Citations

ABSTRACT Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid neoplasms shaped by genetic lesions and immune dysregulation, both of which contribute to disease progression and poor outcomes. Existing prognostic systems, such as IPSS‐R and IPSS‐M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi‐center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia‐free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS‐R, IPSS‐M, and bi‐allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time‐dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS‐high cases demonstrated reduced cytotoxic T‐cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS‐high cases to multikinase and NF‐κB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction. Trial Registration: #201709072RINC, #202109078RINB, #202207050RINB

ABSTRACT Background Chronic obstructive pulmonary disease (COPD) is associated with musculoskeletal comorbidities, including cachexia. Weight loss (WL) is the major criterion for cachexia and increases risk for mortality in COPD. Risk factors for WL in COPD are incompletely understood. We performed this whole genome sequencing (WGS) analysis to identify genetic risk variants for WL in COPD. Methods We studied 16 972 participants from the Trans‐Omics for Precision Medicine (TOPMed) Initiative and All of Us Research Program. COPD was diagnosed using spirometry in TOPMed, while diagnosis codes were used in All of Us. WL was defined as WL ≥ 5% or a final body mass index (BMI) < 20 kg/m 2 . WGS data came from white blood cells in all cohorts. Single‐variant testing was conducted on both race‐ and study‐stratified cohorts and in a cosmopolitan, ancestry‐independent manner using GENESIS in TOPMed and SAIGE in All of Us. SAIGE‐GENE+ gene‐based analyses were performed on race‐stratified and cosmopolitan cohorts. Single variant meta‐analyses were conducted using METAL within (B/AA and NHW analyses of Black/African–American and non‐Hispanic white participants, respectively) and across racial groups (COSMO). Rare variant gene‐based results were combined using Fisher's method. Transcriptomic effects were predicted using MetaXcan. We used the GWAS Catalogue to analyse for colocalization with other related traits. Results Two single variants were associated with WL in COPD among All of Us participants: one intronic variant in HCN1 in Black/African–American participants (chr5:45271359:TACACAC:T, odds ratio with 95% confidence interval (OR (CI 95 )) = 2.43(1.78–3.31), p = 1.95 × 10 −8 ) and one intergenic variant between PPP4R2 and PDZRN3 in the cosmopolitan and NHW cohorts (chr3:73345901:A:G, OR (CI 95 ) = 0.21(0.12–0.35), p = 8.84 × 10 −9 in cosmopolitan and OR (CI 95 ) = 0.18(0.10–0.33), p = 9.44 × 10 −9 in NHW). Single‐variant meta‐analysis identified two loci associated with WL in COPD: five variants within DRAIC in the B/AA meta‐analysis (lead variant chr15:69571341:A:G, OR (CI 95 ) = 1.37(1.23–1.51), p = 1.29 × 10 −9 ) and two intronic variants within RFX3 in the cosmopolitan meta‐analysis (lead variant chr9:3390983:T:C, OR (CI 95 ) = 1.50(1.31–1.73), p = 1.06 × 10 −8 ). Rare variants within RNU6‐565P (NHW analysis in All of Us; p = 2.83 × 10 −7 ) and LOC339298 (B/AA analysis in All of Us, p = 1.85 × 10 −6 ) were associated with WL in COPD. The RNU‐565P signal remained significant after combination with TOPMed results (p combined = 1.23 × 10 −6 ). MetaXcan predicted differential expression of LNC00959 in visceral adipose tissue ( p = 1.16 × 10 −6 in COSMO analysis). Colocalization analyses identified genomic associations between BMI and variants in or near DRAIC , RFX3 , PDZRN3 , and LINC00959 . Conclusions In the first WGS analysis of WL in COPD, we have identified seven novel loci. Further characterization of these loci will validate our findings and improve our understanding of the molecular pathophysiology of this condition.

Abstract Plekha7 associates with p120 catenin and localizes at apical cell-cell junctions where it has been implicated in junction stabilization. However, it’s in vivo function and underlying mechanisms of action remain unclear. Here, we show that constitutive Plekha7 loss in mice disrupts retinal organization, reduces retinal thickness, and induces RPE multinucleation, microglia infiltration, and photoreceptor loss. Plekha7 deficiency reduces the accumulation of cadherin–catenin complexes at apical junctions without altering overall cadherin levels, indicating a defect in junctional maintenance. Mechanistically, PLEKHA7 regulates cadherin trafficking by limiting levels of endocytosed E-cadherin, thereby maintaining junctional cadherin pools. Notably, these effects are largely independent of p120 catenin. In addition, further Plekha7 roles in the regulation of centrosome, cilia, microtubule dynamics, and cytokinesis, likely contribute to the phenotypic changes induced by Plekha7 knockout. These findings establish Plekha7 as a key regulator of cadherin trafficking and epithelial organization with relevance to retinal disease.

