To investigate the efficacy and safety of glucocorticoids combined with cyclophosphamide (CTX) and rituximab (RTX) in elderly patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with renal involvement.

This article reports a case of an elderly male patient presenting with nephrotic syndrome. Renal biopsy pathology indicated membranous nephropathy, with both renal tissue staining for M-type phospholipase A2 receptor (PLA2R) and serum anti-PLA2R antibodies being negative. Nephrotic syndrome achieved remission following treatment with prednisone combined with tacrolimus; however, the patient relapsed during tacrolimus maintenance therapy. Subsequent laboratory evaluation revealed positive anti-nuclear antibodies and anti-double-stranded DNA antibodies, accompanied by decreased complement levels. Exostosin 1 and Exostosin 2 staining performed on the initial renal biopsy specimen yielded positive results, leading to a diagnosis of lupus nephritis. Due to the patient's history of rituximab-related allergic reactions, pulmonary infection, and acute kidney injury, the subsequent treatment regimen consisted of obinutuzumab sequentially combined with belimumab, in addition to prednisone 10 mg/d. During the two-year follow-up period, the patient's anti-double-stranded DNA antibodies converted to negative, complement levels normalized, proteinuria achieved complete remission, and no adverse events such as severe infection occurred. This article reviews the diagnosis, treatment, and relevant literature for this case, aiming to provide clinical insights for the early diagnosis and selection of therapeutic strategies for similar patients.

Osteoarthritis (OA), a highly prevalent degenerative joint disease worldwide, is defined by articular cartilage degradation, abnormal bone remodeling, and persistent chronic inflammation. It severely compromises patients’ quality of life, and currently, there is no radical cure. Abnormal mechanical stress is widely regarded as a core driver of OA pathogenesis, and the exploration of mechanical signal perception and transduction mechanisms has become crucial for deciphering OA’s pathophysiological processes. Piezo1, a key mechanosensitive cation channel belonging to the Piezo protein family, has recently gained significant attention due to its pivotal role in mediating cellular responses to mechanical stimuli in joint tissues. This review systematically examines Piezo1’s expression patterns, regulatory mechanisms, and pathological functions in OA, with a particular focus on its dual roles in modulating chondrocyte homeostasis and bone metabolism disorders, while also delving into the underlying molecular signaling pathways and potential therapeutic implications. Piezo1, consisting of approximately 2 500 amino acids and forming a unique trimeric propeller-like structure, is widely expressed in chondrocytes, osteocytes, mesenchymal stem cells, and synovial cells. It exhibits permeability to cations such as Ca²⁺, K⁺, and Na⁺, and directly responds to membrane tension changes induced by mechanical stimuli like fluid shear stress and mechanical overload. In OA patients and animal models, Piezo1 expression is significantly upregulated, especially in cartilage regions subjected to abnormal mechanical stress (e.g., human temporomandibular joint cartilage). This overexpression is closely associated with aggravated cartilage degeneration, increased chondrocyte apoptosis, accelerated cellular senescence, and intensified inflammatory responses. Mechanical overload and pro-inflammatory cytokines (e.g., IL-1β) are key inducers of Piezo1 upregulation: IL-1β activates the PI3K/AKT/mTOR signaling pathway to enhance Piezo1 expression, forming a pathogenic positive feedback loop that inhibits chondrocyte autophagy, promotes apoptosis, and further accelerates joint degeneration. Mechanistically, Piezo1 mediates OA progression through multiple interconnected pathways. When activated by mechanical stress, Piezo1 triggers excessive Ca²⁺ influx, leading to endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, which directly induce chondrocyte apoptosis. This process involves the activation of downstream signaling cascades such as cGAS-STING and YAP-MMP13/ADAMTS5. YAP, a transcriptional regulator, upregulates the expression of matrix metalloproteinase 13 (MMP13) and aggrecanase (ADAMTS5), thereby accelerating cartilage matrix degradation. Additionally, Piezo1-driven Ca²⁺ overload promotes the accumulation of reactive oxygen species (ROS) and upregulates senescence markers (p16 and p21), accelerating chondrocyte senescence via the p38MAPK and NF-κB pathways. Senescent chondrocytes secrete senescence-associated secretory phenotype (SASP) factors (e.g., IL-6, IL-1β), further amplifying joint inflammation. In terms of bone metabolism, Piezo1 maintains joint homeostasis by promoting the differentiation of fibrocartilage stem cells into chondrocytes and balancing bone formation and resorption through regulating the FoxC1/YAP axis and RANKL/OPG ratio. Therapeutically, targeting Piezo1 shows promising potential. Preclinical studies have demonstrated that Piezo1 inhibitors (e.g., GsMTx4) can reduce joint damage and alleviate pain in OA mice. Simultaneously, siRNA-mediated co-silencing of Piezo1 and TRPV4 (another mechanosensitive channel) decreases intracellular Ca²⁺ concentration, inhibits chondrocyte apoptosis, and promotes cartilage repair. Conditional knockout of Piezo1 using Gdf5-Cre transgenic mice alleviates cartilage degeneration in post-traumatic OA models by downregulating MMP13 and ADAMTS5 expression. Despite existing challenges, such as off-target effects of inhibitors, inefficient local drug delivery, and interindividual genetic variability, strategies like developing selective Piezo1 antagonists, optimizing targeted nanocarriers, and combining Piezo1-targeted therapy with physical therapy provide viable avenues for clinical translation. The authors propose that Piezo1 serves as a critical therapeutic target for OA, and future research should focus on deciphering its context-dependent regulatory networks, developing tissue-specific intervention strategies, and validating their efficacy and safety in clinical trials to address the unmet medical needs of OA patients.

