tbuckley/cabot-search huggingface dataset:
Ubrogepant for the treatment of migraine prodromal symptoms: an exploratory analysis from the randomized phase 3 PRODROME trial
Authors: Peter J Goadsby, Jessica Ailani, David W Dodick, Amaal J Starling, Chengcheng Liu, Yingyi Liu, Sung Yun Yu, Jonathan H Smith, Elimor Brand-Schieber, Joel M Trugman
Journal: Nature Medicine (2025)

Abstract PRODROME was a phase 3, placebo-controlled, double-blind crossover trial evaluating whether ubrogepant 100 mg, a calcitonin gene-related peptide receptor antagonist, dosed during the premonitory (prodromal) phase of migraine, prevented development of headache and resolved prodromal symptoms. Qualifying prodromal events were defined as attacks with symptoms in which the participant was confident headache would follow within 1–6 h. Of 1,087 screened participants, 477 formed the efficacy analysis population. Outcomes were collected across 48 h showing, for example, at 2 h post-dose, absence of photophobia in 19.5% and 12.5% of ubrogepant- and placebo-treated events, respectively (odds ratio (OR) = 1.72 (95% confidence interval (CI) = 1.13–2.61)); at 3 h post-dose, absence of fatigue occurred in 27.3% and 16.8% (OR = 1.85 (95% CI = 1.17–2.92)) and absence of neck pain in 28.9% and 15.9% (OR = 2.04 (95% CI = 1.25–3.32)) of events; at 4 h post-dose, absence of phonophobia in 50.7% and 35.8% (OR = 1.97 (95% CI = 1.38–2.80)) of events; and at 24 h post-dose, absence of dizziness in 88.5% and 82.3% (OR = 1.82 (95% CI = 1.00–3.30)) of events. At 1 h and 6 h post-dose, respectively, absence of difficulty concentrating occurred in 8.7% and 2.1% (OR = 4.26 (95% CI = 1.17–15.54)) and absence of difficulty thinking occurred in 56.9% and 41.8% (OR = 2.05 (95% CI = 1.14–3.71)) of events. Treatment with ubrogepant during the prodromal phase may ameliorate common prodromal symptoms, with improvements possibly as early as 1 h post-dose.
Nanopore direct RNA sequencing of human transcriptomes reveals the complexity of mRNA modifications and crosstalk between regulatory features
Authors: Yerin Kim, Luke Saville, Kieran O'Neill, Jean-Michel Garant, Yilin Liu, Simon Haile-Merhu, Maryam Ghashghaei, Quang Anh Hoang, Amber Louwagie, Yongjin P Park, Steven J M Jones, Ly P Vu
Journal: Cell Genomics (2025)
Intrinsic Capacity Across 15 Countries in the Survey of Health, Aging, and Retirement in Europe
Authors: Meimei Chen, Katja Hanewald, Yafei Si, Yuanyuan Gu, John R. Beard
Journal: JAMA Network Open (2025)

Importance Intrinsic capacity (IC) is a core component of the World Health Organization’s healthy aging framework. Yet, despite multiple validations of IC across various settings, there is still a lack of longitudinal cross-national analysis. Objective To validate the IC construct, describe variance between key demographic groups, and create population centile curves across 15 countries using data from the Survey of Health, Aging, and Retirement in Europe (SHARE). Design, Setting, and Participants In this population-based multicenter cohort study, data from SHARE wave 5 (January to November 30, 2013) were analyzed, and subsequent care dependence in wave 6 (January to November 30, 2015) was determined. Adults 50 years and older from SHARE wave 5 with at least 1 available measure and follow-up data in SHARE wave 6 were included. Data analyses were conducted between December 11, 2022, and June 7, 2024. Exposure SHARE waves 5 and 6. Main Outcomes and Measures Changes in activities of daily living (ADL) and instrumental activities of daily living (IADL). Methods included structural equation modeling, bifactor analysis, and path analysis. Construct validity was tested through multiple linear regression and validity of estimates through mediation analysis. Centile curves were established using the generalized additive models for location, scale, and shape. Results The sample included 64 872 eligible participants aged 50 to 104 years, with a mean (SD) age of 67.24 (10.01) years, of whom 35 976 (55.46%) were women. The bifactor confirmatory factor analysis model achieved good fit (comparative fit index, 0.986; Tucker-Lewis index, 0.981), suggesting an IC structure consisting of 1 general factor and 5 subdomains. Mediation analysis indicated that IC was associated with subsequent declining performance in ADL (standard coefficient [SD], −0.213 [0.002]; P &amp;amp;lt; .001) and IADL (standard coefficient [SD], −0.209 [0.002]; P &amp;amp;lt; .001) after adjusting for age, gender, educational attainment, socioeconomic status, and country. Socioeconomic status was associated with IC both within and between countries. Centile curves for IC by gender and country (5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles) were constructed. Conclusions and Relevance Results of this cohort study of older adults suggest that IC was a valid and reliable measure that effectively captured individual-level aspects of functional ability. The centile curves developed during the study suggest that IC has the potential to serve as a benchmark for health status in older populations.
