tbuckley/cabot-search huggingface dataset:
Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1
Authors: Yizeng Fan, Weichao Dan, Yuzhao Wang, Zhiqiang Ma, Yanlin Jian, Tianjie Liu, Mengxing Li, Zixi Wang, Yi Wei, Bo Liu, Peng Ding, Yuzeshi Lei, Chendong Guo, Jin Zeng, Xiaolong Yan, Wenyi Wei, Lei Li
Journal: Cell Metabolism (2025)

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
Distinctive But Not Exceptional: The Risks of Psychedelic Ethical Exceptionalism
Authors: Katherine Cheung, Brian D. Earp, Kyle Patch, David B. Yaden
Journal: The American Journal of Bioethics (2025)

When used clinically, psychedelics may appear unusual or even unique when compared to more familiar or long-standing medical interventions, prompting some to suggest that the ethical issues raised may likewise be exceptional. If that is correct, then perhaps psychedelics should be treated differently from other medical substances: for example, by being subjected to different ethical or evidentiary standards. Alternatively, it may be that psychedelics have more in common with various existing medical interventions than first meets the eye. We argue in favor of the latter position, drawing on parallels from earlier debates around genetic exceptionalism in bioethics. We suggest there are risks to adopting a stance of "psychedelic ethical exceptionalism," and propose that consistent ethical rules and evidentiary standards should be applied across all relevant areas of clinical medicine. Importantly, this does not preclude the possibility that changes to existing standards should be made; but if so, this should not be justified by appealing to the alleged uniqueness of psychedelics.
Anything but small: Microarousals stand at the crossroad between noradrenaline signaling and key sleep functions
Authors: Anita Lüthi, Maiken Nedergaard
Journal: Neuron (2025)

Continuous sleep restores the brain and body, whereas fragmented sleep harms cognition and health. Microarousals (MAs), brief (3- to 15-s-long) wake intrusions into sleep, are clinical markers for various sleep disorders. Recent rodent studies show that MAs during healthy non-rapid eye movement (NREM) sleep are driven by infraslow fluctuations of noradrenaline (NA) in coordination with electrophysiological rhythms, vasomotor activity, cerebral blood volume, and glymphatic flow. MAs are hence part of healthy sleep dynamics, raising questions about their biological roles. We propose that MAs bolster NREM sleep's benefits associated with NA fluctuations, according to an inverted U-shaped curve. Weakened noradrenergic fluctuations, as may occur in neurodegenerative diseases or with sleep aids, reduce MAs, whereas exacerbated fluctuations caused by stress fragment NREM sleep and collapse NA signaling. We suggest that MAs are crucial for the restorative and plasticity-promoting functions of sleep and advance our insight into normal and pathological arousal dynamics from sleep.
A first-in-human clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy
Authors: Masatoshi Hirayama, Shin Hatou, Masaki Nomura, Risa Hokama, Osama Ibrahim Hirayama, Emi Inagaki, Kumi Aso, Tomoko Sayano, Hiromi Dohi, Tadaaki Hanatani, Naoko Takasu, Hideyuki Okano, Kazuno Negishi, Shigeto Shimmura
Journal: Cell Reports Medicine (2025)

A first-in-human investigator-initiated clinical study of a corneal endothelial cell substitute (CLS001) derived from a clinical-grade induced pluripotent stem cell (iPSC) line shows improvement of visual acuity and corneal stromal edema, with no adverse events for up to 1 year after surgery for the treatment of bullous keratopathy. While preclinical tests, including multiple whole-genome analysis and tumorigenicity tests adhering to the Food and Drug Administration (FDA) draft guidelines, are negative, an additional whole-genome analysis conducted on transplanted CLS001 cells reveals a de novo in-frame deletion of exon22 in the EP300 gene. No adverse events related to the mutation are observed. Our study demonstrates the feasibility of using iPSC-derived cells to replace donor transplant for bullous keratopathy, while shedding light on risk management of gene mutation in cell products. Further follow-up is required for long-term analysis of clinical safety and efficacy.
Impact of co-mutations and transcriptional signatures in non-small cell lung cancer patients treated with adagrasib in the KRYSTAL-1 trial
Authors: Marcelo V. Negrao, Alvaro G. Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M. Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R. Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E. Kopetz, David S. Hong, Don L. Gibbons, Peter Olson, James G. Christensen, John V. Heymach
Journal: Clinical Cancer Research (2025)