Objective To evaluate cancer risk in individuals with cleft lip and/or cleft palate (CL/P). Design Retrospective chart review of patients with CL/P, including abstraction of information on cancer diagnoses was conducted. Cancer risk was compared with national population-based estimates using standardized incidence ratios (SIRs) and exact binomial tests. Subgroup analyses compared demographic and clinical characteristics between patients with and without cancer. Setting Study was performed at a single tertiary academic center with multidisciplinary surgical, pediatric, and genetic care. Patients/Participants Total of 2121 patients with CL/P from 1970 to 2024 with complete medical documentation were included. Main Outcome Measures Main outcomes included prevalence of cancer diagnoses, childhood cancer incidence, and differences in cancer occurrence by age, cleft type, syndromic status, and family history. Results Total of 144 patients (6.8%) had pathologically confirmed cancer diagnoses. Twelve childhood cancers were identified, with 10 cases presenting before age 15. Children younger than 15 with CL/P had a significantly elevated cancer risk (SIR 4.7; 95% confidence interval: 1.8-7.6; P < .00001). Pediatric cancers occurred mainly in syndromic cases. Cancer prevalence was higher in cleft palate only and cleft lip/palate cases compared with cleft lip only ( P < .05). Cancer occurrence was not higher in adults with CL/P compared to the general population. Conclusions Cancer risk is not uniformly elevated over the lifespan in individuals with CL/P. Increased cancer risk is observed in our pediatric cohort. Clinical care should include careful assessment of childhood cancers, syndromic features, and family history, with consideration for genetic counseling and multidisciplinary follow-up.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Abstract Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and alveolar macrophage pneumonia (AMP) are two rare but closely related conditions within the spectrum of smoking-related interstitial pneumonias. Both share characteristic histopathologic features, including the accumulation of pigmented alveolar macrophages alongside varying degrees of interstitial inflammation and fibrosis. RB-ILD is typically a localized, bronchiolocentric process often found in smokers, whereas AMP represents a more diffuse and clinically significant disease that may arise not only from tobacco smoke but also from other causes such as occupational exposures, autoimmune diseases, and drug reactions. This review highlights the clinical presentation, imaging findings, histopathology, and treatment of both entities, emphasizing their overlapping features as well as key distinctions. We further discuss the pathogenic mechanisms driven by cigarette smoke—including oxidative stress, immune activation, and fibrosis—that underlie these diseases. A clear understanding of the similarities and differences between RB-ILD and AMP is essential for accurate diagnosis, effective management, and prognostication, particularly in patients with a history of smoking and diffuse parenchymal lung involvement.

Abstract Background Photon‐counting‐detector (PCD) CT systems offer ultra‐high spatial resolution, yet the visual spatial resolution on clinical images often constrained by large pixel size, yielding resolutions below system capabilities. While reducing pixel size and using sharp kernels enhance visual spatial resolution, it increases noise, compromising image quality. Purpose To investigate the combined effects of pixel size and reconstruction kernels on visual spatial resolution using phantom and clinical images and to develop a dedicated high‐resolution deep convolutional neural network (HR‐CNN) to better utilize the intrinsic high spatial resolution of PCD‐CT in clinical imaging. Methods The relationship between spatial resolution, reconstruction kernel, and pixel size was investigated to identify strategies for utilizing the full spatial resolution potential of PCD‐CT. To overcome the increased noise associated with high‐resolution settings, a dedicated HR‐CNN was developed to push the limit of spatial resolution in routine PCD‐CT exams. The HR‐CNN was trained using patient exams acquired with ultra‐high‐resolution (UHR) mode and reconstructed with a 150‐mm field of view (FOV), matrix size of 1024×1024 (0.15‐mm pixel size) and sharpest quantitative kernel (Qr89). The impact of FOV, kernel, and denoising on spatial resolution was studied using bar‐pattern phantoms and a pilot clinical evaluation including 5 patients with interstitial lung diseases. Two thoracic radiologists evaluated 4 different FOV/reconstruction conditions: (1) FOV‐410/Qr56‐Iterative reconstruction (IR), (2) FOV‐410/Qr89‐IR, (3) FOV‐150/Qr89‐IR, and (4) FOV‐150/Qr89‐HR‐CNN in terms of overall image quality, noise, visual spatial resolution, and overall preference. Results With a FOV of 410 mm, the Qr89 sharp kernel displayed bar‐patterns up to 14 lp/cm, not much higher than the routine lung kernel Qr56. When the FOV was reduced to 150 mm, Qr89‐IR allowed for the visualization of line pair patterns ranging from 18 to 20 lp/cm, with 20 lp/cm being moderately discernible. The application of Qr89‐HR‐CNN yielded further improvement, enabling the display of line pair patterns as high as 20–22 lp/cm. In patient cases, both radiologists consistently ranked the FOV‐150 images processed with HR‐CNN as superior across metrics including overall image quality, noise reduction, visual spatial resolution, and overall preference. The HR‐CNN reduced the noise in patients’ images by 93.0 ± 0.6% and 44.9 ± 5.3% in comparison with the original FBP and IR images, respectively. Conclusions The spatial resolution of PCD‐CT is not maximized in routine practice due to the large FOV and high noise levels at sharp kernels. The proposed HR‐CNN denoising method, along with small pixel size, may allow the high spatial resolution toward the system limit to be implemented in practice, which is beneficial in the diagnosis of many diseases, including interstitial lung disease.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

