Lactate dehydrogenase (LDH) and derived neutrophil-to-lymphocyte ratio (dNLR) are key prognostic factors for renal cancer. However, the association between the Lung Immune Prognostic Index (LIPI), based on dNLR and LDH, and renal cancer prognosis remains unclear. This study evaluates the prognostic value of LIPI for recurrence and survival in clear cell renal cell carcinoma (ccRCC) after nephrectomy. This retrospective study included 687 ccRCC patients who underwent radical or partial nephrectomy at three medical centers. Patients were stratified into good and intermediate/poor (int./poor) LIPI groups based on dNLR and LDH. Propensity score matching (PSM) was performed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and Cox models. Model discrimination was evaluated using C-indices, and subgroup and center-stratified analyses tested robustness. A total of 687 patients were included, with 491 classified into the good LIPI group and 196 into the int./poor group. After 1:1 PSM, each group comprised 196 patients. In the Kaplan-Meier survival analysis, the int./poor LIPI group exhibited significantly worse RFS and OS both before (RFS: P < 0.001; OS: P < 0.001) and after PSM (RFS: P < 0.001; OS: P < 0.001). In the multivariate Cox regression analysis post-PSM, int./poor LIPI remained independently associated with increased risk of recurrence (HR = 2.156, 95% CI: 1.349-3.449, P = 0.001) and mortality (HR = 3.238, 95% CI: 1.437-7.298, P = 0.005). Preoperative LIPI predicts ccRCC prognosis after nephrectomy. Patients in the good LIPI group exhibit significantly better RFS and OS.Trial registration: The study was registered at ClinicalTrials.gov (NCT06775574).

PurposeTo develop a CT-based radiomics model for predicting prognosis and optimizing adjuvant chemotherapy (ACT) decisions in stage II proficient mismatch repair (pMMR) colorectal cancer (CRC).MethodsWe retrospectively enrolled 379 stage II pMMR CRC patients with distinctly good or poor outcomes, including 125 patients in the validation cohort. The radiomics model was developed using features extracted from segmented CT volumes by XGBoost. Clinical model A was constructed via multivariate logistic regression incorporating clinical factors recommended by the European Society of Medical Oncology (ESMO). Model performance was compared using the DeLong test. Survival analysis employed Kaplan-Meier curves and log-rank tests, and ACT subgroup analysis was performed according to risk stratification.ResultsIn the validation cohort, the radiomics model (AUC = 0.800) and combined model A (AUC = 0.811) outperformed clinical model A (AUC = 0.576; both p < 0.05). Patients stratified as low-risk by either the radiomics model or the combined model A exhibited significantly longer overall survival (OS) than high-risk patients in both training and validation cohorts (all p < 0.05). Within the high-risk groups identified by the radiomics model and the combined model A, patients receiving ACT showed significantly longer OS compared to non-recipients (p = 0.015 and p = 0.008, respectively), while no significant difference was observed in low-risk groups (both p > 0.05).ConclusionCompared to ESMO-recommended clinical high-risk factors, the CT-based radiomics model demonstrated superior prognostic prediction performance and could optimize ACT decisions based on risk stratification in stage II pMMR CRC.

ABSTRACT Three‐dimensional (3D) multicellular models are considered ideal methods for bridging the gap between two‐dimensional (2D) cell culture and animal models, which are widely used in organogenesis, disease models, drug development, and regenerative medicine. Cell culture technologies determine the physical and biological properties of multicellular spheroids or organoids that affect the authenticity, stability, assessment, and throughput of the 3D multicellular system. Micro patterns, characterized as a coating of specific adhesion matrices on substrates, can control cell behaviors and fate by limiting the space available for cell spreading. micro patterns are used to culture non‐tumor or tumor spheroids and organoids with effective control of size and arrangement, which is suitable for large‐scale and standardized culture to generate 3D multicellular models. This comprehensive review summarizes the advantages and applications of 3D multicellular models and discusses the characteristics of general 3D cell culture technologies. We discuss the basic applications of micro pattern technologies and highlight the specific advantages and features of micropattern (as a 3D cell culture platform) in non‐tumor research (regenerative medicine, developmental biology, disease modelling, and monoclonal cell culture) and tumor research (tumor microenvironment (TME) and drug screening). Finally, the fabrication of micro patterns (bio inks, fabrication methods for micro patterns, morphology, and quality of micro patterns) is described.

