Background The clinical application of direct-acting antiviral agents has substantially enhanced the sustained virological response (SVR) rates in chronic hepatitis C virus (HCV) infection. Nevertheless, treatment failure continues to occur, primarily due to resistance-associated substitutions arising from HCV's high genetic variability, while real-world data on multigenic resistance in HCV genotype 1b remain limited. Herein, we describe a patient with HCV genotype 1b infection (baseline HCV RNA level of \(\:6.1\times\:{10}^{5}\)IU/mL) who experienced virological breakthrough, with viral rebound to 4.92 × 10⁵ IU/mL, after 12 weeks of elbasvir/grazoprevir (Zepatier) therapy. Case presentation: A 60-year-old man presenting with dry mouth and bitter taste was confirmed to have HCV genotype 1b infection. Resistance testing revealed co-occurring mutations at four sites within the HCV NS5A region: R30Q, L31M, Q54H, and Y93H. The patient received a 12-week course of salvage therapy with sofosbuvir/velpatasvir/voxilaprevir, achieving and maintaining SVR, with HCV RNA levels remaining < 15 IU/mL through 154 weeks of follow-up. Conclusions This case highlights treatment failure associated with four-site NS5A resistance mutations in HCV genotype 1b. It also reminds clinicians of the potential risk of multi-locus drug-resistant mutations even in the so-called "easy-to-treat" HCV genotype 1b, highlighting the importance of strengthened virological monitoring throughout therapy and prompt resistance testing following treatment failure.

BACKGROUND & AIMS:Patients with chronic hepatitis B (CHB) with low hepatitis B surface antigen (HBsAg) levels and suppressed hepatitis B virus (HBV) DNA on nucleos(t)ide analogues (NAs) may achieve functional cure with peginterferon α (PegIFNα)-based therapy. This real-world multicenter study (Everest Project) in China aimed to evaluate the effectiveness and safety of PegIFNα-2b and determine the predictors of HBsAg loss. METHODS:Patients with NA-suppressed CHB who were hepatitis B e antigen (HBeAg)-negative, had HBsAg ≤1500 IU/mL, and undetectable HBV DNA, were administered PegIFNα-2b for 48 weeks, either as a switch-to or add-on therapy. The primary endpoint was HBsAg loss at week 48. RESULTS:Among 15,896 patients in the full analysis set (FAS) and 12,260 in the per-protocol set (PPS), HBsAg loss rate at week 48 was 26.4% and 33.8%, respectively, after propensity score weighting, with no significant difference between switch-to and add-on groups. Key predictors of HBsAg loss included lower baseline HBsAg and HBsAg decline >63.3% at week 12 and >95.3% at week 24. Among patients who underwent >24 weeks of post-treatment follow-up, HBsAg loss rates at week 24 were 28.7% and 35.6% in the FAS and PPS, respectively. Of those who received consolidation therapy, 85.9% maintained HBsAg loss at week 72. Adverse event-related discontinuation occurred in 5.6% and 4.4% of those in the FAS and PPS, respectively. CONCLUSIONS:PegIFNα-2b enhances HBsAg loss in patients with NA-suppressed, HBeAg-negative CHB with low HBsAg levels. Baseline and on-treatment predictors support the achievement of a functional cure. CLINICALTRIALS:gov, Number: NCT04035837.

OBJECTIVE:To explore the key molecules and regulatory mechanisms of lymph node metastasis in gastric cancer. METHODS:The differential genes and key genes of lymph node metastasis in gastric cancer were analyzed by utilizing multiple data sets. The key genes were analyzed by GSEA analysis, transcription factor analysis, nomogram prediction model construction, immune infiltration analysis, GSVA analysis, drug sensitive analysis and single cell data analysis. RESULTS:Abnormal expression of key genes including CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4, PKIA and activation of related signaling pathways might be the result of ultraviolet radiation-induced DNA damage, which was closely related to lymph node metastasis in gastric cancer. The key genes were regulated by a variety of transcription factors, which were strongly connected with the invasion of immune cells and the sensitivity of a variety of drugs. The nomogram prediction model, which is based on the key genes associated with lymph node metastasis and the TNM of gastric cancer, demonstrated a high level of predictive efficiency. CONCLUSION:CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4 and PKIA may be the key genes affecting lymph node metastasis in gastric cancer, and F2R has higher biological importance.

