RNA 5-methylcytosine (m⁵C) is an emerging epitranscriptomic modification implicated in the progression of multiple cancers, yet the landscape of m⁵C in bladder cancer (BCa) and underlying regulatory mechanisms remains largely elusive. In this study, we identified NOP2, an RNA methyltransferase, as a key driver of BCa progression. NOP2 was significantly upregulated in BCa tumors and associated with poor prognosis. Functionally, NOP2 promoted cell proliferation and invasion, enhancing tumor growth in xenograft models. Mechanistically, NOP2-mediated m⁵C deposition facilitates the recruitment of the m⁵C reader YBX1, thereby stabilizing SCD mRNA and boosting SCD expression. The NOP2/SCD axis orchestrated lipid metabolism reprogramming, altering the distribution of saturated, monounsaturated, and polyunsaturated fatty acids to suppress lipid peroxidation and protect BCa cells from ferroptotic stress. Collectively, our findings determine the oncogenic role of the m⁵C methyltransferase NOP2 in BCa and reveal a novel NOP2/YBX1/SCD axis that links epitranscriptomic regulation, metabolic reprogramming and ferroptosis evasion, providing a new target for therapeutic intervention.

Resistance to first-line multikinase inhibitors (MKIs) sorafenib and lenvatinib critically limits hepatocellular carcinoma (HCC) treatment efficacy. It remains largely unknown how long non-coding RNAs (lncRNAs) affect resistance to MKIs. Through integrated analysis of resistant HCC models, we identified lncRNA LMCD1-AS1 as a critical driver of MKI resistance. LMCD1-AS1 overexpression correlates with advanced tumor stage, shortened survival, and resistance to MKI therapy in HCC patients. LMCD1-AS1 confers dual resistance to sorafenib and lenvatinib by suppressing apoptosis, while its knockdown restored drug sensitivity. Mechanistically, LMCD1-AS1 directly bind histone demethylase PHF8, promoting H4K20me1 to epigenetically activate oncogenes (e.g., c-Myc, β-catenin) and upregulate lactate dehydrogenase A (LDHA). This triggers lactate overproduction and alters the NAD⁺/NADH ratio, establishing a protumorigenic metabolic state. Crucially, PHF8 ablation reverses LMCD1-AS1-driven resistance, and in vivo xenografts confirm attenuated sorafenib efficacy with LMCD1-AS1 overexpression. Our work unveils the LMCD1-AS1/PHF8/H4K20me1 axis as a unified epigenetic-metabolic mechanism underlying MKI resistance, representing a promising therapeutic target and prognostic biomarker for HCC.

NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular carcinomas, it appears to act as a tumor promoter in breast and head and neck cancers. This study explored the role of NLRX1 in prostate cancer (PCa), examining its impact on cell proliferation, apoptosis, migration, invasion, and tumor progression, as well as associated molecular mechanisms. Using TCGA data, the association between NLRX1 expression and PCa prognosis was evaluated. NLRX1 expression was upregulated under serum-free stress conditions. Silencing NLRX1 reduced cell proliferation in PC3 cells, but not in LNCaP cells. Additionally, NLRX1 knockdown inhibited migration and invasion, while promoting apoptosis under serum-free conditions. Mechanistically, NLRX1 knockdown reduced AKT and ERK phosphorylation in response to serum deprivation, EGF, and TGF-β, without affecting PDK1 activity under serum deprivation. Pharmacological data showed AKT and ERK as key regulators of viability and invasion, with AKT critical for growth and migration. Co-immunoprecipitation, confocal microscopic examination, domain binding, structural modeling, and molecular dynamics revealed a stable interaction between NLRX1's LRR domain and AKT's PH domain. NLRX1 facilitated cell proliferation, migration, invasion, and resistance to serum-free stress through direct interaction with AKT, highlighting NLRX1 as a promising biomarker for PCa progression.