Abstract In many cancers, a major barrier to effective immunotherapy is the dominance of tumor-associated myeloid cells (TAMs), which establish a profoundly immunosuppressive tumor microenvironment (TME). This challenge is particularly pronounced in glioblastoma (GBM), where myeloid cells represent the predominant immune population and actively suppress antitumor immunity. Identifying targets that can reprogram TAMs from an immunosuppressive state toward a pro-inflammatory, antigen-presenting phenotype remains a critical unmet need. Here, we identify the voltage-gated proton channel Hv1 as an immune-restricted regulator of glioma-associated macrophage function. Hv1 is notable not only for its immune-specific expression but also for its established roles in central nervous system (CNS) pathologies, where Hv1 depletion alters microglial and macrophage polarization, reduces myeloid accumulation, dampens inflammatory cytokine production, and limits secondary tissue damage. However, Hv1’s role in shaping the GBM immune landscape—particularly in vivo—has remained poorly understood due to low Hvcn1 transcript abundance and the lack of reliable antibodies and genetic tools. Given the dominance of myeloid cells in GBM and their central role in tumor immune regulation, we sought to define Hv1 function within this highly immunosuppressive brain TME. Analysis of patient datasets revealed that elevated Hv1 expression correlates with poor clinical prognosis. Consistently, Hv1 loss significantly prolonged survival in multiple murine glioma models. Using in vivo two-photon imaging and spectral flow cytometry, we show that Hv1 depletion reprograms TAMs toward an anti-tumor phenotype characterized by enhanced tumor cell phagocytosis, improved antigen presentation, and increased T cell infiltration. By generating new Hv1 reporter and conditional mouse lines, we further demonstrate that tumor-associated microglia and infiltrating macrophages are the principal sources of Hv1 and markedly upregulate its expression in response to glioma. Notably, selective deletion of Hv1 in infiltrating macrophages phenocopied the survival benefit observed with global Hv1 loss. Mechanistically, using mass spectrometry and genetic models, we identify the Stimulator of Interferon Genes (STING) as a previously unrecognized binding partner of Hv1, placing Hv1 within the STING signaling pathway, a central regulator of innate and adaptive immune responses. Together, these findings fill a critical gap in understanding myeloid Hv1 function in GBM and identify Hv1 as a promising target for reprogramming the tumor immune microenvironment. Citation Format: Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Katayoun Ayasoufi, Meijie Wang, Praveen N. Pallegar, Peter R. Strege, Langni Liu, Yushan Wan, Wenjing Zhang, Emma N. Goddery, Manling Xie, Arthur Beyder, Aaron J. Johnson, Long-Jun Wu. Myeloid Hv1-STING axis tunes glioma immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A016.

Abstract Background: Hemorrhagic necrotizing pancreatitis (HNP) is a highly lethal form of pancreatitis that lacks mechanism-based therapy. Intra-acinar enzyme activation is fundamental to pancreatitis initiation, yet it does not explain why only a subset of episodes progress to catastrophic hemorrhagic necrosis. Objective: To identify determinants of progression to lethal HNP and test a mechanism-based preventive intervention. Design: Using humanized trypsinogen mouse models and secretagogue regimens, we compared high-dose cerulein with low/moderate-dose cerulein and bombesin. We quantified pancreatic protease activity, performed blinded histopathologic scoring, assessed hemorrhage/vascular disruption, and evaluated enzyme localization and ductal injury by PRSS1 immunostaining. De-identified human pancreatic histology from HNP were examined. We tested a repurposed strategy using clinically approved agents for other indications: secretin to stimulate ductal fluid secretion and isosorbide mononitrate (ISMN) to promote ductal outflow via sphincter of Oddi relaxation. Results: High-dose cerulein induced robust intrapancreatic protease activation but predominantly caused edematous pancreatitis. Paradoxically, bombesin and low/moderate-dose cerulein elicited lower total pancreatic protease activity yet produced severe, frequently lethal HNP with vascular disruption and lobular ischemic necrosis. HNP was associated with intraductal enzyme accumulation and ductal injury. Secretin or ISMN alone showed limited protection, whereas combined secretin+ISMN prevented hemorrhagic necrotizing injury. Conclusion: Pancreatitis severity is determined not only by the magnitude of enzyme activation but also by where enzyme activity is exerted, implicating intraductal enzyme accumulation as a mechanistic determinant and therapeutic target in HNP. Coordinated enhancement of ductal secretion and outflow with clinically approved agents prevents HNP in vivo, supporting a translatable prevention strategy.