Background:rtM204I mutation is commonly associated with resistance to nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV), often resulting in virological breakthrough and treatment failure. Owing to unique immunological and virological characteristics of HBV, achieving a functional cure in pediatric patients is easier than in adults, and cases involving concurrent drug-resistant mutations are rare. Case Description:A 4-year-old boy infected with HBV through mother-to-child transmission experienced virological rebound (HBV DNA, 4.66×107 IU/mL) after 12 months of lamivudine (LAM) monotherapy. Resistance testing revealed rtM204I mutation. The treatment regimen was adjusted to tenofovir disoproxil fumarate (TDF) combined with pegylated interferon α-2a (PegIFNα-2a). At 12 weeks of treatment, there was a significant decline in hepatitis B surface antigen (HBsAg) levels accompanied by positive antibody to hepatitis B surface antigen (anti-HBs), thus presenting an atypical serological pattern of double positivity for HBsAg and anti-HBs. By week 24, HBsAg was negative, but hepatitis B e antigen (HBeAg) remained positive, demonstrating an atypical serological pattern of response dissociation whereby HBsAg disappeared before HBeAg. TDF combined with PegIFNα-2a was administered until week 36, resulting in persistent HBsAg negativity and a significant increase in anti-HBs levels. PegIFNα-2a was discontinued, and TDF monotherapy was continued for 10 months. During this period, HBsAg negativity and anti-HBs positivity were maintained, HBeAg became negative, and alanine aminotransferase levels remained normal. These results indicate achievement of a functional cure. Conclusions:This case indicated that in children with rtM204I mutation, optimizing antiviral therapy combined with PegIFNα-2a can achieve a functional cure despite atypical serological response patterns. Long-acting interferons have significant therapeutic value in pediatric patients with drug-resistant mutations.

BackgroundThis study aimed to evaluate the efficacy and safety of tenofovir alafenamide fumarate (TAF) in nucleos(t)ide analogue (NA)-experienced patients with chronic hepatitis B (CHB) who exhibited partial virological response (PRT) or low-level viremia (LLV).MethodsThis single-center, retrospective, real-world study enrolled NA-experienced CHB patients who were switched to TAF treatment. Patients were categorized into the PRT (HBV DNA > 2,000 IU/mL) or LLV (20 IU/ mL < HBV DNA ≤ 2,000 IU/mL) groups according to baseline HBV DNA levels. The dynamic changes in HBV DNA, HBsAg, HBeAg, ALT, and APRI were analyzed after switching to TAF.ResultsA total of 91 CHB patients with prior NA treatment and detectable HBV DNA after at least 48 weeks of therapy were enrolled and subsequently switched to TAF. Among them, 24 patients had PRT, and 67 patients had LLV. The complete virological response rate (HBV DNA < 20 IU/mL) in the PRT group was 29.1% at week 24 and 75.0% at week 48; in the LLV group, it was 76.1% and 88.1%, respectively. Both groups showed a decline in HBeAg levels from baseline to week 24 and 48. In the PRT group, HBsAg levels decreased by 9.0% and 5.0% at week 24 and 48, respectively; in the LLV group, the reductions were 2.1% and 3.6%. The ALT normalization rate increased by 24.2% at week 48 compared with baseline. Additionally, eGFR levels improved after switching to TAF. No serious adverse events (SAEs) or deaths related to adverse events were observed.ConclusionThis real-world study suggests that switching to TAF is an effective and well-tolerated therapeutic strategy for NA-experienced CHB patients with PRT or LLV, offering a promising approach for treatment optimization.

