[摘 要] 目的：探讨复发/转移性鼻咽癌（NPC）接受含PD-1单抗免疫治疗的临床特征和预后影响因素。方法：回顾性分析2019年3月至2024年7月期间南部战区总医院确诊的95例NPC患者的临床资料和外周血生化及免疫学指标。预后分析采用Kaplan-Meier曲线，组间比较使用Log-rank检验，采用Cox比例风险模型进行单因素和多因素分析。结果：95例患者中男性81例，女性14例，中位年龄49.72岁（16~74岁），Ⅳ期91例（95.79%），所有患者均采用免疫治疗，联合或不联合化疗方案治疗，中位无进展生存期（mPFS）为10.5个月，客观缓解率（ORR）70.53%，疾病控制率（DCR）89.47%，接受含铂治疗方案患者PFS相对更长，且差异有统计学意义。紫杉醇 + 顺铂 + 氟尿嘧啶（TPF）对比吉西他滨 + 顺铂（GP）和紫杉醇 + 顺铂（TP）显示出更长的PFS，但差异无统计学意义。不同PD-1单抗治疗组间的PFS未显示出有统计学意义的差异。单因素及多因素Cox回归分析结果显示，肿瘤复发状态、初始血浆EBV感染状态、治疗周期数、基线外周血SII是复发/转移性NPC患者接受PD-1抑制剂治疗疗效预测的独立相关因素（均P < 0.05），并且非复发患者、初始血浆EBV DNA阳性、接受 ≥ 4治疗周期、基线外周血SII < 772.81的患者接受PD-1抑制剂治疗预后相对更好。结论：在接受PD-1抑制剂治疗的复发/转移性NPC患者中，非复发患者、初始血浆EBV DNA阳性、≥ 4治疗周期且外周血SII < 772.81者PFS相对更长，可早期识别免疫治疗效果不佳患者并精准干预。

Objective: To analyze the hepatitis B virus serological markers (HBVM) and abnormal rates of liver function indexes among primary liver cancer (PLC) patients with different HBVM profiles, so as to provide a reference for risk stratification and optimization of diagnosis and treatment strategies for PLC patients. Methods: Patients diagnosed with PLC at Qidong People's Hospital between January 2017 and June 2024 were selected for this study. Basic information such as gender and age was collected through the hospital information management system. Venous blood samples were drawn to test for HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc, as well as ten liver function indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), cholinesterase (CHE), and adenosine deaminase (ADA). Compare the abnormal rates of liver function indexes among the six HBVM profiles: "big three yang" (HBsAg+, HBeAg+, anti-HBc+), "small three yang" (HBsAg+, anti-HBe+, anti-HBc+), triple antibody positive (anti-HBs+, anti-HBe+, anti-HBc+), s/c antibody positive (anti-HBs+, anti-HBc+), e/c antibody positive (anti-HBe+, anti-HBc+), and all negative. Results: A total of 1 434 patients with PLC were enrolled in this study. Among them, 1 043 (72.73%) were males and 391 (27.27%) were females. The median age was 64.00 (interquartile range, 16.00) years. The positive rates for HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc were 51.95%, 29.43%, 10.81%, 60.32%, and 88.42%, respectively. The "big three yang", "small three yang", triple-antibody positive, s/c antibody positive, e/c antibody positive, and all-negative profiles accounted for 85 (5.93%), 491 (34.24%), 170 (11.85%), 148 (10.32%), 100 (6.97%), and 121 (8.44%) cases, respectively. The abnormal rates of ALT among PLC patients with six HBVM profiles were 26.19%, 28.33%, 13.94%, 22.60%, 20.41%, and 14.91%, respectively. The abnormal rates of AST were 33.33%, 36.17%, 23.03%, 24.66%, 22.45%, and 18.42%, respectively. The abnormal rates of LDH were 62.16%, 68.22%, 53.73%, 61.19%, 60.00%, and 68.42%, respectively. The abnormal rates of CHE were 0%, 1.81%, 0%, 2.11%, 2.22%, and 3.88%, respectively. The abnormal rates of ADA were 59.09%, 57.27%, 24.27%, 33.33%, 45.00%, and 37.04%, respectively. These differences were statistically significant (all P<0.05). Conclusions In this study, the HBVM profiles were mainly characterized by "small triple positive" among PLC patients. The significant differences in liver function indexes abnormal rates among PLC patients with six HBVM profiles could reflect the liver injury status.