Generation of a biliary tract cancer cell line atlas identifies molecular subtypes and therapeutic targets
Authors: Vindhya Vijay, Negin Karisani, Lei Shi, Yu-Han Hung, Phuong Vu, Prabhat Kattel, Lauren Kenney, Joshua Merritt, Ramzi Adil, Qibiao Wu, Yuanli Zhen, Robert Morris, Johannes Kreuzer, Meena Kathiresan, Xcanda Ixchel. Herrera Lopez, Haley Ellis, Ilaria Gritti, Lilian Lecorgne, Ines Farag, Alexandra Popa, William Shen, Hiroyuki Kato, Qin Xu, Eranga R. Balasooriya, Meng-Ju Wu, Jinkai Wan, Hiroshi Kondo, Saireudee Chaturantabut, Srivatsan Raghavan, Matthew D. Hall, Samarjit Patnaik, Min Shen, Robin K. Kelley, James M. Cleary, Michael S. Lawrence, David E. Root, Krushna C. Patra, Vanessa S. Silveira, Cyril H. Benes, Vikram Deshpande, Dejan Juric, William R. Sellers, Cristina R. Ferrone, Wilhelm Haas, Francisca Vazquez, Gad Getz, Nabeel Bardeesy
Journal: Cancer Discovery (2025)

Abstract Biliary tract cancers (BTCs) are aggressive malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we report integrative analysis of 63 BTC cell lines via multi-omics and genome-scale CRISPR screens. We identify widespread EGFR dependency in BTC, alongside dependencies selective to anatomic subtypes. Additionally, we delineate strategies to overcome therapeutic resistance, with combined EGFR inhibition potentiating targeting of KRAS-mutant and FGFR2-fusion-driven models, and SHP2 inhibition effective in the latter context. Clustering RNA/protein expression and dependencies data revealed functional relationships transcending single-gene alterations, with biliary, squamous, or dual biliary/hepatocyte lineage signatures stratifying BTC models. These subtypes exhibit distinct dependency profiles— including cell fate transcription factors GRHL2, TP63, and HNF1B, respectively— and demonstrate prognostic significance in patient samples. Potential subtype-specific targetable vulnerabilities include Integrin-a3 and the detoxification enzyme UXS1. This cell line atlas reveals therapeutic targets in molecularly-defined BTCs, unveils disease subtypes, and provides a resource for therapeutic development.
