tbuckley/cabot-search huggingface dataset:
Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification
Authors: Jeremiah Wala, Simona Dalin, Sophie Webster, Ofer Shapira, John Busanovich, Shahab Sarmashghi, Rameen Beroukhim, Pratiti Bandopadhayay, Veronica Rendo
Journal: Cell Genomics (2025)

Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in the BRD4 gene, decreasing expression despite increased copy number. We show that these focal deletions occur in the context of cyclin E1 amplification in breast, ovarian, and endometrial cancers, and serve to disrupt BRD4 regulatory regions and gene expression across isoforms. We analyze open reading frame screen data and find that overexpression of BRD4 long (BRD4-L) and short isoform BRD4-S(a) impairs cell growth across cell lines. We confirm these results in OVSAHO ovarian cancer cells, where the overexpression of BRD4 isoforms significantly reduces tumor growth. Next, we mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation. Our study provides experimental evidence for the first recurrent deletion reducing toxicity in cancer, expanding the landscape of cancer progression mechanisms.
Suicide and Self-Harm Events With GLP-1 Receptor Agonists in Adults With Diabetes or Obesity
Authors: Pouya Ebrahimi, Juan Carlos Batlle, Aryan Ayati, M. Haisum Maqsood, Clarine Long, Constantine Tarabanis, Natalie McGowan, David T. Liebers, Gregory Laynor, Kaveh Hosseini, Sean P. Heffron
Journal: JAMA Psychiatry (2025)

Importance Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data Sources MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study Selection Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data Extraction and Synthesis Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main Outcomes and Measures Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and Relevance There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.
Diagnosis and Management of Mohs Surgery Complications by Large Language Models Using Pre-Constructed Written Scenarios
Authors: Megan H Trager, Emily R Gordon, Alyssa Breneman, Annie Brito, Olivia Vivadelli, Jenna Wenzel, Tatyana R Humphreys, Juliya Fisher, Courtney Ensslin, Faramarz H Samie
Journal: British Journal of Dermatology (2025)

Publicly available large language models are being used in dermatology and perform with high accuracy in determining the diagnosis for common post-operative Mohs micrographic surgery complications, similar to Mohs nurses, but have a lower accuracy in triage management. However, once programmed, custom GPTs are able to obtain the correct information and arrive at a management decision with greater accuracy. This study highlights the potential for large language models to be used for triaging patients with additional training and appropriate human oversight.
Disease modification upon 2 weeks of tofacitinib treatment in a mouse model of chronic epilepsy
Authors: Olivia R. Hoffman, Jennifer L. Koehler, Jose Ezekiel Clemente Espina, Anna M. Patterson, Emily S. Gohar, Emanuel M. Coleman, Barry A. Schoenike, Claudia Espinosa-Garcia, Felipe Paredes, Nicholas H. Varvel, Raymond J. Dingledine, Jamie L. Maguire, Avtar S. Roopra
Journal: Science Translational Medicine (2025)

All current drug treatments for epilepsy, a neurological disorder affecting more than 50 million people, merely treat symptoms, and a third of patients with epilepsy do not respond to medication. There are no disease-modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits. Applying network approaches to whole tissue and single-nucleus transcriptomic data collected from mouse models of temporal lobe epilepsy and publicly available transcriptomic data from human temporal lobectomy samples, we confirmed a previously described pattern of rapid and transient induction of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway within days of epileptogenic insult. This was followed by a resurgent activation of the JAK/STAT pathway weeks to months later with the onset of spontaneous seizures. Targeting the first wave of JAK/STAT activation after epileptic insult did not prevent seizures. However, inhibition of the second wave with CP690550 (tofacitinib) over a 2-week period enduringly suppressed seizures, rescued deficits in spatial memory, and alleviated epilepsy-associated histopathological alterations. Seizure suppression lasted for at least 2 months after the final dose. These results indicate that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the US Food and Drug Administration–approved, orally available drug CP690550.
Interneuron-specific dual-AAV <i>SCN1A</i> gene replacement corrects epileptic phenotypes in mouse models of Dravet syndrome
Authors: John K. Mich, Jiyun Ryu, Aguan D. Wei, Bryan B. Gore, Rong Guo, Angela M. Bard, Refugio A. Martinez, Emily M. Luber, Jiatai Liu, Yemeserach M. Bishaw, Robert J. Christian, Luiz M. Oliveira, Nicole Miranda, Jan-Marino Ramirez, Jonathan T. Ting, Ed S. Lein, Boaz P. Levi, Franck K. Kalume
Journal: Science Translational Medicine (2025)

