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关键词： Circulating recombinant forms (CRFs)   pretreatment drug resistance (PDR)   Transmitted drug resistance (TDR)   v179d/E   China  

摘要： In recent years, an increasing number of HIV-1 circulating recombinant forms (CRFs) have been identified in China. This study presented the first systematic analysis of the molecular epidemiological characteristics and drug resistance mutations (DRMs) profiles of all 69 CRFs identified in China up to 2025, comprising 13 first-generation, 45 second-generation, 10 third-generation, and one fourth-generation CRF . Several CRFs exhibited moderate transmitted drug resistance (5-15%) and elevated pretreatment drug resistance (10.8-55.1%). Notably, V179D/E were prevalent across multiple CRFs and, in combination with other DRMs, may contribute to reduced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTIs). These findings provided critical surveillance data on DRMs and baseline data for NNRTIs selection in China, underscoring the necessity of phenotypic validation in novel CRFs harbouring natural DRMs.

关键词： Type 1 diabetes   cardiovascular risk   risk prediction   subclinical atherosclerosis   precision medicine   risk stratification  

摘要： IntroductionCardiovascular disease (CVD) remains the leading cause of premature mortality in type 1 diabetes (T1D). Despite this burden, current prevention guidelines and risk stratification tools are largely extrapolated from type 2 diabetes or general populations, often failing to capture the unique pathophysiological drivers of atherosclerosis in T1D. This narrative review aims to critically evaluate current cardiovascular prevention strategies, identify the limitations of generic risk calculators, and analyse the clinical utility and discriminatory performance of population-specific risk equations.DiscussionCurrent clinical practice guidelines provide heterogeneous and inconsistent recommendations for T1D. Generic risk calculators (e.g. SCORE2, ACC/AHA pooled cohort equations) are limited by short-term prediction horizons and a lack of validation in T1D cohorts, frequently leading to poor diagnostic performances in this population. Conversely, T1D-specific equations, such as Steno Type 1 Risk Engine (Steno-Risk) and the emerging LIFE-T1D model, incorporate disease-specific variables such as diabetes duration or albuminuria. Available evidence indicates that T1D equations as Steno-Risk demonstrate superior discriminatory performance compared to generic scores identifying those individuals with higher cardiovascular risk. However, despite improved calibration, specific tools still classify a substantial proportion of patients with established subclinical atherosclerotic disease as 'moderate risk,' creating a grey area that complicates therapeutic decision-making.ConclusionGeneric cardiovascular risk algorithms are inadequate for the T1D population. While specific equations represent a significant advancement toward accurate stratification, mathematical models alone may be insufficient. Moving toward precision medicine requires a combined approach that integrates validated T1D-specific risk calculators with subclinical atherosclerosis screening (e.g. carotid ultras

关键词： Rhaponticin   acute pancreatitis   acinar cell   necroptosis   oxidative stress   mitochondrial dysfunction   pancreatic necrosis   HIF-1 alpha  

摘要： ObjectivesThis study investigated the protective effects and mechanisms of rhaponticin (Rha) against acinar cell injury in acute pancreatitis (AP).MethodsPancreatic acinar cell injury was induced using multiple in vitro and in vivo AP models. The mitochondrial function, necrosis, and oxidative stress were assessed. Network pharmacology and molecular docking were applied to predict potential molecular targets, which were subsequently validated experimentally. The involvement of hypoxia-inducible factor 1-alpha (HIF-1 alpha) signaling and necroptosis-related proteins, including receptor-interacting protein kinase 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL was further explored. Both pharmacological inhibition and siRNA-mediated knockdown were employed to verify the target specificity of Rha.ResultsRha treatment significantly preserved mitochondrial function, reduced ROS, and alleviated pancreatic injury. Network pharmacology and molecular dockingresults identified HIF -1a as the key target of Rha. Consistently, Rha treatment markedly downregulated HIF-1 alpha expression and inhibited necroptosis by suppressing the activation of RIP3 and p-MLKL. Notably, neither pharmacological inhibition nor siRNA-mediated knockdown of HIF-1 alpha produced additional protective effects in the presence of Rha, indicating the involvement of HIF-1 alpha in mediating its actions.ConclusionRha effectively attenuates acinar cell necrosis and oxidative via the HIF-1 alpha-mediated necroptosis pathway, highlighting Rha as a promising therapeutic candidate for AP.

