tbuckley/cabot-search huggingface dataset:
Targeting MXD1 sensitises pancreatic cancer to trametinib
Authors: Shaoping Zhang, Shuang Deng, Ji Liu, Shuang Liu, Ziming Chen, Shaoqiu Liu, Chunling Xue, Lingxing Zeng, Hongzhe Zhao, Zilan Xu, Sihan Zhao, Yifan Zhou, Xinyi Peng, Xiaoyu Wu, Ruihong Bai, Shaojia Wu, Mei Li, Jian Zheng, Dongxin Lin, Jialiang Zhang, Xudong Huang
Journal: Gut (2025)

Background The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear. Objective We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC. Design We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism. Results We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib. Conclusions Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC.
Psychological distress in adolescence and later economic and health outcomes in the United States population: A retrospective and modeling study
Authors: Nathaniel Z. Counts, Noemi Kreif, Timothy B. Creedon, David E. Bloom
Journal: PLoS Medicine (2025)

Federal policy impact analyses in the United States do not incorporate the potential economic benefits of adolescent mental health policies. Understanding the extent to which economic benefits may offset policy costs would support more effective policymaking. This study estimates the relationship between adolescent psychological distress and later health and economic outcomes and uses these estimates to determine the potential economic effects of a hypothetical policy. This analysis estimated the relationship between psychological distress in those aged 15 to 17 years in 2000 and economic and health outcomes approximately 10 years later, accounting for an array of explanatory variables using machine learning-enabled methods. The cohort was from the National Longitudinal Study of Youth 1997 and nationally representative of those aged 12 to 18 years in 1997. The cohort included 3,343 individuals under age 18 years in round 4 who completed the Mental Health Inventory-5 (MHI-5). Round 1 captured 50 explanatory variables that covered domains of potential confounders, including basic demographics, neighborhood environment, family resources, family processes, physical health, school quality, and academic skills. The exposure included a binary variable of clinically significant psychological distress (MHI-5 score of less than or equal to 3) and a categorical variable of symptom severity on the MHI-5. Outcomes covered domains of employment, income, total assets at age 30 years, education, and health approximately 10 years later. Forty-seven percent of the cohort were black and Hispanic, and 4.4% had past-month clinically significant psychological distress. Past-month clinically significant psychological distress in adolescence led to a 6-percentage-point (95% confidence interval [CI] [-0.08, -0.03]) reduction in past-year labor force participation 10 years later and $5,658 (95% CI [-6,772, -4,545]) USD fewer past-year wages earned. We used these results to model the labor market impacts of a hypothetical policy that expanded access to mental health preventive care and reached 10% of youth who would have otherwise developed clinically significant psychological distress. We found that the hypothetical policy could lead to $52 (95% credible interval [51,54]) billion USD in federal budget benefits over 10 years from labor supply impacts alone. This study faced limitations, including potential unmeasured confounding, missing data, and challenges to generalizability. Our findings showed the impacts of adolescent mental health policies on the federal budget and found potentially large effects on the economy if policies achieve population-level change.
Development and Validation of a Clinical, CT, Genomic Classifier and BAL Scoring System for Diagnosing IPF
Authors: Michell Li Wei Kam, Elysia LH Tjong, Sachin Chaudhary, Tilman L. Koelsch, Joseph B. Pryor, Matthew Koslow, Michael P. Mohning, Joshua J. Solomon, Tristan J. Huie, Jeffrey J. Swigris, Evans R. Fernández Pérez
Journal: European Respiratory Journal (2025)