BACKGROUND & AIMS:Liver stiffness measurement (LSM) cutoffs for diagnosis of liver fibrosis in untreated patients with chronic hepatitis B (CHB) have been well-established. However, the applicability and the optimal LSM cutoffs for patients undergoing antiviral therapy remain unclear. METHODS:Adults with CHB who had LSM and liver biopsy on the same day during antiviral therapy were enrolled from 2 clinical studies and their extension observations (NCT01938820, NCT01943617, NCT01938781, and NCT03777969). Liver fibrosis was evaluated according to the METAVIR and Ishak scoring system. The performance of LSM measured by vibration-controlled transient elastography (VCTE) devices was estimated using the area under the receiver operating characteristic curve (AUROC). RESULTS:A total of 754 patients were enrolled and randomly divided into derivation and validation sets in a ratio of 2:1. Among them, 75.9% of patients (572/754) were male, with a median age of 42.1 years (interquartile range [IQR], 34.0-49.0 years). The median treatment duration was 1.5 years (IQR, 1.0-2.5 years). The cutoffs of LSM for diagnosis of ≥F2, ≥F3, and F4 during antiviral treatment were 7.6 kPa, 7.6 kPa, and 9.0 kPa, respectively, with a sensitivity of 57.5%, 79.2%, and 74.4%, and a specificity of 86.1%, 73.0%, and 77.2%. The area under the receiver operating characteristic curve (AUROC) for diagnosing ≥F2, ≥F3, and F4 were 0.753 (95% confidence interval [CI], 0.712-0.790), 0.818 (95% CI, 0.778-0.848), and 0.815 (95% CI, 0.755-0.846), respectively. CONCLUSIONS:The optimal cutoffs for diagnosing ≥F2/F3 and F4 in on-treatment patients with CHB were 7.6 kPa and 9.0 kPa. These cut-offs could be reliably and repeatedly applied for long-term monitoring of patients with CHB under antiviral therapy.

Cancer is a significant public health problem worldwide, and its morbidity and mortality are challenging to improve, which is an important obstacle to prolonging life expectancy. Cytotoxic drugs have been used in anti-cancer therapy since the 1940s. They play an important role in tumor therapy. However, drug resistance and systemic toxicity often limit its application. Combination or synergistic chemotherapy can promote therapeutic effects and reduce toxicity. Quercetin (QUE) is a natural flavonoid widely found in fruits and vegetables. It has anti-cancer, anti-inflammatory, antioxidant, and neuroprotective properties. An increasing number of studies have found that the combination of QUE and chemotherapy drugs has a chemosensitization effect. To a certain extent, it can inhibit the side effects of chemotherapeutic drugs, such as nephrotoxicity, cardiotoxicity, reproductive toxicity, and neurotoxicity, which has attracted great attention. The immune system plays a significant role in tumor development. Notably, several studies have revealed that QUE plays an immunomodulatory role by promoting the differentiation of anti-cancer immune cells and inhibiting immune checkpoint expression. In conclusion, current studies have emphasized the potential of QUE in chemosensitization, reduction of toxic side effects, and enhancement of the anti-cancer immune response. However, more preclinical and clinical cohort studies are needed to determine QUE’s efficacy, mechanism, optimal formulation, and long-term effects in synergistic chemotherapy and immunomodulatory effects.

Background:The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC. Methods:FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays. Results:FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05). Conclusion:Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.

BACKGROUND & AIMS: Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liverrelated events (LREs) in chronic hepatitis B patients. METHODS: Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage >= 3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs. RESULTS: A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 x 10(9)/L). CONCLUSIONS: Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.

Background & aimsEpidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China.MethodsWe identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model.ResultsA total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence.ConclusionOur study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

Cancer cells are usually featured by metabolic adaptations that facilitate their growth, invasion, and metastasis. Thus, reprogramming of intracellular energy metabolism is currently one of the hotspots in the field of cancer research. Whereas aerobic glycolysis (known as the Warburg effect) has long been considered a dominant form of energy metabolism in cancer cells, emerging evidence indicates that other metabolic forms, especially oxidative phosphorylation (OXPHOS), may play a critical role at least in some types of cancer. Of note, women with metabolic syndromes (MetS), including obesity, hyperglycemia, dyslipidemia, and hypertension, have an increased risk of developing endometrial carcinoma (EC), suggesting a close link between metabolism and EC. Interestingly, the metabolic preferences vary among EC cell types, particularly cancer stem cells and chemotherapy-resistant cells. Currently, it is commonly accepted that glycolysis is the main energy provider in EC cells, while OXPHOS is reduced or impaired. Moreover, agents specifically targeting the glycolysis and/or OXPHOS pathways can inhibit tumor cell growth and promote chemosensitization. For example, metformin and weight control not only reduce the incidence of EC but also improve the prognosis of EC patients. In this review, we comprehensively overview the current in-depth understanding of the relationship between metabolism and EC and provide up-to-date insights into the development of novel therapies targeting energy metabolism for auxiliary treatment in combination with chemotherapy for EC, especially those resistant to conventional chemotherapy.

