Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Although epigenetic remodeling is central to this process, its impact under therapeutic pressure remains unclear. We profiled longitudinal biopsies from patients with melanoma treated in the phase 1b NIBIT-M4 epi-immunotherapy trial [NCT02608437, DNA (cytosine-5)-methyltransferase 1 inhibitor plus anti-CTLA-4] using single-cell multiome and spatial transcriptomics. Seven malignant meta-programs were identified, including a rare Wnt/β-Catenin melanocytic state and a dedifferentiated neural crest-like state enriched in nonresponders. Spatial analyses showed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact niches. Responders displayed enrichment of antigen presentation/interferon program and coordinated T and B cell expansion, whereas nonresponders retained stable neural crest-like clusters. Epigenetic therapy reactivated transposable elements, priming innate immunity and enhancing immunogenicity. Nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) emerged as a master regulator of neural crest-like states and resistance; its perturbation promoted differentiation and immunogenicity. These findings define mechanisms of resistance and nominate β-Catenin and NFATC2 as therapeutic vulnerabilities.

Patients undergoing curative gastrectomy for gastric cancer are vulnerable to perioperative protein loss, negative nitrogen balance and delayed recovery. Conventional peripheral parenteral nutrition (PN) formulations may not provide sufficient protein at clinically practical infusion volumes, and whether high-protein (amino acid-enriched) PN improves postoperative nitrogen balance after gastrectomy has not been tested in a randomized controlled trial. The PROGAIN trial evaluates the effect of perioperative high-protein PN on nitrogen balance and recovery outcomes in this population.

PROGAIN is a single-center, randomized, open-label, parallel-group superiority trial with blinded laboratory assessment and coded-group analysis of the primary endpoint. The trial will enroll 110 patients with gastric cancer scheduled for curative gastrectomy. Participants are allocated 1:1 to high-protein PN or conventional PN, administered through a peripheral intravenous line on the day before surgery and postoperative day (POD) 1 through POD 5. PN is delivered at a daily caloric target of 20 kcal/kg/day using a stepwise schedule informed by an institutional retrospective audit of oral intake. The primary outcome is nitrogen balance on POD 5, calculated using a simplified Blackburn equation. Secondary outcomes include nutritional indices, skeletal muscle index, glycemic control, postoperative complications classified by Clavien-Dindo grade and functional recovery measures. The primary analysis will compare the two arms using a two-sample t-test in the intention-to-treat population. The trial has 80% power to detect a between-group mean difference of 3 g/day at a two-sided α of 0.05.

The trial is approved by the Institutional Review Board of Soonchunhyang Cheonan Hospital and conducted in accordance with the Declaration of Helsinki and ICH-Good Clinical Practice. Findings will be disseminated through peer-reviewed publication, scientific meetings and results reporting on ClinicalTrials.gov.

ClinicalTrials.gov, NCT07488611.

Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.

We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry.

These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater margin-to-center differences in TIGIT (p=0.0019) and PVR (p=0.0008) in the tumor after ATZ/BEV.

Our exploratory findings suggest that ATZ/BEV may remodel the HCC microenvironment toward a state characterized by concurrent CD8+ T-cell activation and inhibitory signaling through the TIGIT-PVR/NECTIN2 axis, particularly at the tumor margin.

Programmed cell death represents a fundamental process in maintaining organismal homeostasis and responding to pathological challenges. The traditional view considered apoptosis, pyroptosis, and necroptosis as independent death pathways. However, recent research has revealed extensive interactions and synergies among these pathways, leading to the emergence of a novel form of cell death termed "PANoptosis." Triggered by specific stimuli, PANoptosis involves the assembly of a large multiprotein complex called the PANoptosome. This complex integrates key molecules and morphological features from apoptosis, pyroptosis, and necroptosis, culminating in a highly efficient and coordinated inflammatory cell death program. Concurrently, non-coding RNAs, as crucial regulators of gene expression, participate extensively in the regulation of cellular fate at the post-transcriptional and epigenetic levels. This review systematically summarizes the molecular mechanisms by which non-coding RNAs regulate the core components of PANoptosis and its upstream signaling pathways. It further delves into the pathological role of this regulatory axis in infectious diseases, cancer, neurodegenerative disorders, and autoimmune diseases. Additionally, the article explores the diagnostic potential of non-coding RNA-based approaches and therapeutic strategies targeting the non-coding RNA-PANoptosis axis, while also addressing current challenges related to mechanistic complexity, delivery technologies, and safety assessment. This review aims to establish a systematic framework for the "non-coding RNA-PANoptosis-disease" regulatory axis, providing a theoretical basis for understanding the interactive logic of cell death networks and for developing precise interventions for related diseases.

