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Background: Nasopharyngeal carcinoma (NPC) in endemic areas is strongly linked to Epstein-Barr virus (EBV) infection. EBV-specific immunoglobulin (Ig)A and IgG titers have been used for diagnosis and prognosis, but their full potential for prediction and protection remains unclear.

Methods: We analyzed samples from 353 individuals, including patients with NPC at diagnosis or patients with NPC years prior to diagnosis, matched controls, and family members from NPC multiplex families from Taiwan, along with 50 patients with NPC from Singapore with survival data. We used systems serology, a comprehensive approach to assess antibody subclass, isotype, and fragment crystallizable gamma receptor (FcγR) binding, along with effector functions such as complement deposition, cellular phagocytosis, and natural killer (NK) cell activation.

Findings: Patients with NPC showed a broad expansion of antibody levels, FcγR binding, and Fc effector functions, especially neutrophil phagocytosis and complement deposition, compared to controls. Prior to NPC onset, individuals exhibited elevated EBV-specific IgM levels and higher FcγRIIA and FcγRIIIB binding, suggesting an early immune response to viral activity. IgMs appeared as potential correlative markers for NPC. In contrast, controls showed increased IgG2 levels and FcγRIIB binding, indicating lower inflammatory responses. On a per-antibody level, controls exhibited stronger Fc effector functions, suggesting a protective role in preventing NPC. Additionally, we identified a multivariate antibody signature associated with survival after treatment.

Conclusions: This study provides valuable insights into EBV-specific antibodies as predictive biomarkers of NPC progression, offering opportunities for improved disease management.

Funding: This work was supported by the Ragon Institute of Mass General, MIT, and Harvard with support from the National Cancer Institute (CA264646 to E.W.N.).

Background: Cold tumors, characterized by poor T cell infiltration and an immunosuppressive tumor microenvironment (TME), are generally resistant to immune-checkpoint inhibitors (ICIs). Although CD4⁺ T cells play a critical role in anti-tumor immunity, it remains unclear whether major histocompatibility complex (MHC)-II-restricted neoantigen vaccines can reprogram the immunosuppressive TME and overcome ICI resistance.

Methods: Using the B16F10 model, we evaluated the MHC-II-restricted vaccine efficacy, profiled immune responses via flow cytometry and single-cell RNA sequencing, and identified the potential combination therapy targets poliovirus receptor (PVR) via NicheNet analysis. The combined efficacy was then validated in vitro and in vivo.

Findings: MHC-II-restricted neoantigen vaccine promoted inflammatory signaling within the TME and enhanced infiltration of CD4⁺ and CD8⁺ T cells, along with increased interferon (IFN)-γ production and signs of T cell exhaustion, which provided a prerequisite for ICI response. NicheNet analysis revealed enrichment of the inhibitory immune-checkpoint axis PVR-T cell immunoglobulin and ITIM domain (TIGIT) following vaccination. The combination of the vaccines and TIGIT blockade exhibited synergistic anti-tumor efficacy. This combination enhanced cytokine production by antigen-specific T cells, promoted effector memory differentiation, and delayed exhaustion of CD8⁺ T cells.

Conclusions: MHC-II-restricted neoantigen vaccine remodels the immune inhibitory TME with insufficient T cell infiltration and synergizes with TIGIT blockade to suppress tumor growth, providing a promising combinatorial strategy for cold tumors.

Funding: Supported by the National Key Research and Development Program of China (2023YFC2506400), the National Natural Science Foundation (82373263), and the Fundamental Research Funds for the Central Universities (0214-14380506).

Cognitive impairments in depression, driven by both the illness per se and low-grade systemic inflammation, markedly reduce functional capacity and quality of life among patients who suffer. Findings from Badulescu et al.'s placebo-controlled trial reported that semaglutide, a GLP-1 receptor agonist, may improve attention and memory, although there was no significant improvement in overall depressive symptoms.

Hepatology has been revolutionized over 40 years from having almost no therapies to achieving cures for hepatitis C, suppression of hepatitis B, effective therapies for MASH and cancer, liver transplantation, and emerging innovations like gene editing, immune modulation, and regeneration. This personal reflection highlights landmark discoveries, rapid progress, and the promise of continued breakthroughs in the field.