Dravet syndrome (DS) is a severe developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10 to 20% rate of premature death. Most patients with DS harbor loss-of-function mutations in one copy of SCN1A, which encodes the voltage-gated sodium channel (NaV)1.1 alpha subunit and has been associated with inhibitory neuron dysfunction. Here, we generated a split-intein form of SCN1A and used a dual-vector delivery approach to circumvent adeno-associated virus (AAV) packaging limitations. In addition, we applied previously developed enhancer technology to produce an interneuron-specific gene replacement therapy for DS, called DLX2.0-SCN1A. The split-intein SCN1A vectors produced full-length NaV1.1 protein, and functional sodium channels were recorded in HEK293 cells in vitro. Administration of dual DLX2.0-SCN1A AAVs to wild-type mice produced full-length, reconstituted human protein by Western blot and telencephalic interneuron-specific and dose-dependent NaV1.1 expression by immunohistochemistry. These vectors also conferred strong dose-dependent protection against postnatal mortality and seizures in Scn1afl/+;Meox2-Cre and Scn1a+/R613X DS mouse models. Injection of single or dual DLX2.0-SCN1A AAVs into wild-type mice did not result in increased mortality, weight loss, or gliosis as measured by immunohistochemistry. In contrast, expression of SCN1A in all neurons driven by the human SYNAPSIN I promoter caused an adverse effect marked by increased mortality in the preweaning period, before disease onset. These findings demonstrate proof of concept that interneuron-specific AAV-mediated SCN1A gene replacement can rescue DS phenotypes in mouse models and suggest that it could be a therapeutic approach for patients with DS.
New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma
Authors: Noémie Joalland, Agnès Quéméner, Sophie Deshayes, Romain Humeau, Mike Maillasson, Héloïse LeBihan, Apolline Salama, Judith Fresquet, Séverine Remy, Erwan Mortier, Christophe Blanquart, Carole Guillonneau, Ignacio Anegon
Journal: Journal for ImmunoTherapy of Cancer (2025)

Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative approach. A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine (M149K). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1RM149K-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1RM149K-Fc or sCSF-1R-Fc wild type control (sCSF-1RWT-Fc). We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1RM149K-Fc trapped with higher affinity than sCSF-1RWT-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1RM149K-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1RM149K-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids. sCSF-1RM149K-Fc efficiently traps both CSF-1 and IL-34 and inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation induced by pleural mesothelioma cells producing CSF-1 and IL-34, as well as restores cytotoxic T-cell responses. sCSF-1RM149K-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.
T cell receptor precision editing of regulatory T cells for celiac disease
Authors: Raphaël Porret, Ana Alcaraz-Serna, Benjamin Peter, Jeremiah Bernier-Latmani, Rebecca Cecchin, Oscar Alfageme-Abello, Laura Ermellino, Morteza Hafezi, Eleonora Pace, M. Fleur du Pré, Erica Lana, Dela Golshayan, Dominique Velin, Justin Eyquem, Qizhi Tang, Tatiana V. Petrova, George Coukos, Melita Irving, Caroline Pot, Giuseppe Pantaleo, Ludvig M. Sollid, Yannick D. Muller
Journal: Science Translational Medicine (2025)