ObjectiveTo analyze the epidemiological and etiological characteristics of a cluster of human metapneumovirus (HMPV) infection in a kindergarten in Gongshu District of Hangzhou City in May 2024, and to provide reference for the prevention and control of similar outbreaks. MethodsAn on-site investigation was conducted using an epidemiological case investigation form. Throat swab specimens collected from cases were screened for 13 respiratory pathogens using real-time fluorescent polymerase chain reaction (PCR). For HMPV nucleic acid positive specimens, the F gene of HMPV was used as the target gene for amplification and sequencing. The sequencing results were then compared with sequences in GenBank database to determine the virus subtypes and perform phylogenetic analyses. ResultsThe outbreak occurred in a kindergarter junior class with a total of 28 preschoolers and 3 teachers and childcare workers. A total of 11 cases (10 preschoolers and 1 teacher) were identified, including 8 male cases and 3 female cases. Clinical manifestations included fever in all 11 cases (100.00%), cough in 8 cases (72.72%), catarrhal symptoms in 4 cases (36.36%), and headache in 3 cases (27.27%). All symptoms were mild, and no severe cases were observed. A total of 11 throat swab samples were collected. Real-time fluorescent PCR test results showed that 3 samples were positive for HMPV nucleic acid, 2 samples were positive for both HMPV and Streptococcus pneumoniae, and 1 sample was positive for both HMPV and rhinovirus. The sequences of the 6 HMPV nucleic acid positive specimens were amplified and analyzed using specific primers, and all were determined to be HMPV subtype A2b. The F gene fragment sequence showed the highest similarity to PV081665.1/Brazil/2024 (99.65%), and also exhibited high similarity to PP683455.1/Indonesia/2021 (99.48%), PV016275.1/Beijing/2024 (99.31%), and PV052230.1/USA/2024 (99.13%). ConclusionThis cluster of acute respiratory tract infection was caused by HMPV subtype A2b, with co-infection of rhinovirus and Streptococcus pneumoniae. The F gene fragment sequences of the HMPV in this outbreak were highly homologous to those of the A2b strains isolated from Brazil, Beijing, Indonesia, and the the United States.

Gastric cancer is a high-incidence malignancy that poses a serious threat to public health in China, ranking among the top three cancers in both incidence and mortality. The majority of patients are diagnosed at an advanced stage, resulting in limited treatment options and poor prognosis. To address key challenges in gastric cancer diagnosis and treatment, a research team led by Professor Jiafu Ji at Peking University Cancer Hospital has focused on the project "Development and Dissemination of Precision Medicine Approaches in Gastric Cancer Management". Through a series of high-quality multicenter clinical studies, the team established a set of new international standards in perioperative treatment, individua-lized drug selection, intelligent noninvasive diagnostics, and novel immunotherapy strategies. These advances have significantly improved treatment efficacy and reduced surgical trauma, achieving key technological breakthroughs in diagnosis, therapy, and mechanistic understanding, and systematically enhancing outcomes for gastric cancer patients. The project ' s findings had a broad international impact, including hosting China ' s first International Gastric Cancer Congress. Through nationwide dissemination, they have promoted the development of precision diagnosis and treatment of gastric cancer as a discipline, and led the formulation of the National Health Commission's guidelines for gastric cancer diagnosis and treatment. In recognition of its achievements, the project was awarded the First Prize of the 2024 Chinese Medical Science and Technology Award.
Stomach Neoplasms/genetics* ; Humans ; Precision Medicine/methods* ; China ; Immunotherapy/methods*