BACKGROUND: Research has indicated that the disease burden of alopecia areata (AA) in China exceeds the global average. Therefore, accurate and updated epidemiological information is crucial for policymakers. In this study, we aimed to comprehensively assess the disease burden of AA in China. METHODS: The following four key indicators were utilized: the prevalence of cases; disability-adjusted life-years (DALYs); the age-standardized prevalence rate (ASPR); and the age-standardized DALY rate (ASDR) of AA according to the Global Burden of Disease (GBD) study 2021. We analyzed the epidemiological burden of AA in China during 2021, examined changes between 1990 and 2021, and performed a Bayesian age-period-cohort analysis to predict trends over the course of the next decade (2022-2030). Additionally, a Gaussian process regression model was applied to estimate the relationship between the gross domestic product (GDP) and the ASPR and ASDR of AA at the provincial level between 1992 and 2021. RESULTS: In 2021, the estimated number of patients with AA in China was approximately 3.49 million (95% uncertainty interval [UI], 3.37-3.62 million); of these patients, 1.20 million (95% UI, 1.16-1.25 million) were male and 2.29 million (95% UI, 2.20-2.37 million) were female. This large number of patients with AA resulted in a total of 114,431.25 DALYs (95% UI, 74,780.27-160,318.96 DALYs). Additionally, the ASPR and ASDR were 224.61 per 100,000 population (95% UI, 216.73-232.65 per 100,000 population) and 7.41 per 100,000 population (95% UI, 4.85-10.44 per 100,000 population), respectively; both of these rates were higher than the global averages. The most affected demographic groups were young and female individuals 25-39 years of age. Slight regional disparities were observed, with the northern and central regions of China bearing comparatively higher burdens. Between 1990 and 2021, the health loss and disease burden caused by AA in China remained relatively stable. The ASPR and ASDR of AA increased with the GDP when the annual GDP was less than 2 trillion Chinese yuan; however, a downward trend was observed as the GDP surpassed 2 trillion Chinese yuan. A slight upward trend in the disease burden of AA in China is predicted to occur over the next decade. CONCLUSIONS AA continues to be a public health concern in China that shows no signs of declining. Targeted efforts for young individuals and females are necessary because they experience a disproportionately high burden of AA.
Humans ; China/epidemiology* ; Alopecia Areata/epidemiology* ; Global Burden of Disease ; Female ; Male ; Adult ; Disability-Adjusted Life Years ; Middle Aged ; Prevalence ; Adolescent ; Young Adult ; Bayes Theorem ; Child ; Quality-Adjusted Life Years ; Child, Preschool

Objective:This study aims to investigate the influence of microvessel density（MVD） and microlymphatic vessel density（MLVD） on the prognosis of patients with hypopharyngeal squamous cell carcinoma（HPSCC） and to develop a nomogram prediction model for prognosis based on pathological characteristics. Methods:A retrospective analysis was conducted on clinicopathological and follow-up data from HPSCC patients who underwent surgical treatment at our institution between June 2010 and June 2020. Immunohistochemical staining was performed on tumor tissues and adjacent normal margin tissues to evaluate MVD and MLVD. The associations among MVD, MLVD, and clinicopathological features were analyzed. Univariate and multivariate Cox regression analyses were conducted to identify independent risk factors affecting overall survival（OS）. Based on these findings, a nomogram model was constructed and its predictive accuracy was assessed using C-index, receiver operating characteristic（ROC） curve, and calibration curve. Results:Both MVD and MLVD were significantly higher in HPSCC tumor tissues compared to normal tissues. Patients in the high MVD and high MLVD groups exhibited significantly lower OS rates than those in the low MVD and low MLVD groups. Multivariate Cox regression analysis revealed that N stage, recurrence, nerve invasion, lymph node capsule invasion, MVD, and MLVD were independent prognostic factors of OS. Based on these factors, a nomogram prognosis model was successfully constructed. The nomograms demonstrated superior performance in terms of C-index, area under the ROC curve, and calibration, outperforming the AJCC TNM staging system. Conclusion:Elevated MVD and MLVD levels are associated with poorer prognosis in HPSCC patients. The nomogram model based on pathological features provides valuable insights for clinical assessment and decision-making.
Humans ; Hypopharyngeal Neoplasms/blood supply* ; Prognosis ; Retrospective Studies ; Microvascular Density ; Nomograms ; Lymphatic Vessels/pathology* ; Male ; Female ; Middle Aged ; Carcinoma, Squamous Cell/blood supply* ; Microvessels/pathology* ; Lymphatic Metastasis ; Survival Rate