Abstract Background: KRAS inhibitors are revolutionizing the treatment of NSCLC, but clinico-genomic determinants of treatment efficacy warrant continued exploration. Methods: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib (KRYSTAL-1-NCT03785249) were included in the analysis. Pre-treatment NGS data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free and overall survival. KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens. Results: KEAP1MUT and STK11MUT were associated with shorter survival to adagrasib (KEAP1: PFS 4.1m vs 9.9m, HR 2.7, p&amp;lt;0.01; OS 5.4m vs 19.0m, HR 3.6, p&amp;lt;0.01; STK11: PFS 4.2m vs 11.0m, HR 2.2, p&amp;lt;0.01; OS 9.8m vs NR, HR 2.6, p&amp;lt;0.01). KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9m) and OS (NR). Pre-clinical analyses further validate the association between KEAP1 loss-of-function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2m vs 8.4m, HR 2.0, p=0.02; OS: 6.5m vs 19.0m, HR 2.8, p&amp;lt;0.01) even in KEAP1WTNSCLC patients. KEAP1WT/STK11WT/NRF2LOW status identified patients - 32% - with longer survival to adagrasib (PFS 12.0m vs 4.2m, HR 0.2, p&amp;lt;0.01; OS NR vs 8.0m, HR 0.1, p&amp;lt;0.01). Conclusions: KEAP1, STK11 and NRF2 status define KRASG12C-mutant NSCLC patients with markedly distinct outcomes to adagrasib. These results further support the use of genomic features – mutational and non-mutational - for treatment selection of KRASG12C-mutant NSCLC patients.
Enhancement Of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma
Authors: Yago Nieto, Jeremy Ramdial, Benigno Valdez, Peter F. Thall, Roland Bassett, Melissa Barnett, Samer Srour, Chitra Hosing, Amin Alousi, Muzaffar Qazilbash, Uday Popat, Alison Gulbis, Terri Lynn Shigle, Sairah Ahmed, Maria Guillermo Pacheco, Richard Champlin, Elizabeth J. Shpall, Borje S. Andersson
Journal: Clinical Cancer Research (2025)

More active high-dose chemotherapy (HDC) regimens are needed for autologous stem-cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a poly(ADP-ribose) polymerase (PARP) inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT. Patients ages 15-65 with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dose was escalated from 25 mg PO BID on days (d)-11 to -3, plus vorinostat (1,000 mg PO/d, d-10 to -3), gemcitabine (2,475 mg/m2/d IV, d-8 and -3), busulfan (target AUC 4,000 μM.min-1/d IV, d-8 to -5), melphalan (60 mg/m2/d IV, d-3 and -2), and rituximab (CD20+ tumors) (375 mg/m2, d-10), with ASCT. Fifty patients were enrolled (23 Hodgkin, 18 DLBCL, 9 T-NHL); median age 35 (range, 20-61); median 3 prior lines of therapy (range, 2-7); 17 patients had previously relapsed after CAR-T or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dose of 150 mg PO BID was identified as the recommended phase 2 dose. The main extramedullary toxicity was mucositis. The ORR/CR rates were 100%/90%. At median follow-up of 30 months (range, 12-56) months, the EFS/OS rates were 72%/82%, and 71%/88% in patients with prior CAR-T cell failure. In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.
Patients with idiopathic pulmonary fibrosis have fatty lungs impacting respiratory physiology
Authors: Wenying Lu, Affan Mahmood Shahzad, Josie Larby, Maddison Waters, Melinda Wilson, Jade Jaffar, Glen Westall, Darren Sutherland, Greg Haug, Tillie L. Hackett, Sukhwinder Singh Sohal
Journal: Pulmonology (2024)
Lung ultrasound in neonates and children with cardiac diseases with focus on post cardiac surgical period: time for systematic use—an expert opinion report by the Association for European Paediatric and Congenital Cardiology Imaging Working Group
Authors: Massimiliano Cantinotti, Giovanni Di Salvo, Inga Voges, Francesca Raimondi, Gerald Greil, Almudena Ortiz Garrido, Heynric B Grotenhuis, Colin J McMahon
Journal:  (2025)