This study aimed to evaluate the feasibility of CD72 as a complementary CD19-independent B-lineage gating marker for longitudinal measurable residual disease (MRD) surveillance in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) following CD19 CAR-T therapy. Correlation analyses were performed in 66 B-ALL samples to compare MRD detection using CD72, CD19, and cytoplasmic CD79a. CD72 expression specificity was further evaluated in 129 leukemia patients. In addition, 129 patients with R/R B-ALL treated with autologous CD19 CAR-T therapy in registered clinical trials (ChiCTR-IIh-16008711; NCT03173417) between January 2021 and December 2022 were retrospectively analyzed, with follow-up continued until January 2025. CD72 gating showed excellent concordance with both CD19- and cCD79a-based strategies for MRD assessment. CD72 expression demonstrated high specificity in B-ALL, with a positivity rate of 95.77%, compared with 29.27% in AML and 23.53% in T-ALL. All 129 heavily pretreated patients achieved MRD-negative CR at day 28 after CAR-T infusion and subsequently underwent allo-HSCT, with a median interval of 54 days (range, 40-338). A total of 16 patients experienced MRD relapse during follow-up, including four clinically confirmed CD19-negative relapses that retained CD72 expression. Patients with pre-CAR-T MRD ≤1% showed earlier B-cell recovery than those with MRD >1% (median 30 [18-45] vs. 32 [26-79] days, p = 0.028). The MRD ≤1% cohort demonstrated significantly improved 3-year overall survival compared with the MRD >1% cohort (88.1% vs. 69.2%, p = 0.014). The 3-year cumulative incidence of MRD relapse was significantly lower in the MRD ≤1% cohort than in the MRD >1% cohort (3.96% vs. 17.95%, p = 0.019), while non-relapse mortality was also numerically lower in the MRD ≤1% cohort (5.92% vs. 17.95%, p = 0.053). Multivariate analysis identified KMT2A rearrangement, IKZF1 mutation, TP53 mutation, and elevated pre-CAR-T MRD as independent predictors of inferior outcomes. CD72 represents a feasible complementary B-lineage marker for longitudinal MRD surveillance following CD19 CAR-T therapy. Retention of CD72 expression in clinically confirmed CD19-negative relapses supports its potential utility when CD19 expression is lost after targeted therapy.