目的 分析不明原因的慢性血生化异常(NCALBT)患者病因诊断及其肝组织学表现.方法 回顾性分析我院诊治的248 例NCALBT患者的临床资料.所有患者接受肝活检,采用改良Scheuer评分评估.常规检测血生化、血清学和病毒学指标.结果 在248 例NCALBT患者中,诊断药物性肝损伤(DILI)89 例(35.9%),自身免疫性肝病(AILD)67例(27.0%),非酒精性脂肪性肝病(NAFLD)39 例(15.7%),遗传代谢性肝病(IMLD)30 例(12.1%),特发性非硬化性门静脉高压(INCPH)20 例(8.1%)和其他肝病 3 例(1.2%);DILI和AILD患者血生化指标显著高于其他肝病患者(P<0.05);本组168 例(67.8%)NCALBT患者肝组织处于 G2-4/S2-4 状态,即有明显的炎症和纤维化损伤,DILI(61.8%)、AILD(95.5%)、NAFLD(56.4%)、INCPH(65.0%)和其他肝病(100.0%)均以G2-4/S2-4 为主,而IMLD患者肝组织G2-4/S2-4 只占36.7%.结论 NACLBT患者病因以常见病为主,综合血清和组织学检查往往可以明确诊断.

Details on inclusion and exclusion criteria, and supplementary table showing the frequency of patients with discriminatory taxa in fecal samples.

Flow diagram of the study design and details on the establishment of response-prediction classifier.

Objective To investigate the risk factors for non－neoplastic portal vein thrombosis（PVT）in patients with liver cirrhosis and related early predictive factors. Methods A total of 50 cirrhotic patients with non－neoplastic PVT who were hospitalized and treated in Department of Hepatology，The Second Hospital of Lanzhou University，from July 1，2021 to June 30，2022 were enrolled as PVT group，and 100 cirrhotic patients without PVT who were treated during the same period of time were randomly selected as control group. Related clinical data were collected. The independent－samples t test was used for comparison of normally distributed continuous data between two groups，and the Mann－Whitney U test was used for comparison of non－normally distributed continuous data between two groups；the chi－square test was used for comparison of categorical data between two groups. A multivariate Logistic regression model analysis was used to investigate the influencing factors for PVT in liver cirrhosis，and the receiver operating characteristic curve was used to evaluate the predictive performance of influencing factors. Results The univariate analysis showed that there were no significant differences between the two groups in the indicators such as protein C，protein S，prothrombin time，international standardized ratio，fibrinogen，white blood cell count，platelet count，and biochemical parameters（all P>0.05），while there were significant differences between the two groups in history of splenectomy，history of endoscopic treatment of esophageal and gastric varices，history of hepatic encephalopathy，administration of non－selective β－blocker（NSBB）， D－dimer， hemoglobin，and triglyceride（all P<0.05）. The multivariate Logistic regression model analysis showed that D－dimer（odds ratio［OR］＝1.120，95% confidence interval［CI］： 1.006－1.246，P＝0.038），history of splenectomy（OR＝9.320，95% CI：2.928－29.665，P<0.001）， history of hepatic encephalopathy（OR＝16.813，95% CI：1.808－156.336，P＝0.013）， and administration of NSBB（OR＝3.203，95% CI：1.020－10.051，P＝0.046） were independent risk factors for PVT. Conclusion Elevated D－dimer，history of splenectomy，history of hepatic encephalopathy，and administration of NSBB are predictive factors for non－neoplastic PVT in patients with liver cirrhosis.