The utility of incorporating a usual interstitial pneumonia (UIP) genomic classifier (GC) and bronchoalveolar lavage (BAL) cell count analysis alongside traditional clinical-imaging assessment in aiding in the multidisciplinary diagnosis of IPF in patients with a non-definite HRCT UIP pattern is uncertain.We reviewed consecutive adult patients presenting with fibrotic interstitial lung disease (fILD) and non-definite HRCT UIP pattern who underwent BAL and GC. The initial fILD diagnoses were re-evaluated after bronchoscopy and a final multidisciplinary consensus diagnosis was provided. We created a clinical score by analyzing fILD clinical characteristics, GC, and BAL results from 139 National Jewish Health (NJH) patients and validated it at the University of Arizona, n=52. A multivariable model was developed and assessed using receiver operating characteristic curves.43/139 (31%) and 29/52 (56%) of patients in the derivation and validation cohort, respectively, were diagnosed with IPF after bronchoscopy, and 85/139 (61%) and 32/52 (61%) had a change in treatment, respectively. Compared to non-IPF, IPF patients had a similar progression-free survival (HR, 1.50; 95%CI, 0.76, 2.95). The final model, assigned a score to eight predictors: age, sex, HRCT probable UIP pattern, exposures, connective tissue disease signs/symptoms, Velcro crackles, CG results, and BAL lymphocyte and monocyte count. The final score demonstrated an AUC of 0.90 (95% CI 0.85 to 0.95) in the derivation cohort and 0.91 (95% CI 0.83 to 0.99) in the validation cohort.The clinical-HRCT-BAL-GC IPF score may accurately estimate the post-test probability of IPF in patients with a non-definite HRCT UIP pattern.
Nasal CPAP increases alveolar number in a rhesus monkey model of moderate prematurity
Authors: Cindy T. McEvoy, Kelvin D. MacDonald, Lyndsey E. Shorey-Kendrick, Michael H. Davies, Kelli C. Lund, Ryan Lam, Brandy L. Dozier, Lauren Drew Martin, Fiona Corcoran, Robert L. Schelonka, Robert S. Tepper, Eliot R. Spindel
Journal: European Respiratory Journal (2025)

Most premature human infants are born in the moderate to late preterm (MLP) range, ≥30 to <37 weeks gestation and demonstrate increased incidence of wheeze and respiratory illness as they age. Animal models suggest that mechanical lung distention stimulates lung growth and alveolar development. To determine if nasal continuous positive airway pressure (nCPAP) influences MLP infant lung development, we developed a rhesus monkey model of moderate prematurity, randomized to 9 days of nCPAP or sham nCPAP. Timed-pregnant fetuses were delivered by elective hysterotomy at gestational age (GA) 140±1 days (85% gestation, term=165 days; human equivalent of 32-34 weeks), or at GA-149±1 days (GA-control) as a relative gestational age reference. The day after delivery, the GA-140 animals were treated with nCPAP or sham for 9 days, 12 consecutive hours each day. Pulmonary function testing followed by necropsy for analysis of lung structure and gene expression was performed on the equivalent of GA-150 for all animals. The nCPAP and sham groups were clinically similar but distinct from the gestational control group. Stereological analysis of lung structure showed significantly increased numbers of alveoli in the nCPAP group compared to the sham group. Other functional and anatomic changes were consistent with increased alveolarization. Gene expression between the nCPAP and sham groups remained highly similar and distinct from GA-control animals. We show that nCPAP in MLP infants stimulates alveolarization with relatively few other changes. How this may benefit subsequent infant respiratory health requires further study.
Multi-Omics Assessment of Puff Volume-Mediated Salivary Biomarkers of Metal Exposure and Oxidative Injury Associated with Electronic Nicotine Delivery Systems
Authors: Xiaojia He, Maureen Meister, Jennifer Jeon, Akshada Shinde, Qian Zhang, Patrick Chepaitis, Marilyn Black, Jonathan Shannahan, Christa Wright
Journal: Environmental Health Perspectives (2025)

