[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.

Traumatic brain injury (TBI) involves both primary mechanical damage and refractory secondary injuries, resulting in high disability rate and poor prognosis. Current therapeutic strategies for TBI include surgical intervention, neuroprotective agents, moderate hypothermia therapy and spinal cord stimulation. However, most of these therapeutic approaches primarily address wound surface management rather than targeting specific pathogenic mechanisms underlying post-injury inflammation and neurodegenerative diseases, resulting in suboptimal efficacy. Consequently, novel therapeutic strategies targeting TBI pathological mechanisms are urgently needed. The endogenous cannabinoid system (ECS) exerts multifaceted neuroprotective effects in TBI by modulating neuroinflammation, inhibiting glutamate excitotoxicity and activating pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). Investigating the characteristics of ECS components and their related signaling pathways may yield new approaches in the development of neuroprotective drugs for TBI. Nevertheless, few ESC-targeting drugs for TBI treatment have advanced beyond preclinical or clinical trial phases. Breakthroughs in this field depend on a deeper understanding of ECS and its mechanisms in TBI. To this end, the authors reviewed researches on the composition and functions of ECS, as well as the mechanisms underlying its neuroprotective effects following TBI, aiming to provide references for the development of ECS-targeting therapies.

[Purpose]To analyze the trend of prostate cancer mortality in China from 2011 to 2020,and to predict the prostate cancer mortality trend from 2021 to 2030.[Methods]The data were collected from the National Mortality Surveillance System(NMSS)from 2011 to 2020,the burden of prostate cancer in China from 2011 to 2020 were analyzed by the number of deaths,age-standardized mortality rate(ASMR),years of life lost(YLL)and age-standardized YLL rate.Joinpoint regression model was used to calculate the average annual percentage change(AAPC)to describe the trend of change.The Bayesian age-period-cohort model was used to predict the mor-tality rate of prostate cancer from 2021 to 2030 and estimate the number of deaths of prostate can-cer in the future.Decomposition analysis was carried out to explore the potential drivers of changes of mortality.[Results]The number of prostate cancer deaths in China in 2020 was 30 805 with an ASMR of 5.56/105.The ASMR for prostate cancer in urban and rural areas was 6.56/105 and 4.84/105,respectively.From 2011 to 2020,the number of prostate cancer deaths,ASMR and age-standardized YLL rate of prostate cancer in China showed an upward trend,AAPC was 5.4％(95％CI:4.7％～6.1％),1.5％(95％CI:1.4％～1.6％)and 1.1％(95％CI:1.1％～1.2％),respective-ly.The ASMR of prostate cancer was higher in the eastern region than those in the central and western regions.Prostate cancer deaths increased in both urban and rural areas among people aged 60 years old and above.In 2030,it is predicted the ASMR of prostate cancer would increase to 5.74/105.Population aging,changes in age-specific mortality rates,and natural population growth accounted for 24.75％,2.77％,and 7.45％of the changes in total deaths of prostate can-cer,respectively.[Conclusion]The burden of prostate cancer is increasing in China.Targeted measures should be implemented in high-risk areas and high-risk groups to effectively reduce the disease burden caused by prostate cancer.

OBJECTIVE To explore the effects of dihydroartemisinin(DHA)on the functions of cancer-associated fibroblasts(CAFs)in the tumor microenvironment in hypopharyngeal squamous cell carcinoma(HPSCC).METHODS The influence of conditioned media from CAFs and normal fibroblasts(NFs)on tube formation was assessed using a tube formation assay.Secreted protein levels of IL-6,VEGFA,and VEGFC were measured by immunofluorescence and ELISA.Western blotting was used to evaluate the expression of α-SMA,p-STAT3,STAT3,VEGF-A,and VEGF-C within the STAT3 signaling pathway.After treatment with DHA,the optimal concentration for DHA's effect was determined using CCK8 assays and morphological observations of cells.The impact of DHA on angiogenesis was analyzed through tube formation assays,changes in IL-6 expression were detected using ELISA and immunofluorescence,and alterations in α-SMA,p-STAT3,and STAT3 expression were examined by Western blot.RESULTS Both CAFs and NFs exhibited pro-angiogenic and pro-lymphangiogenic effects,with CAFs showing a more pronounced impact.Activated CAFs overexpressed and secreted high levels of IL-6,VEGF-A,and VEGF-C.The concentration of IL-6 in the conditioned medium supernatants of CAF1 and CAF2 was significantly higher than that of NF1 and NF2(P1<0.001,P2<0.05).Similarly,the concentration of VEGF-A was significantly increased(P1<0.05,P2<0.01),and the concentration of VEGF-C was also significantly increased(P1<0.05,P2<0.01).Treatment with DHA inhibited the activated state of CAFs,reducing the expression and secretion of IL-6 and p-STAT3,thereby suppressing tube formation.CONCLUSION Our findings indicate that CAFs promote angiogenesis and lymphangiogenesis in HPSCC via activation of the STAT3 pathway.DHA effectively inhibits this process,suggesting a potential new therapeutic strategy for the treatment of HPSCC.

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