One important pathogenic process that contributes to subsequent damage after myocardial infarction (MI) revascularization is myocardial ischemia/reperfusion injury (MI/RI). Its underlying mechanisms are controlled by traditional post-translational modifications (PTMs) like acetylation, methylation, phosphorylation, and ubiquitination, and involve several cell death pathways, such as autophagy, apoptosis, pyroptosis, and ferroptosis. Histone lysine lactylation (Kla), a novel metabolically related epigenetic regulation mechanism, has attracted a lot of attention in recent years. This review systematically clarifies the crucial role of lactate in cardiac energy metabolism and its influence on Kla modification, exploring Kla's dual regulatory function in MI/RI. It demonstrates a significant interaction between Kla and changes like acetylation, phosphorylation, N6-methyladenosine (m6A) methylation, and ubiquitination, thereby establishing putative connections that regulate cell death in MI/RI. Targeting lactate-related molecules such as lactate dehydrogenase A (LDHA), monocarboxylate transporters (MCTs), and histone deacetylases (HDACs) shows therapeutic potential. Therefore, targeted intervention molecules applicable at different stages of MI/RI are explored. Ultimately, elucidating the dynamic patterns of Kla and its crucial involvement in various biological processes will create new paradigms and potential therapeutic targets for the prevention and treatment of MI/RI.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with limited therapeutic options and a median survival of only 3–5 years. Although antifibrotic agents such as pirfenidone (PFD) and nintedanib can decelerate functional decline, they fail to reverse established fibrosis, underscoring an urgent need for novel therapeutic paradigms. Emerging evidence has positioned mitophagy—the selective autophagic clearance of damaged mitochondria—at the nexus of IPF pathogenesis. In this review, we systematically dissect the regulatory networks governing mitophagy, encompassing the canonical PINK1/Parkin pathway, receptor-mediated mechanisms (BNIP3/NIX/FUNDC1), and their intricate cross-talk with endoplasmic reticulum stress (ERS) and ferroptosis, highlighting how these interconnected pathways converge to determine alveolar epithelial cell (AEC) fate, fibroblast activation, and inflammatory reprogramming. Notably, the pathological impact of mitophagy is highly cell-type-specific and context-dependent, exhibiting protective functions in epithelial cells while paradoxically promoting pro-fibrotic phenotypes in macrophages under certain conditions, which poses both challenges and opportunities for therapeutic intervention. Furthermore, we critically evaluate emerging pharmacological and biological strategies targeting mitophagy, and propose that future combination regimens—guided by non-invasive mitophagy biomarkers—may overcome current clinical bottlenecks. By integrating mechanistic insights with translational perspectives, this review provides a roadmap for developing mitophagy-targeted interventions as a next-generation therapeutic paradigm for IPF.

The significant variation in treatment strategies among breast cancer subtypes establishes precise early subtyping as a critical prerequisite for effective therapy. While molecular profiling offers accurate classification, developing a rapid and reliable detection method remains challenging. Hence, we constructed an integrated platform by integrating a DNA tetrahedral probe (DTP) and surface antiadhesive magnetic micro/nanorobots (MNRs), enabling rapid contact between the MNR-DTP system and target analytes. The probe enhances fluorescence via target-triggered strand displacement and CHA-mediated signal amplification, allowing breast cancer subtypes to be identified through distinct dual-color fluorescence patterns. Furthermore, magnetically driven MNRs improve detection efficiency by enhancing mass transfer, promoting mixing, and accelerating probe-target interactions. Experimental results demonstrate that this strategy markedly enhances fluorescence output, enables rapid detection of dual-miRNA signatures in different breast cell lines, and distinguishes expression heterogeneity at the single-cell level. The system shows high specificity and improved sensitivity, with limits of detection of 1.5 pM for miR-21 and 1.17 pM for miR-31. The biocompatibility and stability of the proposed MNR-DTP system make it a promising tool for early breast cancer subtype discrimination and multiplexed target recognition in complex biological settings.

BackgroundLung cancer remains one of the most common and lethal malignancies worldwide. The advent of immune checkpoint inhibitors (ICIs) has substantially improved survival outcomes in patients with advanced disease; nevertheless, a considerable proportion of patients exhibit suboptimal responses to ICI monotherapy. In recent years, statins have garnered attention for their potential immunomodulatory and anti-inflammatory properties. Preclinical evidence suggests that statins may enhance antitumor immune responses by modulating the tumor microenvironment and facilitating antigen presentation. However, existing clinical data remain inconclusive regarding whether statin use influences prognosis in lung cancer patients receiving ICIs. Accordingly, this meta-analysis was undertaken to evaluate the impact of statin use on survival outcomes in this patient population, with the aim of informing clinical decision-making regarding combination strategies.MethodsWe systematically searched PubMed, Embase, the Cochrane Library, and Web of Science for clinical studies published from database inception to June 2026 that examined the association between statin use and outcomes in lung cancer patients treated with ICIs. Two investigators independently screened the literature, extracted data, and assessed the risk of bias using the Newcastle-Ottawa Scale (NOS). The primary endpoints were overall survival (OS) and progression-free survival (PFS). A meta-analysis was performed using Stata 15.0 software.ResultsTwelve studies comprising 5,156 participants were included. Pooled analysis demonstrated that statin use was associated with significantly improved OS (HR = 0.76, 95% CI (0.63, 0.91), P = 0.003) and PFS (HR = 0.82, 95% CI (0.69, 0.96), P = 0.017). Subgroup analyses revealed that the survival benefit remained significant for both OS and PFS in multivariate-adjusted estimates. In univariate analyses and in larger studies (n > 500), the benefits did not attain statistical significance. Geographically, statins significantly improved OS in non-Asian populations, whereas the PFS benefit in these populations did not reach significance.ConclusionsThis meta-analysis indicates that statin use is associated with significantly prolonged OS and PFS in lung cancer patients receiving ICIs, suggesting a potential role for statins in augmenting ICI efficacy. However, given that the included studies were predominantly retrospective observational designs, these findings should be interpreted with caution. Prospective, large-scale randomized controlled trials are warranted to confirm the survival benefits of combined statin and ICI therapy and to define the optimal timing and target population for such combination.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261420311