Since their inception, electronic nicotine delivery systems (ENDS) have gained increasing popularity, sparking a vaping epidemic among adolescents in the US and globally. Several ENDS safety concerns have emerged as device features and formats that contribute to heavy metal exposure and toxicity continue to evolve and outpace regulatory efforts. Our objective was to integrate ENDS emission profiles with salivary proteome and metabolome data to characterize exposure factors that may influence adverse vaping-mediated health outcomes. A total of 56 participants (38 exclusive ENDS users and 18 non-ENDS users) were recruited. A subset of 15 exclusive ENDS users completed puffing topography assessments to obtain individual vaping behavior patterns using each participant's ENDS device. Inductively coupled plasma mass spectrometry was used to determine the metal content of emissions (12 ENDS devices) generated using a programmable ENDS aerosol generation system and saliva (15 exclusive ENDS users and 5 non-ENDS users). Saliva samples from 10 exclusive ENDS users and 5 non-ENDS users were analyzed for proteomic, metabolomic, inflammatory, and oxidative stress/damage biomarkers. A linear puff volume-dependent increase in particle emissions and heavy metals was observed in ENDS aerosols and saliva of exclusive ENDS users. Elevated puff volume-dependent levels of salivary cytokines, including tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), and IL-6, were observed alongside the oxidative damage indicators malondialdehyde (MDA), superoxide dismutase (SOD), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Proteome-metabolome network analysis showed a higher risk of potentially developing neurological and respiratory diseases in ENDS users compared with non-ENDS users. Integrated salivary proteome-metabolome-metallome network analysis further demonstrated that heavy metals were associated with proteomic and metabolomic perturbations, with notable alterations in inflammatory response, immune function, and disease-related pathways. A significant correlation between heavy metals, cytokines, and oxidative stress markers reveals a potential role of vaping behavior in exposure to metals and changes in markers associated with DNA damage and inflammation. Our study demonstrates the importance of characterizing vaping behavior and puffing topography when examining the human health implications of ENDS use. https://doi.org/10.1289/EHP14321.
Nerve‐Derived Extracellular Matrix Promotes Neural Differentiation of Bone Marrow Stromal Cells and Enhances Interleukin‐4 Efficacy for Advanced Nerve Regeneration
Authors: Huachen Yu, Pei Fan, Xinyue Deng, Miaolin Zeng, Liyun Ge, Enxing Xue, Daqing Chen, Man Zhang
Journal: Advanced Healthcare Materials (2025)

Facilitating neuronal differentiation of stem cells and microenvironment remodeling are the key challenges in cell-based transplantation strategies for central nervous system regeneration. Herein, the study harnesses the intrinsic pro-neural differentiation potential of nerve-derived extracellular matrix (NDEM) and its specific affinity for cytokines to develop an NDEM-gelatin methacryloyl(gelMA)-based bifunctional hydrogel delivery system for stem cells and cytokines. This system promotes the neural differentiation of bone marrow stromal cells (BMSCs) and optimizes the therapeutic index of Interleukin-4 (IL-4) for spinal cord injury (SCI) treatment. It is observed that incorporating NDEM into the hydrogel system intrinsically promotes BMSC differentiation into neuron-like cells and effectively regulates IL-4 release kinetics to match the neural reconstructing timeframe. Further analysis reveals that trace amounts of endogenous basic fibroblast growth factor (bFGF) detected in NDEM exhibit a potent effect in promoting neural differentiation. The sustained release of IL-4 from the NDEM significantly encourages macrophage polarization toward the M2 phase, optimizing the transplant microenvironment throughout the reconstruction process. This study demonstrates an NDEM-based optimization strategy for hybrid hydrogel to achieve synchronized delivery of stem cells and cytokines in regenerative medicine applications.
PSMA+ Extracellular Vesicles are a Biomarker for SABR in Oligorecurrent Prostate Cancer Analysis from the STOMP-like and ORIOLE trial cohorts
Authors: Jack Andrews, Yohan Kim, Edlira Horjeti, Ali Arafa, Heather Gunn, Aurélie De Bruycker, Ryan Phillips, Daniel Song, Daniel S. Childs, Oliver A. Sartor, Jacob J. Orme, Aadel A. Chaudhuri, Phuoc Tran, Ana Kiess, Philip Sutera, Carole Mercier, Piet Ost, Sean S. Park, Fabrice Lucien-Matteoni
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Two randomized clinical trials (STOMP and ORIOLE) demonstrated that stereotactic ablative radiotherapy (SABR) can prolong ADT-free survival or progression-free survival (PFS) in patients with metachronous oligometastatic prostate cancer (omCSPC) patients. While most omCSPC patients have a more modest delay in progression, a small subset achieves a durable response following SABR. We investigated the prognostic and predictive value of circulating PSMA-positive extracellular vesicles (PSMA+EV) and prostate specific antigen (PSA) in a biomarker correlative study using blood samples from three independent patient cohorts. Methods: Plasma samples from 46 patients on the ORIOLE trial and 127 patients on the STOMP trial protocol with omCSPC patients treated with SABR. Pre-SABR PSMA+EV levels (EVs/ml) were measured by nanoscale flow cytometry. Kaplan-Meier curves and logistic regression models were used to determine the association of PSMA+EV and PSA levels with clinical outcomes. Results: In the pooled cohorts, median bPFS were 26.1 and 15.0 months (p=0.005) and median rPFS were 36.0 and 25.0 months (p=0.003) for PSMA+EV low and high groups, respectively. The combination of pre-SABR low levels of both PSMA+EV and PSA was associated with lower risk of radiographic progression (HR=0.34, 95% CI: 0.18-0.58, p=0.0002). In the ORIOLE cohort, which included both a SABR arm and an observation arm, low PSMA+EV was predictive of benefit from SABR (p=0.012). Conclusions: PSMA+EV is a novel prognostic and predictive biomarker of radiographically occult tumor burden in omCSPC. PSMA+EV may inform clinical decisions regarding which patients achieve a durable benefit from consolidative SABR alone
Distinct molecular and clinical features of specific variants of KRAS codon 12 in pancreatic adenocarcinoma
Authors: Bach Ardalan, Aaron Ciner, Yasmine Baca, Andrew Hinton, Sourat Darabi, Anup Kasi, Emil Lou, Jose Ignacio. Azqueta, Joanne Xiu, Jashodeep Datta, Anthony F. Shields, Andrew Aguirre, Harshabad Singh, Rachna T. Shroff, Michael J. Pishvaian, Sanjay Goel
Journal: Clinical Cancer Research (2025)