Lecanemab Treatment in a Specialty Memory Clinic
Authors: Madeline Paczynski, Anna Hofmann, Zachary Posey, Maren Gregersen, Michelle Rudman, Dawn Ellington, Melissa Aldinger, Erik S. Musiek, David M. Holtzman, Randall J. Bateman, Justin M. Long, Nupur Ghoshal, David B. Carr, Alan Dow, Sheyda Namazie-Kummer, Nayid Jana, Chengjie Xiong, John C. Morris, Tammie L. S. Benzinger, Suzanne E. Schindler, B. Joy Snider
Journal: JAMA Neurology (2025)

Importance Two monoclonal antibodies targeting amyloid plaques, lecanemab and donanemab, have received traditional US Food and Drug Administration (FDA) approval for the treatment of early symptomatic Alzheimer disease (AD). The most significant adverse events associated with these therapies are infusion-related reactions and amyloid-related imaging abnormalities (ARIA) with edema/effusion (ARIA-E) and/or hemorrhage/hemosiderin deposition (ARIA-H). The feasibility and safety of providing these treatments in clinical practice is unclear. Objective To examine the feasibility and safety of treating patients in specialty memory clinics with lecanemab. Design, Setting, and Participants This retrospective analysis of consecutive patients in whom lecanemab was initiated between August 1, 2023, and October 1, 2024, at Washington University Memory Diagnostic Center, an outpatient specialty memory clinic. Lecanemab was initiated in 234 patients with early symptomatic AD. Eligibility was based on the FDA label and appropriate use recommendations with occasional exceptions. Exposure Patients were treated with lecanemab, 10 mg/kg, intravenously every 2 weeks. Main Outcomes and Measures Infusion-related reactions, ARIA, and withdrawal from treatment were assessed. Results The 234 patients treated with lecanemab had a mean age of 74.4 (SD, 6.7) years, 117 were female (50%), and 117 were male. (50%) Infusion-related reactions occurred in 87 patients (37%) and were typically mild. Of the 194 patients at risk for ARIA during the study period, 44 had at least 1 microhemorrhage and/or superficial siderosis before initiation of lecanemab (23%). Over an average treatment period of 6.5 months, 42 total patients (22%) developed ARIA; 29 developed ARIA-E with or without ARIA-H (15%) and 13 developed isolated ARIA-H (6.7%). Eleven patients (5.7%) developed symptomatic ARIA, 2 of those patients (1.0%) with clinically severe symptoms. No patients developed a macrohemorrhage or died. Patients with mild dementia had a 27% rate of symptomatic ARIA; those with mild cognitive impairment or very mild dementia had a 1.8% rate. Overall, 23 of 234 patients (9.8%) withdrew from treatment for various reasons, 10 for ARIA (4.3%). Conclusions and Relevance A single-specialty memory clinic initiated lecanemab treatment in 234 patients over 14 months. The frequency of significant adverse events, including ARIA, was manageable. These results may inform discussions about the risks of anti-amyloid treatments.
Biomarker‐adapted treatment in high‐risk large B‐cell lymphoma
Authors: Sirpa Leppä, Leo Meriranta, Maare Arffman, Judit Jørgensen, Marja‐Liisa Karjalainen‐Lindsberg, Klaus Beiske, Mette Pedersen, Kristina Drott, Annika Pasanen, Kristiina Karihtala, Susanna Mannisto, Bente Wold, Marianne Brodtkorb, Unn‐Merete Fagerli, Thomas Stauffer Larsen, Lars Munksgaard, Kaisa Sunela, Øystein Fluge, Sirkku Jyrkkiö, Peter Brown, Harald Holte
Journal: HemaSphere (2025)

Abstract Survival rates for patients with high‐risk large B‐cell lymphoma (LBCL), particularly those with biological risk factors, remain inadequate. We conducted a biomarker‐driven phase II trial involving 123 high‐risk patients aged 18–64 with LBCL. Based on their biological risk profiles, patients received either R‐CHOEP‐14 (without risk factors) or DA‐EPOCH‐R‐based regimens (with risk factors). Biological high‐risk factors included C‐MYC translocation, C‐MYC and BCL2 co‐translocation, 17p/TP53 deletion, co‐expression of MYC and BCL2, and P53 and/or CD5 immunopositivity. Additionally, we evaluated circulating tumor DNA (ctDNA) kinetics during therapy. Sixty‐one patients (50%) were classified into biologically high‐risk group. Three‐year failure‐free survival and overall survival rates for the entire study population were 79% and 88%, respectively. DA‐EPOCH‐R did not improve survival compared to our previous trial, where patients with the same biological risk factor criteria received R‐CHOEP‐14‐based therapy. High pretreatment ctDNA levels, 17p/TP53 deletion, and TP53 mutations were associated with worse outcomes. In contrast, ctDNA negativity at the end of therapy (EOT) was indicative of a cure and effectively addressed false residual PET positivity. The findings demonstrate promising survival for high‐risk LBCL patients, aside from those with TP53 aberrations, high ctDNA levels, and/or EOT ctDNA positivity.