6091 Background: Neoadjuvant immunotherapy combined with chemotherapy is a promising strategy for resectable LAHNSCC. While most regimens employ single-target PD-1 inhibitors, dual-target agents (PD-1/CTLA-4 or PD-1/VEGF) have shown superior efficacy in recurrent/metastatic HNSCC. Building on our preliminary data (ASCO 2025) which suggested high pathological response rates, this ongoing randomized phase II trial aims to compare single- versus dual-target NAI regimens in an expanded cohort to identify the optimal treatment strategy. Methods: This is an ongoing randomized, open-label, phase II trial. Eligible pts were randomized (1:1:1) to receive 3 cycles of neoadjuvant therapy as follows: Cohort 1 will receive ivonescimab (PD-1/VEGF bispecific antibody, 10 mg/kg every 3 weeks), Cohort 2 will receive cadonilimab (PD-1/CTLA-4 bispecific antibody, 6 mg/kg every 3 weeks), and Cohort 3 will receive penpulimab (PD-1 antibody, 200 mg every 3 weeks), all in combination with cisplatin and nab-paclitaxel. After neoadjuvant treatment, Surgery was performed with the surgical margins based on pre-treatment (baseline) evaluation. Pts with pCR received adjuvant immunotherapy for up to 16 cycles. Pts without pCR received adjuvant radiotherapy or chemoradiotherapy, followed by 16 cycles of adjuvant immunotherapy. Results: Up to Dec. 2025, all 59 pts completed 3 cycles of neoadjuvant therapy and were evaluable, with a median follow-up of 12 months. The pCR rates were 60% (12/20) in Cohort 1, 42.1% (8/19) in Cohort 2, and 40% (8/20) in Cohort 3. The major pathologic response (MPR) rates were 75% (15/20), 57.9% (11/19), and 55% (11/20) in Cohort 1, 2, and 3, respectively. The ORR was 95% in Cohort 1 (CR: 8/20, PR: 11/20) and 84.2% in Cohort 2 (CR: 5/19, PR: 11/19), while Cohort 3 had an ORR of 80% (CR: 4/20, PR: 12/20). To date, pts have received a median of 6 cycles of adjuvant immunotherapy. The most common treatment-related adverse events (TRAEs) (>20%) were: leukopenia, anemia, neutropenia, thrombocytopenia, lymphocytopenia, hypothyroidism, hypertriglyceridemia, radiation dermatitis, stomatitis, vomiting, decreased appetite, and fatigue. Conclusions: Neoadjuvant dual-target (PD-1/VEGF) immunotherapy combined with chemotherapy demonstrated a higher pCR rate compared to dual-target (PD-1/CTLA-4) and single-target PD-1 regimens in resectable LAHNSCC. The treatment was well-tolerated, with all pts completing the intended neoadjuvant therapy and the observed most common TRAEs consistent with expected chemotherapy and radiotherapy profiles. Further analyses are ongoing with continued enrollment. Clinical trial information: NCT06444009 . RECIST and pathologic response. RECIST Pathologic Response CR PR SD PD pCR MPR pPR pNR (RVT=0) (0 （RVT:10-49%） (RVT:≥50%) Cohort 1 (n=20) 8 11 1 12 3 2 3 Cohort 2 (n=19) 5 11 3 8 3 2 6 Cohort 3 (n=20) 4 12 4 8 3 0 9