Celiac disease, a gluten-sensitive enteropathy, demonstrates a strong human leukocyte antigen (HLA) association, with more than 90% of patients carrying the HLA-DQ2.5 allotype. No therapy is available for the condition except for a lifelong gluten-free diet. To address this gap, we explored the therapeutic potential of regulatory T cells (Tregs). By orthotopic replacement of T cell receptors (TCRs) through homology-directed repair, we generated gluten-reactive HLA-DQ2.5-restricted CD4+ engineered (e) T effector cells (Teffs) and eTregs and performed in vivo experiments in HLA-DQ2.5 transgenic mice. Of five validated TCRs, TCRs specific for two immunodominant and deamidated gluten epitopes (DQ2.5-glia-α1a and DQ2.5-glia-α2) were selected for further evaluation. CD4+ eTeffs exposed to deamidated gluten through oral gavage colocalized with dendritic and B cells in the Peyer's patches and gut-draining lymph nodes and specifically migrated to the intestine. The suppressive function of human eTregs correlated with high TCR functional activity. eTregs specific for one epitope suppressed the proliferation and gut migration of CD4+ eTeffs specific for the same and the other gluten epitope, demonstrating bystander suppression. The suppression requires an antigen-specific activation of eTregs given that polyclonal Tregs failed to suppress CD4+ eTeffs. These findings highlight the potential of gluten-reactive eTregs as a therapeutic for celiac disease.
Longitudinal Genomic Analysis to Fine-Tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients With BRAF V600-Mutant Metastatic Melanoma
Authors: Reinhard Dummer, Shahneen Sandhu, Wilson H. Miller, Marcus O. Butler, Matthew H. Taylor, Lucie Heinzerling, Christian U. Blank, Eva Munoz-Couselo, Howard A. Burris, Michael A. Postow, Bartosz Chmielowski, Mark R. Middleton, Carola Berking, Jessica C. Hassel, Anja Heike. Gesierich, Cornelia Mauch, Joseph F. Kleha, Anna Polli, Allison S. Harney, Alessandra di Pietro, Paolo A. Ascierto
Journal: Clinical Cancer Research (2025)

Abstract Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced unresectable or metastatic BRAF Patients and Methods: Adults with locally advanced unresectable or metastatic BRAF V600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi)-treatment naive or pretreated received encorafenib plus binimetinib (Part I/Run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; Part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed. Results: In Part I/Run-in, 75 BRAFi/MEKi-naive patients and 83 BRAFi/MEKi-pretreated patients were treated; in Part II, 58 patients were treated (ribociclib, n=38; infigratinib, n=1; capmatinib, n=13; buparlisib, n=6). The overall confirmed response rate was 73.3% (95% CI, 61.9–82.9) in BRAFi/MEKi-naive patients, 25.3% (95% CI, 16.4–36.0) in pretreated patients, 2.6% (95% CI, 0.1–13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug. Conclusions: LOGIC 2 supports the use of encorafenib plus binimetinib for treatment naive and previously treated locally advanced unresectable or metastatic BRAF V600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance.
BASTA, a simple whole-blood assay for measuring β cell antigen–specific CD4 <sup>+</sup> T cell responses in type 1 diabetes
Authors: Matthew Lacorcia, Pushpak Bhattacharjee, Abby Foster, Melinda Y. Hardy, Jason A. Tye-Din, John A. Karas, John M. Wentworth, Fergus J. Cameron, Stuart I. Mannering
Journal: Science Translational Medicine (2025)

Type 1 diabetes (T1D) is an autoimmune disease where T cells mediate the destruction of the insulin-producing β cells found within the islets of Langerhans in the pancreas. Autoantibodies to β cell antigens are the only tests available to detect β cell autoimmunity. T cell responses to β cell antigens, which are known to cause T1D, can only be measured in research settings because of the complexity of assays and the large blood volumes required. Here, we describe the β cell antigen-specific T cell assay (BASTA). BASTA is a simple whole-blood assay that can detect human CD4+ T cell responses to β cell antigens by measuring antigen-stimulated interleukin-2 (IL-2) production. BASTA is both more sensitive and specific than the CFSE (carboxyfluorescein diacetate succinimidyl ester)-based proliferation assay. We used BASTA to identify the regions of preproinsulin that stimulated T cell responses specifically in blood from people with T1D. BASTA can be done with as little as 2 to 3 milliliters of blood. We found that effector memory CD4+ T cells are the primary producers of IL-2 in response to preproinsulin peptides. We then evaluated responses to individual and pooled preproinsulin peptides in a cross-sectional study of pediatric patients: without T1D, without T1D but with a first-degree relative with T1D, or diagnosed with T1D. In contrast with other preproinsulin peptides, full-length C-peptide (PI33-63) showed high specificity for T1D [area under the curve (AUC) = 0.86)]. We suggest that BASTA will be a useful tool for monitoring changes in β cell-specific CD4+ T cell responses both in research and clinical settings.
The T cell receptor landscape of childhood brain tumors
Authors: Itay Raphael, Zujian Xiong, Chaim T. Sneiderman, Rebecca A. Raphael, Moshe Mash, Lance Schwegman, Sydney A. Jackson, Casey O’Brien, Kevin J. Anderson, ReidAnn E. Sever, Liam D. Hendrikse, Sarah R. Vincze, Aaron Diaz, James Felker, Javad Nazarian, Yael Nechemia-Arbely, Baoli Hu, Udai S. Kammula, Sameer Agnihotri, Jeremy N. Rich, Alberto Broniscer, Jan Drappatz, Taylor J. Abel, Shikhar Uttam, Eugene I. Hwang, Thomas M. Pearce, Michael D. Taylor, Michal Nisnboym, Thomas G. Forsthuber, Ian F. Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash
Journal: Science Translational Medicine (2025)

The diverse T cell receptor (TCR) repertoire confers the ability to recognize an almost unlimited array of antigens. Characterization of antigen specificity of tumor-infiltrating lymphocytes (TILs) is key for understanding antitumor immunity and for guiding the development of effective immunotherapies. Here, we report a large-scale comprehensive examination of the TCR landscape of TILs across the spectrum of pediatric brain tumors, the leading cause of cancer-related mortality in children. We show that a T cell clonality index can inform patient prognosis, where more clonality is associated with more favorable outcomes. Moreover, TCR similarity groups' assessment revealed patient clusters with defined human leukocyte antigen associations. Computational analysis of these clusters identified putative tumor antigens and peptides as targets for antitumor T cell immunity, which were functionally validated by T cell stimulation assays in vitro. Together, this study presents a framework for tumor antigen prediction based on in situ and in silico TIL TCR analyses. We propose that TCR-based investigations should inform tumor classification and precision immunotherapy development.
Palmoplantar epidermal differentiation disorders: a new classification towards pathogenesis-based therapy
Authors: Eli Sprecher, Akemi Ishida-Yamamoto, Janice Schwartz, Masashi Akiyama, Mandy Aldwin-Easton, Keith Choate, Judith Fischer, Antoni Gostyński, Céline Granier Tournier, Angela Hernandez-Martin, Alain Hovnanian, Kiril Malovitski, Juliette Mazereeuw-Hautier, Amy S Paller, Matthias Schmuth, Gianluca Tadini, Joyce Teng, Christine Bodemer, Edel A O’Toole
Journal: British Journal of Dermatology (2025)

Abstract More than 50 palmoplantar epidermal differentiation disorders (pEDDs) have been reported in the literature. Various descriptors have been used to name these conditions including clinical features often designated as acronyms or evocative terms, names of clinicians and of geographical locations. Not only has this nomenclature been criticized for its lack of methodological consistency, it has progressively lost its clinical relevance. Indeed, the advent of a wide range of pathogenesis-targeting therapeutic solutions for these disorders has raised the need for a novel classification of pEDDs, based on their causative genetic defects, to provide clinicians with genuine therapeutic guidance. Here, we present a novel classification scheme for pEDDs and its application in the form of a practical algorithm for the rapid diagnosis of pEDDs.
Low rates of chronic graft-versus-host disease with ruxolitinib maintenance following allogeneic HCT
Authors: Zachariah DeFilipp, Haesook T Kim, Laura W. Knight, Suzanne M. O'Connor, Shilton E. Dhaver, Meghan White, Bhagirathbhai Dholaria, Mark A Schroeder, Sumithira Vasu, Sameem M Abedin, Jooho Chung, Areej El-Jawahri, Matthew J. Frigault, Steven L. McAfee, Richard A. Newcomb, Paul V O'Donnell, Thomas R. Spitzer, Yi-Bin Chen, Gabriela S Hobbs
Journal: Blood (2025)