Organoid morphology-guided classification for oral cancer reveals prognosis
Authors: Mi Rim Lee, Sumin Kang, Jonghyun Lee, Sun-Young Kong, Youngwook Kim, Yu-Sun Lee, Hye Won Shon, Gyeongmin Kang, Jiyoung Lee, Suk Min Youn, Da Woon Kwack, Joo Yong Park, Soung Min Kim, Wonyoung Choi, Jong-Ho Lee, Dongkwan Shin, Ik-Jae Kwon, Sung-Woen Choi, Yun-Hee Kim
Journal: Cell Reports Medicine (2025)
Early-phase trial of IAP antagonist tolinapant and definitive radiation in cisplatin-ineligible patients with advanced head and neck cancer
Authors: Nicole C. Schmitt, William A. Stokes, James E. Bates, Brendan L.C. Kinney, Jill Remick, Mark W. McDonald, Soumon Rudra, Madison Steininger, Mosope Oyewole, Mihir R. Patel, Azeem S. Kaka, Jennifer H. Gross, Jeffrey Switchenko, Conor E. Steuer, Dong M. Shin, Nabil F. Saba
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Tolinapant is an inhibitor of apoptosis (IAP) antagonist that enhances apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) enhances anti-tumor immunity. We conducted an open-label, single-arm trial to evaluate safety and feasibility of concurrent tolinapant and RT in cisplatin-ineligible patients with head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Eligible patients had locally/locoregionally advanced HNSCC, human papillomavirus (HPV) positive or negative, and were cisplatin ineligible. RT was delivered via intensity-modulated radiation therapy (IMRT) or proton therapy to a total of 70 Gy (35 fractions). Tolinapant was given every other week during RT at 180 mg/day with option to de-escalate to 90 mg for toxicity. Blood samples for research were collected at baseline and during RT. Results: Ten patients were enrolled. Treatment was well tolerated, with the most common adverse events similar to standard chemoRT (radiodermatitis, fatigue, dysphagia, pain, dysgeusia, dry mouth). All patients completed treatment, and tolinapant dose de-escalation was not required. One patient experienced brief treatment interruptions due to severe dysphagia. Two patients developed distant metastases after treatment. Another patient developed second and third tumors outside the radiation field after treatment, treated surgically. At a median follow-up of 13.8 months, the remaining 7 patients (70%) remained free of disease. Blood samples showed a burst of activated (CD38+HLA-DR+) CD8+ T lymphocytes in 40% of patients. Conclusions: Tolinapant + RT is well tolerated and induced proliferation of activated T cells in a subset of patients. Larger prospective studies are needed to better assess efficacy.