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

Objective To explore the effect of maternal exercise on blood pressure,cardiac pheno-type and susceptibility to myocardial is chemia/reperfusion(MI/R)injury in adult male offsprings of mice.Methods Pregnant mice were randomly divided into a sedentary group(p-Ctr)and an exercise group(p-EX),each of 12.The exercise group underwent daily 60-minutenon-weight bearing swim-ming from gestational day(GD)1 to 18,6 days a week.Then,their male offsprings at 3 months of age(3M)were selected as the research subjects,namely the Ctr-3M group and the EX-3M group,with 12 mice in each group.The MI/R model was established by ligation of the anterior descending branch of the left coronary artery(LAD)surgery(30 min of ischemia,24 h of reperfusion).Then,the systolic blood pressure(SBP),diastolic blood pressure(DBP),and mean arterial pressure(MAP)were monitored non-invasively via tail artery blood pressure measurement,while the cardiac function was detected by using the small animal ultrasound.Moreover,the cardiac morphology and col-lagen volume fraction(CVF)of myocardium was observed by HE staining and Masson staining,respec-tively.Meanwhile,the cross-sectional area(CSA)of myocardial cells and myocardial infarction area(INF/AAR)was measured using WGA staining and Evans Blue-TTC double staining,accordingly.What's more,the apoptosis index(AI)of myocardial cells and serum cardiac troponin I(cTnI)were de-tected by using TUNEL staining and ELISA,respectively,while the expression levels of Bax and Bcl-2 proteins were determined by using Western blotting.Results 1)From GD11 to GD19,the body weight of females in the p-EX group was always significantly lower than that in the p-Ctr group(GD11,GD13;P<0.05;GD12,GD14～GD19;P<0.01),but there was no significant difference in the litter size and abortion rate(P>0.05).2)There were no significant differences between the EX-3M and Ctr-3M groups in the heart weight(HW),body weight(BW)and heart weight to body weight ratio(HW/BW),SBP,DBP,MAP,myocardial CVF,and CSA of male offsprings(P>0.05).After MI/R surgery,in both p-Ctr and p-EX groups,myocardial transverse striations disappeared and cardiomyocytes were disarranged with degeneration and necrosis.Moreover,CVF of the EX-3M group was significantly lower than the Ctr-3M group after MI/R surgery(P<0.05).3)No significant differenc-es were found between the Ctr-3M and EX-3M groups in the average cardiac ejection fraction(EF),fractional shortening(FS),left ventricle internal diameter in diastole(LVIDd),and left ventricle inter-nal diameter in systole(LVIDs)(P>0.05).However,after the MI/R surgery,the postoperative EF and FS(P<0.01),and LVIDs(P<0.05)in the EX-3M group were significantly higher than the Ctr-3M group,without significant difference in LVIDd(P>0.05).4)After MI/R surgery,the average AI,INF/AAR and serum cTnI level of the EX-3M group were significantly lower than the Ctr-3M group(P<0.01 for all).5)The relative expression level of myocardial Bcl-2 protein after MI/R surgery in the EX-3M group was significantly higher than the Ctr-3M group(P<0.05),while that of myocardial Bax protein(P<0.05)and the Bax/Bcl-2 ratio(P<0.01)were significantly lower than the latter.Conclu-sions Prenatal exercise significantly reduces the susceptibility to myocardial ischemia injury in 3-month-old male mice offspring,improves the contractile function of their heart,and attenuates the degree of cardiomyocyte apoptosis and necrosis,exerting a cardioprotective effect in MI/R injury.

AIM:To investigate the antiviral effica-cy and mechanism of Qingre Xiaoyanning(QRXYN)in vivo,and provide experimental basis for their prevention and treatment of influenza A virus.METHODS:We constructed a mouse model infect-ed with influenza A H3N2 virus.To evaluate the therapeutic effect of QRXYN on influenza A virus,we measured the body weight changes,pathologi-cal changes in lung tissue,hemagglutination titer,and viral load in mouse.To evaluate the possible mechanism of QRXYN's anti influenza A virus infec-tion,we used the ELISA to measure the levels of TNF-α,IL-1β,IL-4,IFN-γ,and vascular cell adhesion molecule-1(VCAM-1)in mouse bronchoalveolar Ia-vage fluid;used flow cytometry to assess the pro-portions of macrophages(F4/80),helper T lympho-cytes(CD4+T lymphocytes),and natural killer(NK)cells in lung tissue;and used Western blotting to detect the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MYD88),inhibitor of kappa B kinase-β(IKK-β),NF-kappa-B inhibitor al-pha(IκBα),and phospho-IKB alpha(p-IκBα)in lung tissue.RESULTS:Compared to the model group,both Oseltamivir and QRXYN can alleviate the se-verity of lung tissue lesions in mice,decrease the blood coagulation titer and viral load of mouse lung tissue(P＜0.01),lower the levels of TNF-α,IL-4,and VCAM-1 in bronchoalveolar lavage fluid(P＜0.05,P＜0.01),reduce the proportion of macro-phages(P＜0.05,P＜0.01),and increase the propor-tion of CD4+T lymphocytes and NK cells(P＜0.05,P＜0.01).Additionally,oseltamivir can reduce the ex-pression of MYD88 protein in mouse lungs(P＜0.05),while QRXYN can decrease the expression of IKK-β and P-IκBα proteins in mouse lungs(P＜0.05).CONCLUSION:QRXYN have good in vivo antiviral ef-fects against the influenza A virus,and their mecha-nism may be related to the regulation of the immu-nologic function and NF-κB signal pathway.