Song et al. systematically characterize how an MHC-II-restricted neoantigen vaccine remodels the cold tumor microenvironment. The vaccine promotes T cell infiltration and effector function while upregulating the PVR-TIGIT checkpoint axis. Combining vaccination with TIGIT blockade achieves synergistic anti-tumor efficacy by enhancing antigen-specific CD4 T cell function and delaying exhaustion, providing a promising strategy to overcome immunotherapy resistance in cold tumors.

Background: Inflammatory bowel disease (IBD) research is a dynamic field. However, the growing volume of electronic health records (EHRs) and research data presents significant challenges. Traditional methods for structuring unstructured EHRs are labor-intensive and lack scalability. Large language models (LLMs) may present a solution, however, their usefulness in data standardization in the context of IBD remains unknown. We sought to evaluate LLMs in structuring free-text histology and radiology reports from IBD patients (n = 32,041), compare their performance to manual clinician curation, and assess the usefulness of fine-tuning and retrieval-augmented generation (RAG).

Methods: We developed an IBD-specialized LLM-based framework utilizing structured prompt engineering and fine-tuning. Free-text reports from two independent sites were manually curated and processed using various LLMs (n = 120).

Findings: Overall, Llama 3.3 achieved the highest F1 scores for histology and imaging (1.00 ± 0 and 0.85 ± 0.29, respectively) in extracting findings and anatomical regions, surpassing other models in structured data generation. Fine-tuning improved the performance of the smaller Llama 3.1 8B model for imaging reports (0.70 ± 0.46 vs. 0.82 ± 0.35), enabling better extraction with reduced computational requirements.

Conclusions: Our findings demonstrate the feasibility of LLM-based automated structuring of IBD-related medical records. Unstructured data from free-text reports can be reliably converted into standardized ontologies with location, severity, and qualifiers. These advancements enable scalable, privacy-compliant AI-driven solutions for data standardization.

Funding: The Institute for Life Sciences, University of Southampton, the NIHR Southampton BRC, and EPSRC (EP/Y01720X/1).

Tuberculosis screening faces challenges of under-detection, costly approaches, and inequitable access. AI-enabled digital stethoscopes have demonstrated promising accuracy and feasibility for detecting lung and cardiovascular abnormalities, with promising results in early TB studies. Training and validation in diverse, high-burden settings are essential to explore the potential of this tool further.

Over the past decade, endovascular therapy (EVT) has transformed the management of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Building on the pivotal randomized controlled trials (RCTs) of 2015, subsequent evidence has refined indications, extended time windows, and advanced technical approaches. Yet, overall outcomes remain modest, with only half of patients achieving functional independence at 90 days. This has spurred efforts to expand EVT to new subgroups, including patients with medium-distal occlusions and mild deficits while optimizing workflows such as direct-to-angiosuite triage and tailored technical strategies. Recent RCTs have also revisited intra-arterial thrombolysis. Beyond revascularization, emerging research explores peri- and post-reperfusion targets, particularly anti-inflammatory and thromboinflammatory pathways. Collectively, these efforts reflect a paradigm shift, from reperfusion alone toward a broader, physiology-informed strategy aimed at improving functional recovery. Ten years on, EVT continues to evolve, promising greater precision, safety, and impact across AIS care.

Background: Evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs) might have pro-cognitive effects. No prior study has evaluated the efficacy and safety of a GLP-1RA for the treatment of cognitive dysfunction in adults with major depressive disorder (MDD) in a randomized clinical trial.

Methods: This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345). Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese. Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide. The primary outcome was an executive function composite score comprising the digit symbol substitution test, the Stroop test, and the n-back test. Secondary outcomes included a global cognition composite score, measures of functioning, depressive symptom severity, suicidality, and body weight.

Findings: 72 participants were randomized to oral semaglutide (n = 35) or placebo (n = 37). Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60). Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03) and body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p < 0.001). Treatment did not affect depressive symptom severity or the frequency of suicidal ideation. Gastrointestinal side effects were common in the semaglutide group, with no serious adverse events.

Conclusion: Semaglutide did not improve executive function; results from secondary analyses suggested effects on specific domains of cognition. Semaglutide was safe for patients with MDD.

Funding: This work was supported by the Physicians' Services Incorporated Foundation.

Pregnancy triggers profound physiological changes, yet postpartum recovery remains under-recognized despite its predictive significance for lifelong health. The fourth trimester offers a critical window to detect cardiometabolic, immunological, and mental-health vulnerabilities. We propose a precision postpartum medicine framework integrating human-relevant models, longitudinal multi-omics, and AI-enabled risk stratification to transform postpartum care.