Abstract PURPOSE Oncogenic mutations in KRAS have been identified in &amp;gt; 85% of pancreatic ductal adenocarcinoma (PDAC) cases. G12D, G12V, and G12R are the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. METHODS PDAC samples were tested using DNA and RNA sequencing. MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by X2 and Fisher-Exact tests. RESULTS 3,755 PDAC patients harboring KRAS G12D (n = 1,766), G12V (n = 1,294) G12R (n = 621) or G12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared to G12D overall (12.7 vs 10.1 months, p-value=0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs 10.4 months, p-value=0.0002) or FOLFIRINOX (18.3 vs 14.0 months, p-value&amp;lt;0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several glucose and glutamine metabolism genes were less expressed in G12R vs G12D. PD-L1 expression was lower in G12R vs G12D (13% vs 19%). CONCLUSION KRAS G12D tumors exhibited a distinct molecular profile compared to G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared to G12R. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.
Elacestrant in women with estrogen receptor-positive and HER2-negative early breast cancer: results from the preoperative window-of-opportunity ELIPSE trial.
Authors: Maria Vidal, Claudette Falato, Tomás Pascual, Rodrigo Sanchez-Bayona, Montserrat Muñoz-Mateu, Isaac Cebrecos, Xavier Gonzalez-Farré, Tomás Cortadellas, Mireia Margelí Vila, Miguel A. Luna, Christian Siso, Kepa Amillano, Patricia Galván, Milana A. Bergamino, Juan M. Ferrero-Cafiero, Fernando Salvador, Alejandra Espinosa Guerrero, Laia Pare, Esther Sanfeliu, Aleix Prat, Meritxell Bellet
Journal: Clinical Cancer Research (2025)