Homozygous Familial Hypercholesterolemia Is a Life-Limiting Condition
Authors: Janneke W.C.M. Mulder, M. Doortje Reijman, D. Meeike Kusters, Eric Boersma, Fahad Alnouri, Dirk J. Blom, Alberico L. Catapano, Marina Cuchel, Eldad J. Dann, Tomas Freiberger, Urh Groselj, Mariko Harada-Shiba, G. Kees Hovingh, Iulia Iatan, Daiana Ibarretxe, Meral Kayikcioglu, Ngoc-Thanh Kim, Reinhard Klingel, Frederick J. Raal, Laurens F. Reeskamp, Fouzia Sadiq, Willemijn A.M. Schonck, Tycho R. Tromp, Thanh-Huong Truong, Albert Wiegman, Jeanine E. Roeters van Lennep, Khalid Al-Waili, Marcello Arca, Maurizio Averna, Mahmoud H. Ayesh, Francesco Baratta, Andrea Bartuli, Vladimir Blaha, Liam R. Brunham, Paola S. Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Angelo B. Cefalù, Arturo Cesaro, Sergio D’Addato, Maria Del Ben, Laura D'Erasmo, Marat V. Ezhov, Gordon A. Francis, Federica Galimberti, Antonio Gallo, Daniel Gaudet, Jacques Genest, Antonina Giammanco, Mika Hori, Lisa C. Hudgins, Shamanna S. Iyengar, Jessica Lago, Isabelle Ruel, Samir Saheb, Raul D. Santos, Nitika Setia, Handrean Soran, Patrizia Tarugi, Daniele Tramontano, Luya Wang
Journal: Journal of the American College of Cardiology (2025)
Associations of pre-COPD indicators with lung function decline and their longitudinal transitions
Authors: Jing Fan, Shu Cong, Yang Zhang, Xiao Jiang, Ning Wang, Liwen Fang, Yahong Chen
Journal: Pulmonology (2025)

Pre-chronic obstructive pulmonary disease (COPD) indicators are associated with COPD development, but their associations with lung function decline in persons without COPD and their longitudinal transitions remain uncertain. In this prospective cohort study, 3526 subjects without COPD from the 2014-2015 national COPD surveillance in China were investigated for a second time during 2018-2020. Four potential pre-COPD indicators at baseline were chronic bronchitis, preserved ratio impaired spirometry (PRISm), low peak expiratory flow (PEF), and spirometric small airway dysfunction (sSAD). To include the incident COPD subjects in the lung function decline analysis for consistent indicators, forced expiratory volume in 1 s (FEV1) <80% predicted was used instead of PRISm. Lung function outcomes were the declines in post-bronchodilator FEV1, forced vital capacity (FVC), and FEV1/FVC. Subjects with initial chronic bronchitis had faster declines in FEV1 and FVC compared with those without initial chronic bronchitis among smokers. Consistent chronic bronchitis was associated with faster declines in FEV1 and FVC among non-smokers. Consistent sSAD was associated with faster declines in FEV1/FVC among smokers and non-smokers. Consistent FEV1 <80% predicted and consistent low PEF were associated with a faster decline in FEV1/FVC among smokers. Incident COPD developed from sSAD in almost half of the cases. Initial chronic bronchitis and consistent FEV1 <80% predicted, sSAD, and low PEF are associated with excessive lung function decline among smokers, while consistent chronic bronchitis and sSAD are associated with excessive lung function decline among non-smokers. Initial sSAD accounts for a larger proportion of incident COPD than initial chronic bronchitis, PRISm, and low PEF.
Effect of newborn genomic screening for lysosomal storage disorders: a cohort study in China
Authors: Xin Wang, Yun Sun, Xian-Wei Guan, Yan-Yun Wang, Dong-Yang Hong, Zhi-Lei Zhang, Ya-Hong Li, Pei-Ying Yang, Tao Jiang, Zheng-Feng Xu
Journal: Genome Medicine (2025)

Abstract Background Lysosomal storage disorders (LSDs) have a relatively high incidence among rare diseases and can lead to severe consequences if not treated promptly. However, many countries and regions have not included these disorders in their newborn screening programs, resulting in missed early detection, underdiagnosis, and delayed treatment. Newborn genomic screening (NBGS) has shown good screening effectiveness for traditional biochemical screening diseases; however, its effectiveness for LSDs has not yet been evaluated in the general newborn population. Methods To evaluate the outcome of NBGS for LSDs, a cohort study was conducted involving newborns recruited from Nanjing Women and Children’s Healthcare Hospital in China from March 18, 2022, to September 21, 2023. All participants underwent NBGS of 15 LSDs (18 genes) via dried blood spots, followed