The oral mucosa maintains a delicate immunological equilibrium amidst constant microbial and environmental challenges. Within this unique microenvironment, the cytosolic DNA-sensing cGAS-STING signaling pathway has emerged as a central innate immune hub characterized by critical duality across a spectrum of pathologies. While transient STING activation is vital for protective anti-microbial defenses and driving anti-tumor immunity in oral squamous cell carcinoma, chronic, maladaptive signaling-often driven by self-DNA accumulation-fuels pathology in autoimmune and inflammatory conditions. Consequently, emerging therapeutic strategies targeting this pathway involve dichotomous applications, utilizing STING agonists for malignancies versus inhibitors for inflammatory disorders. Safely harnessing the significant therapeutic potential of the cGAS-STING pathway for managing recalcitrant oral diseases urgently requires precise, localized modulation strategies.

During the development of oral squamous cell carcinoma (OSCC), multiple danger signals can initiate chronic oral mucosal inflammation, which then gives rise to precancerous and cancerous lesions. Modulation of immune homeostasis is essential to intercept inflammation-driven OSCC. In this study, we aimed to identify key inflammatory danger signals involved in precancerous oral mucosal inflammation and to develop a locally applicable immunomodulatory strategy to prevent this precancerous inflammation. We first identified that saliva cell-free DNA (cfDNA) levels and cfDNA-induced TLR9 activation were linked to OSCC development and progression. Hypothesizing that removing cfDNA would be beneficial for OSCC prevention, we created a cationic nanoparticles-enabled mouthwash that regulates precancerous inflammation via removing negatively charged cfDNA. Both cationic nanoparticles and polymers inhibited the in vitro cellular proinflammatory response induced by plasma from OSCC patients and suppressed OSCC patient plasma-induced tumor cell migration and stemness. In the precancerous mouse model, cationic nanoparticles-enabled mouthwash alleviated oral mucosal inflammation via inhibiting TLR9 activation. Overall, our study highlights the role of cfDNA in OSCC progression and the potential of cationic nanoparticle-enabled mouthwash for treating OSCC-related precancerous oral mucosal inflammation.

Sarcopenia is a progressive, generalized skeletal muscle disease closely associated with increased risks of falls, disability, and mortality. It imposes a substantial disease burden on the elderly population in China. Current clinical practice lacks systematic, standardized protocols for the screening, assessment, and rehabilitation of sarcopenia grounded in high‑quality evidence. To address this gap, this guideline was developed through the joint efforts of the Rehabilitation Medicine Center of West China Hospital, Sichuan University, the Chinese Society of Physical Medicine and Rehabilitation, and a multidisciplinary panel of experts. Following evidence‑based guideline development methodology, it focused on 23 clinical questions​ covering rehabilitation assessment, prevention, exercise, nutrition, rehabilitation techniques, and implementation strategies for sarcopenia. A total of 58 recommendations were formulated through systematic evidence retrieval, evidence grading, and multiple rounds of expert consensus. This guideline provides rehabilitation physicians, physiotherapists and relevant personnel with systematic, evidence‑based guidance to improve standardized rehabilitation assessment and comprehensive intervention. It identifies future research needs to advance sarcopenia management in older adults in China.