Elacestrant has shown significantly prolonged progression-free survival compared to standard-of-care endocrine therapy in estrogen receptor-positive (ER-positive), HER2-negative metastatic breast cancer (BC), while potential benefit in early-stage disease requires further exploration. The SOLTI-ELIPSE window-of-opportunity trial investigated the biological changes induced by a short course of preoperative elacestrant in postmenopausal women with early BC. Eligible patients with untreated T1c (≥1.5 cm)-T3, N0, ER-positive/HER2-negative BC with locally assessed Ki67≥10% received elacestrant at a daily dose of 345mg for 4 weeks. The primary efficacy endpoint was complete cell cycle arrest (CCCA), defined as Ki67≤2.7%, at day 28. Overall, 22 patients were evaluable for the primary endpoint. Elacestrant was associated with a CCCA rate of 27.3% and a statistically significant geometric mean change of -52.9% (p=0.007; 95%CI, -67.4 to -32.1). The treatment with elacestrant led to a shift toward a more endocrine-sensitive and less proliferative tumor phenotype based on PAM50-based gene signatures. Elacestrant increased the expression of immune-response genes (GZMB, CD4, CD8A) and suppressed proliferation and estrogen-signaling (MKI67, ESR1, and AR). These biological changes were independent of the levels of Ki67 suppression at day 28. Most common adverse events were grade 1: anemia (21.7%), hot flushes, constipation and abdominal pain (8.7%, each). One patient experienced a grade 3 cutaneous rash leading to treatment discontinuation. No other serious adverse events were reported. Preoperative treatment with elacestrant in early BC demonstrated relevant biological and molecular responses and exhibited a manageable safety profile. These findings support further investigation of elacestrant in the early setting.
Privacy preserving strategies for electronic health records in the era of large language models
Authors: Jitendra Jonnagaddala, Zoie Shui-Yee Wong
Journal: npj Digital Medicine (2025)

Electronic health records (EHRs) secondary usage with large language models (LLMs) raise privacy challenges. National regulations like GDPR and HIPAA offer protection frameworks, but specific strategies are needed to mitigate risk in generative AI. Risks can be reduced by using strategies like privacy-preserving locally deployed LLMs, synthetic data generation, differential privacy, and deidentification. Depending on the task, strategies should be employed to increase compliance with patient privacy regulatory frameworks.
Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older — United States, 2025
Authors: A. Patricia Wodi, Anindita N. Issa, Charlotte A. Moser, Sybil Cineas
Journal: MMWR Morbidity and Mortality Weekly Report (2025)

At its October 2024 meeting, the Advisory Committee on Immunization Practices* (ACIP) approved the Recommended Immunization Schedule for Adults Ages 19 Years or Older, United States, 2025. The schedule supports health care providers, as well as public health and other professionals, by providing a consolidated summary of current ACIP recommendations for adult vaccination. The 2025 schedule includes several updates to the cover page, tables, notes, and appendix.† The addendum remains part of the schedule and will be used to summarize new or updated ACIP recommendations that occur before the next annual schedule update. Health care providers are strongly encouraged to use all parts of the schedule (the cover page, tables, notes, appendix, and addendum) together when making recommendations for individual patients. The 2025 adult immunization schedule can be found on the CDC website (https://www.cdc.gov/vaccines/hcp/imz-schedules/index.html).
Gaps in Mental Health Care–Seeking Among Health Care Providers During the COVID-19 Pandemic — United States, September 2022–May 2023
Authors: Anthony Papa, John P. Barile, Haomiao Jia, William W. Thompson, Rebecca J. Guerin
Journal: MMWR Morbidity and Mortality Weekly Report (2025)

Health care workers experience substantial chronic stress, burnout, and mental distress, and the COVID-19 pandemic might have exacerbated these conditions. To identify ways to improve mental health care-seeking among this population, mental health symptoms, care-seeking, and self-reported barriers to seeking mental health care among U.S. health care providers during the pandemic were studied. During September 2022-May 2023, 2,603 primary care physicians, pediatricians, nurse practitioners, and physician assistants participated in a national Internet panel survey. Approximately one half (45.4%) of participants reported that they did not need mental health care, and only one in five (20.3%) had sought care. One quarter (25.6%) of providers reported mental distress severe enough to meet diagnostic criteria for psychopathology. Among these providers, only 38% reported seeking care; 20.1% indicated that they did not need care, despite severe symptoms. The average number of years in practice was lower for providers reporting care-seeking. Providers who identified as female were also more likely to report care-seeking. The most frequently reported barriers to care-seeking included difficulty getting time off from work, cost of care, and concerns about confidentiality. Increased pandemic-related work stressors were associated with increased symptom severity, but support from work supervisors mitigated these effects. Organizational human resources practices, supervisor training on managing employee stress, and public health messaging to normalize mental health care-seeking and its effects on licensing might help address gaps in provider care-seeking and improve patient outcomes.