Breast invasive carcinoma (BRCA) remains a leading cause of female cancer mortality, necessitating novel biomarkers and therapeutic targets. Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) emerges as a potential regulator in tumor progression and immune modulation, yet its comprehensive role in BRCA remains uncharacterized.

We conducted an integrated multiomics analysis of HNRNPA3 in BRCA using data from TCGA, GEO datasets, single-cell RNA sequencing, and spatial transcriptomics. Bioinformatics approaches included differential expression analysis, survival analysis, functional enrichment, immune microenvironment characterization, and drug sensitivity prediction.

HNRNPA3 was significantly upregulated in BRCA tissues and correlated with advanced tumor grade, metastasis, and poor prognosis across multiple cohorts. Functional enrichment revealed HNRNPA3's involvement in cell cycle regulation and immune-related pathways. Immune profiling demonstrated that high HNRNPA3 expression was associated with altered immune cell distribution, particularly CD4+ T cells, and reduced immunotherapy response. Spatial transcriptomics confirmed predominant HNRNPA3 expression in malignant regions. Drug sensitivity analysis identified potential therapeutic agents (CD-437 and talazoparib) targeting HNRNPA3-associated pathways.

HNRNPA3 functions as a critical oncogenic regulator in BRCA by promoting tumor progression through cell cycle dysregulation and immune microenvironment remodeling. Its strong association with therapy resistance positions HNRNPA3 as both a prognostic biomarker and promising therapeutic target for breast cancer intervention strategies.

Bloom syndrome protein (BLM), a RecQ family DNA helicase, is consistently overexpressed in multiple malignancies, yet its therapeutic potential remains largely unexplored. Herein, we focused on targeting the BLM promoter G-quadruplex (BLM-G4) to inhibit the BLM signaling pathway. We first characterized the parallel BLM-G4 in the BLM promoter region. Subsequently, it is shown for the first time that BLM-G4 recruits phosphorylated signal transducer and activator of transcription 1 (pSTAT1) to activate BLM expression. Importantly, two natural alkaloids, berberine (BER) and coptisine (COP), compete with STAT1 for binding to BLM-G4, thereby significantly suppressing BLM expression in colon cancer cells. The BER/COP-BLM-G4 complex structures were determined using nuclear magnetic resonance experiments, which provide valuable insights for the rational design of next-generation BLM-G4-targeting ligands. Beyond BLM regulation, the conjoint analysis of genome-wide STAT1-CUT&Tag-seq, G4-CUT&Tag-seq, and COP-RNA-seq demonstrated STAT1 as a general G4-binding transcription factor and COP as a pan-genomic G4 stabilizer. Furthermore, BER/COP exhibited a pronounced synergistic effect with olaparib in inducing colon cancer cell death by disrupting DNA repair pathways and intensifying DNA damage. Collectively, our findings reveal a novel epigenetic mechanism of BLM gene upregulation mediated by BLM-G4-STAT1 interaction and suggest that the combination therapy of G4 stabilizers with poly(ADP) ribose polymerase (PARP) inhibitors is a promising strategy for treating complex cancers.

The COVID-19 pandemic was associated with a substantial prevalence of physicians intending to reduce their clinical hours (ITR) or intending to leave their current organization (ITL). It is unclear how work intentions have changed since that time.

To characterize how the prevalence of ITR and ITL changed among physicians since the COVID-19 pandemic, factors associated with ITR and ITL, and factors associated with physicians' decision to remain at their current clinical workload or their current organization.

This serial cross-sectional study was conducted from January 7, 2022, to November 3, 2024, among 160 organizations across the US with 100 or more physicians across specialties. Physicians responded to the American Medical Association's Organizational Biopsy study in 2022, 2023, or 2024.

Main outcomes were ITR within the next 12 months and ITL within the next 24 months.