关键词： Antimicrobial peptide   acinetobacter baumannii   carbapenem-resistance   cell membrane   lipopolysaccharide   oxidative stress  

摘要： The treatment of carbapenem-resistant A. baumannii (CRAB) infections has become a major global medical challenge;therefore, there is an urgent need for new antimicrobial development. Antimicrobial peptides hold great promising potential due to their rapid bactericidal activity and low induction of drug resistance. In this study, we screened and synthesized the antimicrobial peptide lachnospirin-1, which exhibited significant bactericidal activity against CRAB and can also effectively eliminate its biofilms and persister cells. Mechanism studies, including fluorescent probe detection, transmission electron microscopy observations, and molecular dynamics simulations, et al. indicated that lachnospirin-1 exerts its effects through multiple mechanisms, such as disrupting bacterial cell membranes, neutralizing lipopolysaccharide, as well as inducing oxidative stress, which also demonstrates its certain potential. In addition, the favorable safety profile and effective in vivo bactericidal activity of lachnospirin-1 were determined by mouse models. Overall, our study found that lachnospirin-1 has considerable research potential as a lead compound and possesses latent value as a clinical therapy for refractory infections caused by CRAB.

关键词： immune checkpoint inhibitors   pembrolizumab   nivolumab   melanoma   renal cell carcinoma   triple-negative breast cancer   early-stage cancer   Hungary   I10   C02  

摘要： AimAnti-PD-(L)1 agents, inhibitors of programmed cell death protein 1 (PD-1) or its ligand (PD-L1 are established therapies that improve cancer management as well as the disease and societal burden of specific metastatic and early-stage cancers. The aim of the study was to determine the impact of adopting anti-PD-(L)1 agents for the treatment of all eligible patients with early-stage cancers versus reserving anti-PD-(L)1 agents for patients with metastatic disease alone in Hungary.MethodsThis study evaluated two scenarios, one where anti-PD-(L)1 agents were used to treat all eligible early-stage disease cases (ESD scenario) of melanoma (stage IIB-C and III renal cell carcinoma (RCC and triple-negative breast cancer (TNBC) versus a reference scenario where anti-PD-(L)1 agents were only used to treat metastatic disease cases in Hungary (2024-2033). A Markov-modeling approach estimated the health outcomes and productivity losses from each scenario from a societal perspective. Outcomes included recurrence-/event-/disease-free life-years, total life-years, quality-adjusted life-years (QALYs productive years (patients and caregivers recurrences/events, active treatments for metastatic disease, and deaths. The cumulative health and productivity impact of ESD treatment with anti-PD-(L)1 agents in Hungary was the difference in health and productivity outcomes between the ESD and reference scenarios for the time horizon of the model.ResultsESD treatment with anti-PD-(L)1 agents was estimated to increase recurrence-/event-/disease-free life-years (+13.8% total life-years (+3.7% and QALYs (+4.7% as well as productive work years for patients (+39.6%) and caregivers (+27.6%). Concurrently, there would be fewer recurrences/events (-31.0% active treatments for metastatic disease (-34.0% post-recurrence deaths (-30.3% and total deaths (-23.1%).ConclusionInvesting in anti-PD-(L)1 agents for early-stage disease may not only increase the life expectancy and QALYs for patients in Hungar

关键词： PD-1 fate-mapping   PD-1 blockade   cytotoxic drug   combination therapy   TCR diversification   single cell analysis  

摘要： Combined cytotoxic chemotherapy and immune checkpoint inhibition (ICI) improves outcomes in PD-L1-low lung cancer, but transient and broad PD-1 expression across immune cells complicates the understanding of the underlying mechanisms. We generated Pdcd1-CreERT2 fate-mapping mice to trace PD-1-expressing cells via tdTomato during PD-1 blockade. PD-1-fate-mapped lymphocytes downregulated PD-1 in the spleen but largely retained it in tumors, except for NK cells, which lost PD-1 and regained function. Single-cell transcriptional profiling was performed on immune cells in PD-L1-low Lewis lung carcinoma (LLC) treated with cyclophosphamide (CTX) and/or anti-PD-1 antibodies. Anti-PD-1 monotherapy showed limited efficacy, whereas CTX plus anti-PD-1 markedly improved tumor control. Single-cell analysis identified 15 transcriptionally distinct immune clusters with treatment-dependent abundances. Combination therapy expanded cytotoxic CD8 T cells and a dysfunctional Treg cluster, enhancing CTL activity, including PD-1-fate-mapped CD8 T cells expressing Tpex1 markers. Single-cell TCR analysis revealed that clonotypes selectively expanded by combination therapy, mediating potent cytotoxicity against LLC tumors. PD-1 blockade synergizes with cytotoxic chemotherapy to diversify and expand PD-1 lineage-traced CTL clonotypes, driving robust antitumor immunity. Thus, our fate-mapping system is a valuable tool to search for immune cells responsive to ICI therapy.