The co-expression of proteins and microRNAs (miRNAs) carried by tumor-derived extracellular vesicles (EVs) has emerged as a critical biomarker source for cancer diagnosis and monitoring. However, achieving high-throughput, rapid, and non-destructive co-detection of multiple EV markers remains challenging. Here, we present a DNA-based dual-probe system combined with flow cytometry for efficient co-profiling of EV protein-miRNA. This flow cytometry-integrated strategy enables high-throughput, highly sensitive co-expression profiling of EV surface proteins and intravesicular miRNAs, allowing quantitative analysis of EV heterogeneity with single-particle resolution. The system employs a fluorescent aptamer to specifically recognize programmed death-ligand 1 (PD-L1) on the EV surface, while a fluorescent internal targeting hairpin-tetrahedral (FITHT) probe non-destructively penetrates and amplifies miR-21 signals via catalytic hairpin assembly (CHA). This strategy enables high-throughput, rapid and lysis-free detection of multiple markers in intact EVs. Validation with clinical samples from 24 non-small cell lung cancer (NSCLC) patients and 12 healthy donors (HDs) demonstrated excellent diagnostic accuracy (AUC = 0.986), with co-expression levels correlating with disease stage. This approach provides a powerful platform for precise NSCLC diagnosis and real-time disease monitoring.

To explore the prognostic value of baseline contrast-enhanced CT features imaging combined with clinical indicators in patients with unresectable hepatocellular carcinoma (uHCC) treated with hepatic arterial infusion chemotherapy plus targeted therapy and immunotherapy (HAIC-TI). Patients with uHCC who received at least two cycles of HAIC-TI were retrospectively analyzed. Inclusion required pre-treatment contrast-enhanced CT and modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessments after two HAIC-TI cycles. Patients were classified into progressive disease (PD) group and non-PD group (complete response [CR], partial response [PR], or stable disease [SD]) to identify predictors of early progression. Baseline predictors of early progression were identified using binary logistic regression analysis. For survival analysis, the patients were reclassified into the responder group (CR or PR) and the non-responder group (SD or PD). Overall survival (OS) was estimated using the Kaplan–Meier method and compared by log-rank test. Prognostic factors for OS were identified using Cox regression. A total of 132 patients were included in this study. The objective response rate (ORR) was 47.7

BACKGROUND: While more than 30% of patients with Parkinson’s disease (PD) are prescribed statins, the impact of statin use on the progression of PD remains incompletely elucidated. We aimed to comprehensively investigate the impact of statin use on PD progression. We analyzed longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI) to examine associations between statin use and clinical manifestations and cerebrospinal fluid (CSF) biomarkers. Mendelian randomization and Bayesian colocalization analyses were employed to assess genetic relationships between HMGCR inhibition (a proxy for statins) and PD phenotypes. Multi-omics analyses utilized postmortem substantia nigra RNA-seq data and CSF proteomics from living patients to explore potential mechanisms. In the PPMI cohort, statin use was associated with a faster cognitive decline among PD patients during longitudinal follow-up, ​​which was partially mediated by reduced CSF Aβ42. Genetic analyses indicated detrimental effects of HMGCR inhibition on cognitive function, dyskinesia, and restless legs syndrome in PD. In addition, RNA-seq analysis of substantia nigra suggested that HMGCR expression gradually decreases with PD progression, showing significant reductions in moderate and advanced stages. Finally, CSF proteomics revealed that statin use was associated with 238 upregulated and 203 downregulated proteins in PD, among which 28 proteins were linked to cognitive decline and significantly enriched in pathways related to substantia nigra development and PD. Our study suggests that statins may accelerate cognitive decline in PD patients through mechanisms potentially involving reduced CSF Aβ42 levels, inhibition of HMGCR in the substantia nigra, and disruption of PD-related protein pathways.

2529 Background: Salvage surgery is standard of care for patients with recurrent, resectable head and neck squamous cell carcinoma (HNSCC); However, the efficacy of salvage surgery remains limited. Therefore, there is an urgent need to explore new therapeutic strategies to further improve the survival of this patient subset. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, uses an IgG-ScFv structure with Fc domain point mutations, allowing for high retention in tumor tissue, and providing enhanced stability and improved safety. In this study, we aim to explore the efficacy and safety of neoadjuvant and adjuvant Cadonilimab combined with salvage surgery in patients with recurrent, resectable HNSCC. Methods: This was an open-label, single-institutional phase II clinical trial (ChiCTR2400079741). Patients aged 18-75 years, pathologically confirmed recurrent HNSCC (oral, laryngeal, hypopharyngeal, and oropharyngeal carcinoma), and with resectable diseases assessed by surgeons were included. Eligible patients received two cycles of Cadonilimab (6mg/kg, ivgtt, q2w) 2-4 weeks before surgery, then treated by salvage surgery, followed by 12 cycles of adjuvant Cadonilimab. Primary endpoint was 1-year disease free survival (DFS), and secondary endpoints were objective response rate (ORR), major pathological response (MPR), OS and safety. Results: From November 2023 to December 2024, a total of 32 patients were enrolled. One patient refused surgery, and 31 patients were included in the final analysis. According to radiological assessment, the ORR was 28.1% (9/32), with 2 cases of complete response (CR) and 7 cases of partial response (PR). Among the patients receiving surgical resection, the MPR rate was 32.3% (10/31), with 9.7% (3/31) of patients achieving pathological CR. With a median follow-up of 18.8 months (range, 13.0-25.7 months), the 1-year DFS rate was 77.4%, and the 1-year OS rate was 87.1%. Treatment-related adverse events (TRAEs) occurred in 74.2% (23/31) of patients. The majority of TRAEs were grade 1 or 2. Grade ≥3 TRAEs occurred in 6.5% (2/31) of patients, including one case of grade 3 neutropenia and one case of grade 4 immune-related hepatitis. The most common TRAEs were hypothyroidism (25.8%, n=8), anemia (25.8%, n=8), lymphocytopenia (19.4%, n=6), fatigue (16.1%, n=5), myocarditis (12.9%, n=4), constipation (12.9%, n=4), rash (12.9%, n=4), elevated ALT/AST levels (12.9%, n=4), and neutropenia (6.5%, n=2). Conclusions: Cadonilimab demonstrated encouraging anti-tumor activity and acceptable safety profile in patients with recurrent, resectable HNSCC. Cadonilimab may change the therapeutic approach for recurrent, resectable HNSCC. Clinical trial information: ChiCTR2400079741.

Glacial ecosystems on the Tibetan Plateau undergo pronounced hydrological shifts across the glacial ablation cycle, driven by the onset and retreat of the Indian summer monsoon. To elucidate how transitions between four distinct hydrological ablation stages (pre-ablation, early ablation, late ablation, and frozen) shape microbial community structures and antibiotic resistance gene (ARG) profiles, we analyzed 112 samples collected across four stages from multiple glacier catchments on the southeastern Tibetan Plateau using metagenomic sequencing. Our results indicated that warmer stages favored thermotolerant Proteobacteria and reduced overall community diversity and evenness. ARG abundances exhibited ablation-dependent fluctuations, with Betaproteobacteria identified as predominant potential hosts. Furthermore, ARGs and virulence factors associated with mobile genetic elements were enriched during early and late ablation stages relative to the frozen stage, suggesting elevated potential for horizontal gene transfer coinciding with peak meltwater discharge. Notably, while upstream meltwaters generally exhibited higher ARG abundances, the upstream-downstream disparity tended to diminish from the pre-ablation to the late ablation stage, likely reflecting enhanced microbial mixing driven by glacier melt. Together, these findings reveal that glacier meltwater microbiomes are primarily shaped by ablation dynamics rather than spatial heterogeneity. More importantly, dynamics across the glacial ablation cycle drive shifts in meltwater hydrology that facilitate the downstream environmental mobility of glacial resistomes, posing growing antimicrobial resistance risks within the One Health framework.