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

BACKGROUND: Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS. METHODS: Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results. RESULTS: UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk. CONCLUSIONS Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major chronic respiratory condition with high morbidity and mortality, imposing a serious economic and public health burden. The World Health Organization ranks COPD among the top 4 chronic diseases worldwide. Zangsiwei Qingfei Mixture (ZSWQF), a novel Tibetan herbal formulation independently developed by our research team, has shown therapeutic potential for chronic respiratory diseases. This study aims to evaluate the effects of aerosolized ZSWQF on cigarette smoke-induced COPD in mice and explore its underlying mechanisms. METHODS: Thirty C57 mice were randomly divided into a Control group, a COPD group, and a ZSWQF group. The Control group received saline aerosol inhalation without cigarette smoke exposure; both the COPD group and the ZSWQF group were exposed to cigarette smoke, with the former receiving saline inhalation and the latter treated with ZSWQF aerosol. White blood cell (WBC) count was performed using a fully automatic blood cell analyzer. Serum, alanine transaminase (ALT), and serum creatinine (SCr), as well as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α levels in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). BALF cell classification was determined using a hematology analyzer. Lung function was assessed with a small animal pulmonary function system, including airway resistance (RI) and cyclic dynamic compliance (CyDN). Lung tissues were stained with hematoxylin and eosin (HE), and mean linear intercept (MLI) and destruction index (DI) were calculated to evaluate morphological changes. Network pharmacology was applied to identify disease-related and ZSWQF-related targets, followed by intersection and protein-protein interaction (PPI) network analysis, and enrichment analysis of biological functions and pathways. Primary type II alveolar epithelial cell (AEC II) from SD rats were isolated and divided into a Control group, a lipopolysaccharide (LPS) group, a normal serum group, a water extract of ZSWQF (W-ZSWQF) group, a ZSWQF containing serum group, and a MLN-4760 [angiotensin-converting enzyme (ACE) 2 inhibitor]. Western blotting was performed to assess protein expression of ACE, p38 [a mitogen-activated protein kinase (MAPK)], phospho (p)-p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2), p-ERK1/2, c-Jun N-terminal kinase (JNK), p-JNK, inhibitor of nuclear factor-kappa B alpha (IκBα), p-IκBα, and p-p65 subunit of nuclear factor-kappa B (NF-κBp65). RESULTS: WBC counts were significantly higher in the COPD group than in controls (P<0.01) and decreased following ZSWQF treatment (P<0.05). No significant intergroup differences were found in organ weights, ALT, or SCr (all P>0.05). Serum and BALF levels of IL-6, IL-8, and TNF-α, as well as total BALF cells, neutrophils, and macrophages, were elevated in the COPD group compared with controls and reduced by ZSWQF treatment (P<0.05). COPD mice exhibited increased RI, decreased CyDN, marked alveolar congestion, inflammatory infiltration, thickened septa, and higher MLI and DI values versus controls (P<0.05); ZSWQF treatment significantly reduced MLI and DI (P<0.05). Network pharmacology identified 151 potential therapeutic targets for ZSWQF against COPD, with key nodes including TNF, IL-6, protein kinase B (Akt) 1, albumin (ALB), tumor protein p53 (TP53), non-receptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT) 3, matrix metalloproteinase (MMP)-9, and beta-catenin (CTNNB1). Enrichment analysis indicates involvement of cancer-related, phosphatidylinositol 3-kinase (PI3K)/Akt, hypoxia-inducible factor (HIF)-1, calcium, and MAPK signaling pathways. Western blotting results showed that compared with the LPS group, AEC II treated with ZSWQF-containing serum exhibited decreased expression of ACE, p-p38/p38, p-ERK1/2/ERK1/2, p-JNK/JNK, p-IκBα/IκBα, and p-NF-κBp65, while ACE2 expression was upregulated, consistent with the MAPK/nuclear factor-kappa B (NF-κB) pathway regulation predicted by network pharmacology. CONCLUSIONS Aerosolized ZSWQF provides protective effects in COPD mice by reducing airway inflammation and remodeling.
Animals ; Pulmonary Disease, Chronic Obstructive/etiology* ; Drugs, Chinese Herbal/therapeutic use* ; Mice ; Mice, Inbred C57BL ; Male ; Network Pharmacology ; Smoke/adverse effects* ; Bronchoalveolar Lavage Fluid ; Administration, Inhalation ; Inflammation/drug therapy* ; Tumor Necrosis Factor-alpha ; Lung/drug effects* ; Interleukin-6/blood*

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.