can cause acute liver failure and even death in severe cases5. DILI accounts for many drug

Objective To investigate the expression of CD160 in HIV-specific T cells and their subsets in peripheral blood of asymptomatic human immunodeficiency virus (HIV) infected individuals.Methods A total of 43 asymptomatic HIV-infected individuals without antiretroviral therapy (ART) and 18 healthy controls were recruited from the No.302 Hospital of PLA between June 2014 and November 2015.Peripheral blood mononuclear cells (PBMC) were isolated from peripheral bloods of these subjects.CD160 was stained with fluorescent antibody.Expression of CD160 in HIV-specific T cells and their subsets was detected by flow cytometry.Results The frequency and median fluorescence intensity (MFI) of CD160 on the whole HIV-specific CD4 + T cells and CD8 + T cells were higher than those in the healthy controls (P＜0.01).In subsets ofHIV-specific CD4+ T cells,the MFI of CD160 in CD4+ Tn cells and CD4+ Teff cells,and the frequency of CD160 in CD4 + Teff cells were significantly increased (P ＜ 0.01).CD8 + Tn fine,CD8 + Tcm cells and CD8 + Tem cells showed a significant upregulation in the frequency and MFI of CD160 (P ＜0.01).Conclusions Chronic HIV infection can lead to high expression of CD160 in HIV-specific T cells and their different subsets,causing cellular immune dysfunction,which may further impair the ability to control the HIV virus.

肝硬化的早期治疗是至关重要的,尽管现有的疗法并不能彻底治愈肝硬化,但可以预防和延缓它对肝脏造成的损害. 肝硬化的治疗包括药物治疗、手术治疗和其他一些方法.每个病人都应根据自己肝硬化的病因和肝硬化所带来的问题选择相应的治疗.

OBJECTIVES:In this study, we studied the N and H genes from wild type measles viruses (MeVs) isolated during the 2013-2014 outbreak.METHODS:Clinical samples were collected, and the genotyping, phylogenetic analysis were performed.RESULTS:The vaccination rate of the study population was 4%. Genotype H1a was the predominant genotype. Wild type viruses were classified into clusters A and B, C and may have different origins. N-450 sequences from wild type viruses were highly homologous with, and likely evolved from MeVs circulating in Tianjing and Henan in 2012. MVs/Shenyang.CHN/18.14/3 could have evolved from MeVs from Liaoning, Beijing, Hebei, Heilongjiang, Henan, Jilin, and Tianjin. Our data suggested that one or more of the same viruses circulated between Beijing, Shenyang, Hong Kong, Taiwan and Berlin.CONCLUSIONS:Important factors contributing to outbreaks could include weak vaccination coverage, poor vaccination strategies, and migration of adult workers between cities, countries, and from rural areas to urban areas.

To evaluate the clinical efficacy and safety of Yinchen Zhufu Decoction (eOE mu e (TM) aee-e (TM)"ae +/- currency sign, YCZFD) in the treatment of acute-on-chronic liver failure caused by hepatitis B virus (HBV-ACLF) with cold pattern in Chinese medicine (CM).This is a multi-center randomized controlled trial of integrative treatment of CM and Western medicine (WM) for the management of HBV-ACLF patients. A total of 200 HBV-ACLF patients with cold pattern were equally randomly assigned to receive YCZFD and WM (integrative treatment) or WM conventional therapy alone respectively for 4 weeks. The primary end point was the mortality for HBV-ACLF patients. Secondary outcome measures included Model for End-Stage Liver disease (MELD) score, liver biochemical function, coagulation function and complications. Adverse events during treatment were reported.The mortality was decreased 14.28% in the integrative treatment group compared with WM group (chi(2) =6.156, P=0.013). The integrative treatment was found to signifificantly improve the MELD score (t=2.353, P=0.020). There were statistically signifificant differences in aspartate transaminase, total bilirubin, indirect bilirubin, direct bilirubin and prothrombin time between the two groups (P < 0.05 or P < 0.01). The complications of ascites (chi(2)=9.033, P=0.003) and spontaneous bacteria peritonitis (chi(2)=4.194, P=0.041) were improved signifificantly in the integrative treatment group. No serious adverse event was reported.The integrative treatment of CM and WM was effective and safe for HBV-ACLF patients with cold pattern in CM. The Chinese therapeutic principle "treating cold pattern with hot herbs" remains valuable to the clinical therapy. (Trial registration No. ChiCTR-TRC-10000766).

老年人由于其特殊的生理状况及各种退行性病变,特别是心脑血管病、高血压、骨质松症等疾病的存在,平日生活要特别注意,防止出现以下3种情况. 其一:防激动老年人切忌激动,一定要心平气和.人到老年,体力已经虚弱,不要再竭力追求或操心过多的身外之事.激烈的情绪变化,可使血压大幅度上升,体内释放出一系列不利于健康的生物活性物质,可导致中风、心绞痛、心肌梗死、甚至猝死.为此,老年人应加强心理调适能力,学会自我控制,不让自己陷入“悸动万分”的困境,进而造成意外不测.

肝炎病人在潜伏期末就有传染性,尤其是发病初期的传染性最强.如果家中有人表现为乏力、发热、食欲不振、腹部堵胀或饱满时,要及时就医检查,以便早发现、早诊断、早隔离、早治疗. 肝炎病以隔离治疗最为理想.家属应在病人住院期间,及时对病人用过的物品进行一次彻底的消毒.如果无条件住院,在家里隔离治疗,应做到“一独”“二保”“三分开”“四消毒”. 一独让病人单独使用餐具、茶具、洗漱用具等生活用品.

Objective To investigate the changes of serum of vascular endothelial growth factor receptor 2 ( VEGFR-2) and alpha fetal protein (AFP) levels for using sorafenib in the treatment of HBV related hepatocellular carcinoma (HCC). Methods 46 patients who meet the diagnostic criteria of Barcelona in the late stage of HBV related HCC patients were select-ed and divided into 2 groups, 23 cases in each group , the control group were treated with anti HBV , anti symptomatic , sup-portive and other conventional treatment , the treatment group were treated with sorafenib 400 mg orally on the basis of conven-tional therapy, 2 times a day.6 weeks as 1 observation period.Serum VEGFR-2 and AFP levels were observed in both of the 2 groups.Results Control group’s VEGFR-2’s level in before treatment (8 603.2 pg /ml ±573.4 pg /ml) and after treatment (8 303.1 pg /ml ±527.7 pg /ml) did not show significant changes ( P >0.05); treatment group’s after treat-ment’s level (6 313.8 pg /ml ±559.9 pg /ml) were significantly lower than those before treatment (8 401.1 pg/ml ± 414.6 pg/ml), the difference has statistical significance ( P <0.05).The treatment group’s index was decreased more than that of control group ( P <0.05).The control group and the treatment group ’ s AFP level before treatment were 100.8 (25.0,1 925.1) pg /ml and 89.2 (21.7, 1 567.2) pg /ml, after treatment were 103.7 (18.5.2 083.2) pg/ml and 78.4 (21.6, 684.3) pg/ml, respectively, before and after treatment, AFP had no obvious change in both of the two groups ( P >0.05).VEGFR 2 and AFP level had no correlation( r =-0.337, P =0.048).Conclusion Sorafenib can decrease VEG-FR 2 in patients with HCC , it has certain significance to the clinical treatment of liver cancer .