Abstract Background Despite lung ultrasound (LUS) gaining consensus for the diagnosis of pulmonary complication in paediatric acute care setting and in adult cardiology, its use in paediatric cardiology remains limited. Aim The aim of the present investigation is to provide an expert opinion on the applications of LUS in neonates and children with congenital heart disease, with a special focus on the post-surgical period. Methods and Results A complete guide for identification of landmarks and major signs (A and B lines) and their characteristics is provided. Diagnostic criteria, tips, and tricks for the diagnosis, and differential diagnosis of common pulmonary diseases such as pleural effusion, pneumonia, and consolidation are provided. To perform diagnosis of pneumothorax is illustrated. Applications of LUS for evaluation of hemidiaphragm motility and for a comprehensive assessment of retrosternal area are also discussed. The use of LUS for guidance of minor, common interventional procedures such as lung recruitment and drainage insertion is also described. The report also highlights current gaps of knowledge, including the difficulty for quantitative estimation of pleural effusion and atelectasis, and future prospective. Conclusion There is sufficient evidence to support a systematic use of LUS for the diagnosis and follow-up of neonates and children with cardiac disease especially those undergoing paediatric cardiac surgery. LUS is an easy, accurate, fast, cheap, and radiation-free tool that should become a routine in daily practice.
Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies
Authors: Nadeen Anabtawi, Deedra Nicolet, Najla Alotaibi, Daelynn R. Buelow, Shelley Orwick, Thomas Gregory, Ruchika Raj, Kennedy Coleman, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Maria R. Baer, John C. Byrd, Wendy Stock, Geoffrey L. Uy, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Xiaolin Cheng, Sharyn D. Baker, James S. Blachly
Journal: Leukemia (2025)
Allergic Reactivity and Memory Occur Independently of Sequential Switching Through <scp>IgG1</scp>
Authors: Joshua F. E. Koenig, Adam K. Wade‐Vallance, Rodrigo Jiménez‐Saiz, Kelly Bruton, Siyon Gadkar, Emily Grydziuszko, Tina D. Walker, Melissa E. Gordon, Amy E. Gillgrass, Justin J. Taylor, Susan Waserman, Manel Jordana
Journal: Allergy (2025)

ABSTRACT Allergic reactions to foods are primarily driven by allergen‐binding immunoglobulin (Ig)E antibodies. IgE‐expressing cells can be generated through direct switching from IgM to IgE or a sequential class switching pathway where activated B cells first switch to an intermediary isotype, most frequently IgG1, and then to IgE. It has been proposed that sequential class switch recombination is involved in augmenting the severity of allergic reactions, generating high affinity IgE, differentiation of IgE plasma cells, and in holding the memory of IgE responses. We directly tested these possibilities by comparing the allergic immunity of wild‐type and IgG1‐deficient (hMT) mice. We found that sequential switching through IgG1 was not required to maintain the binding capacity of IgE nor for its ability to promote degranulation and elicit anaphylaxis against bona fide food allergens. Furthermore, the absence of sequential switching modestly impacted IgE affinity and clinical reactivity against hapten antigens, suggesting that the nature of the antigen impacts the requirement for sequential switching. At a cellular level, the capacity to undergo sequential switching through IgG1 provided no competitive advantage for subsequent IgE expression among germinal center B cells or plasma cells. Furthermore, the recall of allergic immunity at memory timepoints was preserved in the absence of sequential switching through IgG1, a finding that corresponded with intact type 2 memory B cell polarization. Together, these data demonstrate that sequential switching through IgG1 is redundant in sensitization, anaphylaxis, and the persistence of allergy, ultimately revealing that IgE derived from any switching source should be targeted by novel therapeutics seeking to ameliorate allergic diseases.
Evaluation of Intestinal Permeability Using Serum Biomarkers in Learning Early About Peanut Allergy Trial
Authors: Ozge Nur Aktas, Allyson Mateja, Min (Jenny) Li, Lindsay Chatman, Megan C. Grieco, Carolyn H. Baloh, Michelle Huffaker, Lisa M. Wheatley, George du Toit, Gideon Lack, Erica Brittain, Pamela A. Frischmeyer‐Guerrerio
Journal: Allergy (2025)

ABSTRACT Background Intestinal barrier dysfunction may lead to a break in tolerance and development of food allergy (FA). There is contradictory evidence on whether intestinal permeability (IP) is altered in IgE‐mediated FA. Thus, we sought to determine whether IP differed between children with eczema who did (FA group) or did not (atopic controls, ACs) develop FA and whether peanut sensitization, allergy, and early introduction impacted IP using serum biomarkers zonulin, soluble CD14, and Intestinal Fatty Acid Binding Protein among randomly selected participants enrolled in the Learning Early About Peanut allergy trial. Methods FA group was defined as having at least one FA at either baseline (4–11 months) or 60 months of age (V60). ACs had eczema at baseline and no FA at either visit. Serum IP markers (sIPMs) were measured by ELISA at baseline and V60, and their relationship with the clinical characteristics of participants was analyzed using parametric tests and linear regression models. Results We evaluated 237 FA subjects and 76 ACs. sIPM levels were similar in FA subjects and ACs at baseline and V60. Age when the child first developed any FA (&lt; 1 year vs. &gt; 1 year), eczema severity, peanut sensitization, peanut allergy, and early peanut introduction were not statistically significantly associated with sIPM levels. Total IgE and eosinophil levels, peanut‐specific IgE, IgG4, and IgG4/IgE ratio were not correlated with sIPM levels. Conclusions No differences in sIPMs were detected to support altered IP in infants with FA compared to ACs or following early peanut introduction among peanut‐sensitized children.
Explainable AI associates ECG aging effects with increased cardiovascular risk in a longitudinal population study
Authors: Philip Hempel, Antônio H. Ribeiro, Marcus Vollmer, Theresa Bender, Marcus Dörr, Dagmar Krefting, Nicolai Spicher
Journal: npj Digital Medicine (2025)