The sample consisted of 37 112 physicians (7176 physicians in 2022, 12 248 in 2023, and 17 688 in 2024; median organizational response rate of 41.5% [IQR, 29%-60%]; 18 626 of 35 202 male physicians [52.9%]) from 160 organizations, including 81.4% physicians (25 381 of 31 182) who identified as practicing clinically full-time. The overall point prevalence of ITR decreased from 25.6% (1489 of 5815) in 2022 to 22.5% (3266 of 14 540) in 2024 (P = .002), while the prevalence of ITL decreased from 19.9% (1345 of 6760) in 2022 to 15.1% (2414 of 15 935) in 2024 (P = .002). Decreases in ITR and ITL were seen across multiple physician groups. In multivariable-adjusted models, female physicians had higher odds of ITR than male physicians (odds ratio [OR], 1.11; 95% CI, 1.04-1.20), but lower odds of ITL (OR, 0.93; 95% CI, 0.87-0.99). Part-time physicians had 1.18 (95% CI, 1.09-1.29) times the odds of ITR and 1.35 (95% CI, 1.25-1.45) times the odds of ITL compared with full-time physicians. The most prevalent factors that would make respondents reconsider ITR or ITL-including a desire for increased workflow efficiency, improved staffing, and enhanced compensation-were common across the 2 outcomes.

This serial, cross-sectional, multisite study of US physicians suggests that while the prevalence of ITR and ITL have decreased since the COVID-19 pandemic, more than one-fifth of physicians continued to report ITR and nearly 1 in 6 reported ITL. In aggregate, compared with historical data, current rates represent mixed progress with favorable overall trends in ITL but unfavorable trends in ITR. Common factors, including greater workflow efficiency and consistent staffing, were reported as potentially mitigating both ITR and ITL. These findings can help leaders prioritize and target interventions to sustain the effort of the physician workforce.

Membrane oxygenator exchange can be a frequent requirement during extracorporeal membrane oxygenation (ECMO). In low-income health systems, the scarcity and cost of disposables pose significant challenges to timely exchanges. We describe a 48-year-old woman placed on veno-venous ECMO for refractory hypoxemic respiratory failure secondary to pneumonia. Within 30 min, the oxygenator developed thrombosis, characterized by a transmembrane pressure gradient of 229 mmHg. A total of 10 mg of recombinant tissue plasminogen activator (rt-PA) was administered through the premembrane port. Sixty minutes after infusion, the gradient decreased to 116 mmHg, with subsequent improvement in oxygenation. No bleeding occurred. The patient was successfully weaned from ECMO and discharged from the ICU without complications. Low-dose rtPA instillation into a failing oxygenator can postpone exchange and represents a viable salvage strategy for resource-limited ECMO programs.

Recurrent respiratory tract infections (RRTIs) in children are associated with substantial morbidity and healthcare burden. Modulation of the gut microbiota via probiotics represents a potential adjunctive strategy to prevent recurrent infections. This study evaluated the efficacy and safety of Bifidobacterium animalis subsp. lactis XLTG11 and Lactobacillus plantarum CCFM8661 in children with RRTIs.

In a double-blind, randomized, placebo-controlled trial, 120 children with RRTIs received either daily probiotic supplementation (1 × 10¹⁰ CFU/day; n = 60) or placebo (n = 60) for 3 months, with a 6-month follow-up. Primary outcome was clinical efficacy; secondary outcomes included gut microbiota composition (16 S rRNA sequencing) and plasma immune biomarkers (IgA, IgG, IgM, C3, C4).

Probiotics significantly improved clinical efficacy compared with placebo in both per-protocol [82.1% vs. 64.2%, p = 0.033] and intention-to-treat analyses [76.7% vs. 56.7%, p = 0.020]. Children in the probiotic group experienced fewer and shorter respiratory episodes, including fever, cough, and pharyngeal congestion (all p < 0.05). Probiotic supplementation increased beneficial taxa (B. breve, L. plantarum, S. salivarius, W. cetiin) and reduced potentially pathogenic taxa (Anaerostipes, Vibrio). IgG and IgM levels remained stable or decreased in the probiotic group, contrasting with increases in the placebo group, indicating a balanced humoral response. No adverse events were reported.