by enzyme activity testing for NBGS-positive individuals. The study calculated the incidence and carrier rates for each LSD though NBGS, as well as the positive screening rate, the false positive rate and the positive predictive value of the screening process. Results Among 22,687 newborns (11,996 males [52.88%]), 1344 (6.0%) were identified as carriers, and 30 (0.13%) were initially positive for LSDs. Of these, 4 were excluded, 15 were diagnosed as LSD-presymptomatic individuals based on enzyme deficiency and pathogenic variants conforming to inheritance patterns, and 11 remain under follow-up. The estimated combined birth incidence of LSDs in Nanjing was 1/1512, primarily including Fabry disease, Krabbe disease, glycogen storage disease type II, Niemann–Pick disease, and mucopolysaccharidosis type II. Rather than directly comparing NBGS and enzyme activity screening, this study evaluated two sequential screening strategies: (1) NBGS-first with reflex enzyme testing and (2) enzyme activity-first with reflex genomic testing. The NBGS-first strategy demonstrated higher sensitivity and specificity, with a significantly lower false positive rate and higher positive predictive values compared to the enzyme-first strategy ( P &lt; 0.05). Conclusions This study highlights the potential of NBGS to enhance early detection of presymptomatic LSD individuals, enabling timely interventions and improving newborn health outcomes. Integrating NBGS into routine newborn screening programs could provide an effective and proactive approach for LSD identification and management.
Sitravatinib targets TYRO3 to augment the anti-tumor immune response of PD-1 blockade in hepatocellular carcinoma
Authors: Hongkai Zhuang, Chenwei Tang, Wentao Wang, Bo Chen, Bingkun Wang, Yonglin Hua, Xiaowu Ma, Qingbin Wang, Wenliang Tan, Lei Yang, Zhiqin Xie, Yajin Chen, Changzhen Shang
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Tyrosine kinase inhibitors (TKIs) combined with immune checkpoint blockades (ICBs) produce enhanced anti-tumor activity in the treatment of advanced hepatocellular carcinoma (HCC). Sitravatinib is a novel multi-target TKI that targets TYRO3, AXL, MERTK (TAM) receptors, c-MET, etc. This study aimed to investigate the anti-tumor efficacy and immunomodulatory activity of sitravatinib in HCC. Experimental Design: Human HCC cell lines and xenograft models were used to explore the anti-tumor activity of sitravatinib. Subcutaneous and orthotopic immunocompetent murine HCC models were used to assess the therapeutic efficacy of sitravatinib and PD-1 blockade combination therapy. Co-cultures for tumor cells and T cells were performed to verify the immunomodulatory effect of sitravatinib in tumors. Results: Sitravatinib showed potent anti-tumor activity and immunomodulatory capabilities from in vitro to in vivo. Sitravatinib treatment synergized with PD-1 blockade to generate an increased anti-tumor efficacy, leading to significant enrichment of cytotoxic CD8+ T cells as well as reduction of Treg cells infiltration in tumors. Mechanically, on one hand, sitravatinib reinforced MHC-I expression by blocking TYRO3-STAT1 axis, thereby sensitizing tumor cells to T cell liking. On the other hand, sitravatinib suppressed tumor-secreted IL33 by inhibiting TYRO3 activity in HCC cells, resulting in reduced Treg cells differentiation and consequently liberating CD8+ T cell cytotoxic capacity. In the clinic, one advanced HCC patient treated with Sitravatinib plus PD-1 blockade achieved near complete response and remains disease progression-free for more than two years. Conclusions: Collectively, we demonstrated a rationale for combining sitravatinib with PD-1 blockade in the treatment for HCC.
Patient rights in precision oncology: right treatment, right time, right dose, right order, right place
Authors: Elena Fountzilas, Apostolia-Maria Tsimberidou, Razelle Kurzrock
Journal: Genome Medicine (2025)

Precision oncology has facilitated a transition from a one-size-fits-all to a precise individualized approach. This Comment discusses the broader challenges in the implementation of personalized treatments to further improve patients' outcomes, towards comprehensive strategies that address tumor complexity and patients' molecular portfolios, as well as quality of life and diversity considerations.