Aging affects the 12-lead electrocardiogram (ECG) and correlates with cardiovascular disease (CVD). AI-ECG models estimate aging effects as a novel biomarker but have only been evaluated on single ECGs-without utilizing longitudinal data. We validated an AI-ECG model, originally trained on Brazilian data, using a German cohort with over 20 years of follow-up, demonstrating similar performance (r2 = 0.70) to the original study (0.71). Incorporating longitudinal ECGs revealed a stronger association with cardiovascular risk, increasing the hazard ratio for mortality from 1.43 to 1.65. Moreover, aging effects were associated with higher odds ratios for atrial fibrillation, heart failure, and mortality. Using explainable AI methods revealed that the model aligns with clinical knowledge by focusing on ECG features known to reflect aging. Our study suggests that aging effects in longitudinal ECGs can be applied on population level as a novel biomarker to identify patients at risk early.
ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion
Authors: Jie Cheng, Yifeng Xiao, Ting Peng, Zijian Zhang, You Qin, Yuqian Wang, Jiangzhou Shi, Jinxin Yan, Zihao Zhao, Liangtao Zheng, Zhijun He, Jianwei Wang, Zemin Zhang, Cheng Li, Haichuan Zhu, Peng Jiang
Journal: Nature Cancer (2025)
ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer
Authors: Jackson Liang, Xiaosai Yao, Patrick Aouad, Bu-Er Wang, Lisa Crocker, Subhra Chaudhuri, Yuxin Liang, Spyros Darmanis, Jennifer Giltnane, Heather M Moore, Junko Aimi, Ching-Wei Chang, Mary R Gates, Jennifer Eng-Wong, Marc Hafner, Ciara Metcalfe
Journal: Nature Cancer (2025)
Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters
Authors: Naitao Wang, Mohini R. Pachai, Dan Li, Cindy J. Lee, Sarah Warda, Makhzuna N. Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R. Shah, Li Yao, Cheng Qian, Elissa W. P. Wong, Juan Yan, Fanny V. Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P. Gao, Jiaqian Luo, Alison E. Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. Al-Ahmadie, Ping Chi, Yu Chen
Journal: Nature Genetics (2025)

Abstract Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c / d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c / d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c / d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c / d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c / d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities.
Longitudinal serum proteome mapping reveals biomarkers for healthy ageing and related cardiometabolic diseases
Authors: Jun Tang, Liang Yue, Ying Xu, Fengzhe Xu, Xue Cai, Yuanqing Fu, Zelei Miao, Wanglong Gou, Wei Hu, Zhangzhi Xue, Kui Deng, Luqi Shen, Zengliang Jiang, Menglei Shuai, Xinxiu Liang, Congmei Xiao, Yuting Xie, Tiannan Guo, Yu-ming Chen, Ju-Sheng Zheng
Journal: Nature Metabolism (2025)

The blood proteome contains biomarkers of ageing and age-associated diseases, but such markers are rarely validated longitudinally. Here we map the longitudinal proteome in 7,565 serum samples from a cohort of 3,796 middle-aged and elderly adults across three time points over a 9-year follow-up period. We pinpoint 86 ageing-related proteins that exhibit signatures associated with 32 clinical traits and the incidence of 14 major ageing-related chronic diseases. Leveraging a machine-learning model, we pick 22 of these proteins to generate a proteomic healthy ageing score (PHAS), capable of predicting the incidence of cardiometabolic diseases. We further identify the gut microbiota as a modifiable factor influencing the PHAS. Our data constitute a valuable resource and offer useful insights into the roles of serum proteins in ageing and age-associated cardiometabolic diseases, providing potential targets for intervention with therapeutics to promote healthy ageing. Tang, Yue, Xu and colleagues map the proteome of several thousand individuals over a 9-year period to identify potential biomarkers of ageing and of age-associated diseases.
Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses
Authors: Xin Chen, Mustafa Ghanizada, Vamsee Mallajosyula, Elsa Sola, Robson Capasso, Karan Raj Kathuria, Mark M. Davis
Journal: Nature Immunology (2025)

Abstract Here we analyzed the relative contributions of CD4 + regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8 + regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4 + and CD8 + regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8 + regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8 + and CD4 + T cells. These findings highlight the distinct yet complementary roles of CD8 + and CD4 + regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity.