Citations

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

Abstract Introduction Multiple pulmonary nodules (MPNs) are commonly encountered in patients at elevated risk for thoracic malignancy and represent a spectrum of disease states and stages. We evaluated the safety, and procedural outcomes of a combined robotic assisted bronchoscopy (RaB) and linear endobronchial ultrasound (EBUS) approach to patients with MPNs during a single bronchoscopic procedure. Methods This multicenter observational registry included patients who underwent RaB for evaluation of MPNs. Data were prospectively collected from six centers between 2019 and 2025. Demographics, imaging characteristics, safety events, and procedural outcomes were analyzed and associated with final diagnosis. Results A total of 191 patients underwent RaB with biopsy of MPN during a single procedure; 167 patients also underwent linear EBUS lymph node sampling. The strict per nodule diagnostic yield was 71.5% overall (first nodule 70.7%, second 74.3%, third 71.4%). At least one malignant nodule was identified in 127 patients (66.8%), and 85 patients (44.5%) had two or more malignant nodules; 15 patients (17.6%) demonstrated heterogeneous histopathology between malignant nodules. Among patients with non–small cell lung cancer, adequate cellularity for next generation sequencing was achieved in 82.6% of nodules. Malignant lymph nodes were identified in 10.8% (18/167). No patients with two pure ground glass nodules (0/8) had malignant nodal involvement. Pneumothorax occurred in 7.3% of cases, with 2.1% requiring chest tube placement; unplanned admissions occurred in 3.7%. Conclusion This study provides a large multisite registry evaluation of performance of simultaneous bronchoscopic sampling of multiple pulmonary nodules with EBUS staging during a single anesthesia event demonstrating an acceptable safety profile and adequacy for molecular profiling.

ABSTRACT Background Most genomic studies of adult-type diffuse gliomas have focused on predominantly European ancestry populations, limiting the generalizability of molecular classifications and precision medicine approaches. We assembled a multi-institutional glioma cohort of diverse patients to investigate how germline ancestry, molecular subtypes, and mutational processes shape tumor biology and clinical outcomes. Methods We analyzed 1,102 adults with WHO 2021–classified diffuse gliomas (IDH-mutant, 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype glioma) from seven U.S. institutions. Whole-exome sequencing (WES) of FFPE tumors identified somatic alterations and COSMIC SBS v3.2 mutational signatures. Genetic ancestry was estimated from WES using 1000 Genomes reference populations. Overall survival was assessed using Kaplan–Meier and multivariable models. Results The cohort included 66.9% European (EUR), 21.1% Admixed American/Hispanic (AMR), 10.3% Admixed African (AFR), and 1.6% Asian (AS) ancestry. Survival followed expected molecular hierarchy (median overall survival: oligodendroglioma 15.7 years, astrocytoma 10.6 years, IDH-wildtype glioma 1.9 years). Within oligodendroglioma, AMR patients showed improved survival versus EUR (HR 0.67, 95% CI 0.48–0.94; p=0.011), with similar trends across subtypes. Somatic profiling confirmed canonical subtype-defining alterations and revealed higher ATRX alterations in AFR and AMR IDH-wildtype tumors compared with EUR. ATRX alterations were associated with improved survival only in AFR (p=0.003). Mutational signature analysis identified subtype-specific signatures, including therapy-associated signatures. Chemotherapy-related signatures were more frequent in EUR and AMR than in AFR. Conclusions This ancestrally diverse glioma cohort confirms established molecular classifications and identifies ancestry-associated differences in survival, somatic alterations, and mutational processes, indicating the critical need for broad representation to inform precision neuro-oncology. Key Points A multi-institutional glioma cohort validates subtype and survival patterns across ancestries. Therapy-associated mutational signatures differ by ancestry, suggesting distinct treatment-related mutational processes. Admixed American patients show improved survival, particularly in oligodendroglioma. Importance of the Study Most genomic studies of adult-type diffuse glioma have focused on populations of predominantly European ancestry which limits the ability to examine variation in tumor biology and clinical outcomes across populations. In this study, we assembled one of the largest ancestrally diverse cohorts of molecularly characterized adult diffuse gliomas, integrating germline ancestry inference with tumor whole-exome sequencing and mutational signature analysis. We confirm that established molecular classifications and survival hierarchies remain robust across ancestry groups. However, we also identified ancestry-associated differences in survival within specific tumor subtypes, higher ATRX alteration frequencies in African American and admixed American patients with IDH-wildtype tumors, and variation in therapy-associated mutational signatures across ancestry groups. These findings highlight the importance of incorporating population differences into genomic studies of glioma and provide a resource for future multi-ancestry investigations of glioma risk, tumor evolution, and treatment response, ultimately supporting more inclusive precision neuro-oncology.

Abstract Background and Objectives Cholangiocarcinoma (CCA) is an aggressive, highly lethal cancer of the biliary tract epithelium for which tumor resection is the only curative treatment. However, approximately half of patients present with nonresectable disease and median survival of these patients is just 8-12 months. A significant need exists for tumor-targeted therapeutics for patients with advanced disease who currently have limited treatment options. We aimed to address this need by developing an aptamer-targeted therapy for delivery of siRNAs inhibiting undruggable components of the Hippo pathway, a key driver of cholangiocarcinoma. Method We applied cell-SELEX against human CCA model cell line HuCCTl with negative selection against normal hepatocytes and cholangiocytes to identify an aptamer that selectively bound tumor cells. This aptamer, termed MC7122, was chemically modified to include fluorescent labels that enabled whole-animal biodistribution studies to assess in vivo selectivity. MC7122 was then deployed onto the surface of siRNA-loaded nanovesicles to drive tumor-targeted nucleic acid delivery. Tumor-bearing mice were treated with siRNAs three times per week for two weeks alone or in combination with standard of care chemotherapy. Results Combined treatment with siRNAs and standard of care chemotherapy reduced tumor burden in mice versus vehicle controls and slowed the spread of metastasis. Importantly, we found tumor-specific target gene knockdown without corresponding off-target knockdown in healthy surrounding liver tissue. Further, we demonstrated that sites in the lung, the primary location of metastasis in this model, were reduced not because of global target knockdown in lung but due to tumor-specific knockdown at the site of liver implantation. Conclusions Aptamer-guided vesicles represent a promising platform for targeted therapy delivery for previously undruggable targets. With this platform, tumor-selective therapies can be designed to exhibit exceptionally potent cytotoxicity, as healthy tissues remain unaffected by off-target effects. Future work will focus on refinement of therapeutic siRNA target selection and modification of nanovesicle components for enhanced levels of tumor specificity.

Abstract Background Cholangiocarcinoma (CCA) is a deadly cancer of the hepatic bile duct epithelial cells. Loss-of-function mutations of epigenetic regulator ubiquitin C-terminal hydrolase deubiquitinase BRCA1associated protein 1 (BAP1) occur in 26-32% of human CCA and are associated with worse prognosis and resistance to cytotoxic therapy. The goal of this study is to identify how BAP1 loss promotes cell death evasion through metabolic rewiring. Materials and methods Isogenic wild-type and BAP1-deficient human and murine CCA cell lines were generated with shRNA/siRNA or CRISPR/Cas9 and were used to assess ferroptosis sensitivity by treatment with ferroptosis inducers. In vitro, ferroptosis was assessed by phospholipid peroxidation (C-11BODIPY), mitochondrial phospholipid peroxidation (MitoPeDPP, MitoCLox), iron overload (MitoFerro green) and cell death (CellTiter-Glo). Phospholipidomics and proteomics were performed in isogenic cells by LC-MS/MS. Syngeneic liver orthotopic CCA murine models and patient-derived xenografts (PDX) were used for in vivo pre-clinical studies. Results Our findings indicate that BAP1 loss confers CCA ferroptosis resistance. BAP1 loss protects CCA against mitochondrial iron overload, ROS accumulation, and phospholipid peroxidation. BAP1 loss protects from mitochondrial phospholipid peroxidation and cardiolipin oxidation. Unbiased phospholipidomic profiling revealed that BAP1 loss remodels membrane phospholipid composition, enriching for ferroptosis blocking monounsaturated phospholipids (MUFA-PLs) at the expense of ferroptosis-inducing polyunsaturated (PUFA-PLs). We found that BAP1 loss upregulates TLCD1, a phosphatidylethanolamine acyltransferase that incorporates MUFAs into membrane phospholipids, thereby stabilizing membranes against peroxidation. TLCD1 knockdown in ferroptosis-resistant BAP1-deficient CCA cells, restored ferroptosis sensitivity. Notably, TLCD1 is significantly upregulated in human BAP1-mutant CCA as compared to BAP1-expressing tumors. While not a mitochondrial protein, TLCD1 localizes in the ER and by the mitochondrial outer membrane, as demonstrated by our immunofluorescence analysis in human CCA cells. From a therapeutic perspective, we developed EpCAM (adhesion molecule highly expressed in CCA cells)-aptamer coated lactosomes packaged with siRNA against glutathione peroxidase 4 (GPX4), as a proof-of-concept strategy to safely induce ferroptosis selectively in CCA in vitro and in vivo. Administration of siGPX4-lactosomes in pre-clinical syngeneic liver orthotopic CCA murine models demonstrated a favorable safety profile, achieved robust intratumoral GPX4 knockdown (>50%), exhibited optimal biodistribution, induced significant tumor lipid peroxidation, and resulted in reduced tumor burden. Lastly, ferroptosis inducer JKE-1674, combined with gemcitabine/cisplatin (Gem/Cis) significantly blocked tumor growth of Gem/Cis-resistant patient-derived xenografts. Conclusions Our findings reveal that BAP1 loss reprograms mitochondrial phospholipid metabolism thus conferring CCA resistance to ferroptosis, identifying TLCD1 as a targetable metabolic vulnerability in BAP1-mutant CCA. Additionally, our findings support ferroptosis inducing compounds as promising therapeutic approaches for CCA.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Introduction: There is growing focus on community-engaged research (CEnR) in the clinical and translational sciences, supportive policies, environments, and processes within academic medical centers. The purpose of this evaluation was to gather academic and community member perspectives on key actionable strategies for supporting CEnR in an academic medical center. Materials and Methods: We used a sequential mixed method design by first conducting qualitative in-depth interviews with academic leaders, investigators, and staff (total, n = 54) and focus group discussions with community members ( n = 33). Themes from these qualitative data informed the adaptation of an institutional survey that gathered perspectives from a broader group of academic and community members affiliated with the institution ( n = 85). Both qualitative and quantitative data were integrated to inform actionable strategies. Results: Survey findings revealed that the institution was perceived as committed to health equity and CEnR, but institutional respondents expressed more concerns than community members about instrumental support of the work. Interviews and focus groups highlighted the opportunity to better align research efforts with community needs through more robust CEnR infrastructure and through interface with the clinical practice to promote patient access. Academic and community members emphasized the need for authentic, sustained engagement beyond federal mandates, including financial investment, capacity-building, and fostering trust. Leaders acknowledged structural challenges, siloed efforts, and the necessity for stronger coordination to increase integration of community engagement into the institutional mission. Conclusion: Findings suggest that aligning academic leaders, researchers, staff perspectives, and community members is essential to support and promote CEnR at an institutional level.

The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of advanced spinal cord imaging techniques. Finally, we discuss spinal cord–specific processing pipelines and reproducibility challenges. Collectively, these insights underscore the need to integrate advanced and quantitative spinal cord imaging into clinical trials, research studies, and—when feasible—clinical care, to fully capture the extent of MS pathology, and ultimately improve patient outcomes.