The intestinal microbiome is fundamental to host physiological homeostasis, while deviations from its balanced state have been linked to inflammatory bowel diseases (IBD). To address the limitations of conventional antibiotic therapies, this study explored snake gut microbiota as a novel source of anti-inflammatory probiotics. We explored the gut microbiota of five snake species (Deinagkistrodon acutus, Trimerodytes annularis, Trimerodytes percarinatus, Lycodon rufozonatus, and Trimeresurus stejnegeri) through metagenomic sequencing. Community composition analysis revealed that the phylum-level composition was mainly Proteobacteria, Bacteroidetes, Actinomycetota, and Firmicutes. We further detected some potential probiotic species, such as Enterococcus, Lactobacillus, and Limosilactobacillus. From 196 isolated strains, Lactobacillus johnsonii DA0116 and Limosilactobacillus reuteri DA0218 were selected through rigorous safety and functional assessments, including acid/bile tolerance, pathogen inhibition, and adhesion capacity. In a DSS-induced murine colitis model, both strains significantly reduced disease activity index (DAI), pro-inflammatory cytokines (TNF-α, IL-6, and IL-8), and restored gut microbiota diversity. Additionally, whole-genome analysis identified bacteriocin synthesis clusters (gassericin-S/T) and carbohydrate metabolism genes, explaining their antimicrobial and immunomodulatory properties. This study not only emphasizes the untapped latent value of reptilian gut microbiota for probiotic discovery but also provides two candidate strains with therapeutic promise for IBD and functional food applications.

Background:Hepatocellular carcinoma ranks among the most prevalent malignancies worldwide. While stress can modulate tumor initiation, progression, metastasis, and therapeutic response through diverse mechanisms, its specific role in hepatocellular carcinoma pathobiology remains elusive. This study aimed to elucidate the role of the gut microbiota in stress-promoted hepatocellular carcinoma progression and to uncover the pathways associated with disease progression. Methods:Integrating clinical and preclinical models, we delineated stress-induced restructuring of the gut microbiota and functionally restored specific microbial constituents. Mechanistic insights into the microbial metabolite indole-3-propionic acid were derived through in vitro and in vivo interrogations of the hepatocellular carcinoma tumor microenvironment. Results:Stress profoundly remodels the gut microbiota, with Phocaeicola vulgatus being significantly reduced. Restoration of Phocaeicola vulgatus or administration of its tryptophan-derived metabolite indole-3-propionic acid significantly attenuated hepatocellular carcinoma progression in vivo. Indole-3-propionic acid treatment reduced endothelial JAM2 expression and was associated with reduced JAM2-F11R-mediated endothelial-macrophage crosstalk in hepatocellular carcinoma, which may contribute to suppression of tumor progression. Conclusions:These findings support a role for the stress-gut microbiota-metabolite-tumor microenvironment axis in hepatocellular carcinoma progression and suggest potential translational targets for microbiome-based therapeutic strategies.

Head and neck squamous cell carcinoma (HNSCC) involves aggressive invasion at the tumor-host interface, particularly at the leading edge. However, the mechanisms sustaining this invasive front remain unclear. Here, we performed spatially resolved multiomics profiling to characterize the leading-edge multicellular ecosystem (LEMCE) of HNSCC. We identified a set of twelve autocrine ligands, including TGFB1, ICAM1, and TNC, that support a stable invasive transcriptional state. Impaired fatty acid (FA) degradation in this region enhances autocrine ligands and amplifies proinvasive gene expression. Spatial single-cell analysis revealed that the specific resident cells in the LEMCE, which exhibited increased expression of autocrine ligands and impaired FA degradation, participated in a fibroblast-macrophage-T cell interaction circuit involving MMP1+ fibroblasts and C1QC+/SPP1+ macrophages, followed by interactions between C1QC+ macrophages and cytotoxic T cells. These interactions may contribute to the structural organization and immunosuppressive features of the LEMCE. Therapeutically, targeting this niche via a combination of autocrine cytokine blockade, FA metabolic restoration, and PD-1 immune checkpoint inhibition suppressed invasion, reduced metastasis, and prolonged survival in mouse models. Our findings define the LEMCE as a self-reinforcing invasive and immunosuppressive niche and highlight its potential as a targetable vulnerability in HNSCC.