LIMD1, a tumour suppressor located at chromosome 3p21.3, is frequently lost in non-small-cell lung cancer, yet its role in tumour-immune interactions remains unclear. Here, we show LIMD1 loss increases PD-L1 protein abundance across multiple lung cancer models and primary airway epithelial cells. Mechanistically, LIMD1 restrains PD-L1 through post-transcriptional and post-translational mechanisms. LIMD1 loss can relieve microRNA-mediated repression of the CD274 3'UTR, and LIMD1 loss can also disrupt ARIH1-PD-L1 association, reduce PD-L1 polyubiquitination, and stabilise PD-L1 protein without a commensurate increase in CD274 transcript levels in isogenic models. Functionally, LIMD1-deficient tumour cells suppress CD8⁺ T-cell activation in vitro and show enhanced sensitivity to PD-1/PD-L1 blockade in tumour-PBMC co-culture assays. Analysis of TRACERx non-small-cell lung cancer samples revealed clonal LIMD1 loss of heterozygosity in ∼40% of lung adenocarcinomas, where it is associated with increased tumour PD-L1 expression. Across independent patient cohorts receiving immune checkpoint blockade, low LIMD1 expression was enriched among responders. We identify LIMD1 as a tumour-intrinsic regulator of PD-L1 turnover and suggest that tumour suppressor loss can shape immune checkpoint biology and influence immunotherapy response.

Mitochondria activate immunity, but the role in cancer is unknown. Here, we report that transgenic expression of Parkin, a regulator of mitochondrial fitness, induces inflammation and interferon (IFN) gene signatures, suppresses prostate cancer formation and generates CD8⁺ and CD20⁺ intraprostatic immune aggregates. These had hallmarks of mature tertiary lymphoid structures (TLS), expressing markers of B cell maturation (CXCL13, CCL21), germinal center formation (BCL6, GL7), mature dendritic cells (MHC-II/CD208) and high endothelial venules (LYVE-1). Parkin TLS showed high Ig gene expression, recruitment of CXCR5⁺ follicular T helper cells and expansion of CD69⁺/KLRG1⁺ effector T cells. Conditioned medium from Parkin-positive cells expanded memory B and plasma cells, increased IgG1 production, and sustained B and T cell migration. Finally, conditional expression of Parkin induced TLS formation, upregulated Ig chains and inhibited prostate cancer growth, in vivo, whereas Parkin reconstitution in IFNAR1, CD8 or CD20 knockout mice had no effect. Therefore, mitochondrial immunity orchestrates antitumor responses, and TLS formation contributes to tumor suppression.

There is a growing number of research suggesting that there is an association between gut microbiota and central nervous system (CNS) tumor. However, the causal relationships and the mediation effects of inflammatory proteins in the associations are unclear. We extracted genetic variants associated with gut microbiota, inflammatory proteins, and 4 subtypes of CNS tumors from published genome-wide association studies and performed a Mendelian randomization analysis to identify potential causal effects. The inverse variance weighted method was used as the main method. Mediation analysis and single-cell RNA-seq analysis were performed to explore the mediation effects and the expression in cells. This study identified 73 gut microbial taxa and 11 inflammatory proteins that were significantly associated with CNS tumors. The inflammatory proteins may act as intermediate mediators in the potential causal association between gut microbiota and 4 CNS tumor subtypes. Mediation analysis suggested that CX3CL1 may partially mediate the relationship between gut microbiota and Glioblastoma, while Eotaxin, CSF-1, IL-15RA and the other 5 cytokines may serve as subtype-specific potential mediators for the remaining 3 tumor types. Our research supports a hypothesized "gut-immune-brain" axis that may mediate the effects of gut microbiota on different CNS tumor subtypes, with distinct immune proteins implicated for each. These findings strongly suggest potential targets for microbiome therapy and immune therapy, though the underlying mechanistic links require experimental validation.

Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs.

STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective.

The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress.

EU Clinical Trials Register: 2024-5 19 225-38-00.

The UK Severe Asthma Registry (UKSAR) was established to facilitate research and quality improvement including performance monitoring across UK severe asthma centres. We here describe its development and refinement for the latter of those objectives. The selection of performance outcome measures for severe asthma clinical outcomes from clinician and patient perspectives, data collection and assessment of clinical variation across severe asthma centres is described. We report on the aim of UKSAR to assess for unwarranted clinical variation in those clinical outcomes between severe asthma centres and discuss the utility of UKSAR and associated registry meetings in addressing clinical variation and providing optimal severe asthma care. After stakeholder consultation, outcomes measures relating to exacerbations, oral corticosteroid exposure, asthma control and quality of life were selected with appropriate case-mix adjustment to help identify unexplained clinical variation. The registry data fields were then modified to collect the required data. Twice-yearly meetings of the registry steering committee were held to discuss data quality. Over 2018-2025 the number of participating centres increased from 17 to 42. To date, baseline data have been entered for 18 473 patients, with data meeting the agreed quality threshold for 12 792 patients. Analysis of variation in outcomes between centres, after case-mix adjustment and allowing for effect of centre size, shows relatively few examples of significant variation in outcomes between centres. Best-practice case studies from high-performing centres are presented. Twice-yearly discussion at registry meetings, attended by representatives from each severe asthma centre, of outcome measures and related research, together with sharing of best practice may explain the relatively low variation in clinical outcomes between centres. However, a limitation of UKSAR is that it cannot evaluate the presence and clinical impact of 'hidden' severe asthma not known to specialist services.

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a globally burdensome chronic disease characterized by persistent respiratory symptoms and progressive airflow limitation, which severely impairs patients' quality of life and prognosis. Effective self-management is crucial for COPD management, as targeted self-management interventions have been shown to improve disease outcomes. Digital health technologies (DHTs) offer an innovative approach to address the challenges of traditional self-management and provide sustainable support for patients' long-term disease management. However, existing digital interventions for COPD commonly face several major challenges, including low user engagement, poor long-term adherence, and high participant withdrawal rates, highlighting an urgent need for optimized digital solutions.ObjectiveThis study aimed to develop a user-centered mobile application tailored to meet self-management needs of patients with COPD under the guidance of the Centre for eHealth and Wellbeing Research (CeHRes) Roadmap and persuasive system design (PSD) principles, as well as to evaluate its usability performance.MethodsThe development of the COPD Digital Health Self-Management System (COPD DHSS) was guided by the CeHRes Roadmap.The process commenced with a comprehensive literature review, semi-structured interviews involving fifteen COPD patients and five healthcare providers, and expert panel discussions (n=7) to identify challenges in COPD self-management and define the key values for the DHTs into self-management protocols. Based on these key values, the research team identified PSD features. These PSD features were integrated with COPD self-management evidence synthesis and were utilized to inform the design of the COPD DHSS prototype. A mixed-methods evaluation was employed: Sixteen COPD patients were recruited to test the COPD DHSS. After one month of system deployment, the System Usability Scale (SUS) was administered to evaluate usability metrics. Participants subsequently engaged in focus group discussions to provide feedback on user experience.ResultsA User-Centered Mobile Application for COPD was successfully developed through a structured process. The system integrated patient self-reported data with evidence-based best practices for COPD self-management, generating personalized recommendations to enhance patients' self-management capabilities and improve disease prognosis and quality of life. Usability testing was conducted with 16 COPD patients, whose average age was 71.5 (±6.9) years. Of these participants, 14 (87.5%) maintained twice-weekly app usage throughout the evaluation period. The median SUS score was 76.25(66.88, 83.13),indicating an acceptable level of usability. User feedback consistently indicated that the COPD DHSS demonstrated favorable usability characteristics.ConclusionsIntegrating the CeHRes Roadmap with PSD principles, this study successfully developed a usable, user-centered mobile application tailored to the self-management needs of older patients with COPD. It also demonstrates how a structured, theory-driven approach can translate patient and stakeholder insights into a practical digital tool that is both acceptable and usable for this target population. It can serve as a paradigm for applying mobile health technology in chronic disease self-management.