Daily administration of XLTG11 and CCFM8661 for three months is safe and improves clinical outcomes in children with RRTIs, reducing new respiratory episodes and modulating gut microbiota and immune function. These findings support strain-specific probiotics as a viable adjunctive therapy in pediatric respiratory infections.

We define adherent, difficult-to-treat asthma as 'true severe asthma.' In preschool children, evidence for add-on long-acting beta-agonists (LABA) to inhaled corticosteroids (ICS) in those with persistent uncontrolled disease despite high-dose ICS remains limited. We evaluated clinical outcomes of ICS-LABA therapy in this population.

This retrospective observational study (2021-2024) included children aged 6-72 months with severe, uncontrolled asthma despite medium- to high-dose ICS and verified adherence, who were initiated on LABA therapy. Primary outcomes were severe exacerbations (systemic corticosteroid use, hospitalizations, and uncontrolled symptoms). Secondary outcomes included PICU admissions and spontaneously reported adverse events. Outcomes 6 months before and after LABA initiation were compared using generalized estimating equations (GEE), adjusting for seasonality, age, sex, and atopy.

Fifty-three children were included (mean age 38.8 ± 17.6 months, 41.5% male, atopy 49.1%). LABA initiation was associated with a substantial reduction in clinical burden: hospitalizations declined from 41.5% to 3.8% (p < 0.001), systemic corticosteroid use from 86.8% to 52.8% (p < 0.001), and daily symptoms from 86.8% to 37.7% (p < 0.001). PICU admissions decreased from 9.4% to 0%. These associations remained significant after adjustment for covariates (p < 0.001). No adverse events were spontaneously reported by patients or caregivers during the follow-up period; however, systematic adverse event surveillance was not conducted.

In adherent preschool children with true severe asthma, LABA initiation was associated with observed improvements in clinical outcomes. Still, prospective controlled studies with systematic safety surveillance are warranted.

Early-onset asthma (EOA) significantly increases the risk of chronic obstructive pulmonary disease (COPD), yet the causal mechanisms and molecular mediators underlying this progression remain poorly understood. Multi-omics integration provides a powerful framework for prioritizing potential mediating proteins and disease-specific therapeutic candidates.

This study integrated large-scale genetic and proteomic data using Mendelian randomization (MR) approaches to investigate the progression from EOA to COPD. Proteome-wide MR evaluated protein quantitative trait loci (pQTLs) in relation to EOA and COPD risk, with mediation analysis evaluating their roles and single-cell transcriptomics defining the cell-type-specific expression of the mediating proteins. Finally, colocalization, multi-tissue expression quantitative trait loci (eQTLs), and druggability assessment were used to prioritize potential disease-specific therapeutic targets.

Evidence from genetic instruments supports a causal relationship between EOA and COPD. Proteome-wide analyses of 7847 pQTLs identified 339 proteins with potential effects on EOA and 389 on COPD. Six proteins, KREMEN1, BLMH, CNTN5, IL1RN, MIA, and PILRA, showed statistically significant mediation effects in the EOA-to-COPD pathway. PILRA strongly colocalized at shared genetic loci between the two diseases and was significantly downregulated in macrophages from COPD patients. For disease-specific targets, immune-tissue eQTL validation supported ITPKA in EOA. Integration of druggability assessment with multi-tissue eQTL analyses prioritized FES, CCN3, NMI, and NMT1 as promising therapeutic candidates for COPD.

These findings provide genetic evidence supporting a causal relationship between EOA and COPD, reveal putative mediating proteins, and prioritize therapeutic candidates with translational potential, offering new insights into pathogenesis, prevention, and intervention.