tbuckley/cabot-search huggingface dataset:
Abstract B026: NEBNext® enzymatic solutions for DNA methylation profiling at picogram scale
Authors: Vaishnavi panchapakesa, Chaithanya Ponnaluri, Daniel Evanich, Matthew Campbell, Laura Blum, Bradley Langhorst, Louise Williams
Journal: Cancer Research (2025)

Abstract DNA methylation is an important epigenetic regulator of gene expression. 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) play distinct roles in epigenetic regulation, however the ability to distinguish between 5mC and 5hmC is often lost as they are frequently read as a combined signal in traditional sequencing approaches. NEBNext Enzymatic Methyl-seq v2 (EM-seq v2) and NEBNext Enzymatic 5hmC-seq (E5hmC-seq) are enzymatic approaches used to investigate cytosine methylation. EM-seq v2 detects both 5mC and 5hmC whereas E5hmC-seq detects only 5hmC. The first step for each method protects either 5mC and/or 5hmC from deamination by APOBEC enzyme. Cytosines are deaminated to uracil in EM-seq v2 whereas for E5hmC-seq, 5mC and cytosine bases are converted to thymine and uracil respectively. Using a subtractive data analysis approach, whereby E5hmC-seq data is subtracted from EM-seq data, the locations of 5mC and 5hmC can be decoupled at single base resolution. EM-seq v2 libraries and E5hmC-seq libraries were prepared using 0.1 ng to 200 ng of genomic DNA. Both methods leave DNA intact and result in superior sequencing libraries with longer insert sizes, lower duplication rates and minimal GC bias as well as accurately detecting methylation down to 0.1 ng DNA. These methods are streamlined due to reduced library preparation time as well as the removal of a cleanup step. Coverage of genomic features such as CpG islands and enhancers, for both methods were maintained to 1 ng but dropped as expected with the 0.1 ng inputs. EM-seq v2 and E5hmC-seq provides consistent methylation metrics for inputs ranging from 0.1 ng to 200 ng. EM-seq v2 and E5hmC-seq libraries provide accurate measurements across inputs from 0.1 ng – 200 ng with expected methylation, insert sizes and minimal GC bias. In addition, combining E5hmC-seq and EM-seq data to discriminate between 5mC and 5hmC will provide key insights into the role of these cytosine modifications in development and disease. Citation Format: Vaishnavi panchapakesa, Chaithanya Ponnaluri, Daniel Evanich, Matthew Campbell, Laura Blum, Bradley Langhorst, Louise Williams. NEBNext® enzymatic solutions for DNA methylation profiling at picogram scale [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B026.
Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Authors: Florencia P. Madorsky Rowdo, Rachel Martini, Sarah E. Ackermann, Colin P. Tang, Marvel Tranquille, Adriana Irizarry, Ilkay Us, Omar Alawa, Jenna E. Moyer, Michael Sigouros, John Nguyen, Majd Al Assaad, Esther Cheng, Paula S. Ginter, Jyothi Manohar, Brian Stonaker, Richard Boateng, Joseph K. Oppong, Ernest K. Adjei, Baffour Awuah, Ishmael Kyei, Francis S. Aitpillah, Michael O. Adinku, Kwasi Ankomah, Ernest B. Osei-Bonsu, Kofi K. Gyan, Syed Hoda, Lisa Newman, Juan Miguel Mosquera, Andrea Sboner, Olivier Elemento, Lukas E. Dow, Melissa B. Davis, M. Laura Martin
Journal: Cancer Research (2025)

Abstract Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407
In Search of Representative Translational Cancer Model Systems
Authors: Hannah E. Trembath, Philip M. Spanheimer
Journal: Cancer Research (2025)

Racial disparities in cancer outcomes are well documented across tumor types. For patients with breast cancer, Black women are more likely to present with more aggressive molecular features and more likely to die from disease, even after accounting for those features. Recent efforts have been aimed at developing translational model systems for precision medicine strategies, and a major focus has been on patient-derived organoids. Organoids allow for robust in vitro experimental platforms, including drug and CRISPR screens while maintaining more complex cancer and tumor microenvironment subpopulations than cell lines. For results that are broadly translationally relevant, it is important that cancer models are derived from the spectrum of human disease and humans with disease. In this issue of Cancer Research, Madorsky Rowdo and colleagues derive breast cancer organoids from patients with African ancestry and use CRISPR-Cas9 screens to identify novel therapeutic vulnerabilities. These findings demonstrate the promise of representative cancer model systems to facilitate discoveries that are most likely to translate to improved therapy for all patients. See related article by Madorsky Rowdo et al., p. 551
Reduced organ damage accumulation in adult patients with SLE on anifrolumab plus standard of care compared to real-world external controls
Authors: Zahi Touma, Ian N Bruce, Richard Furie, Eric Morand, Raj Tummala, Shelly Chandran, Gabriel Abreu, Jacob Knagenhjelm, Kellyn Arnold, Hopin Lee, Eleanor Ralphs, Aleksandr Bedenkov, Danuta Kielar, Miina Waratani
Journal: Annals of the Rheumatic Diseases (2025)

Anifrolumab is approved for the treatment of systemic lupus erythematosus (SLE). We aimed to determine if anifrolumab plus standard of care (SOC) was associated with reduced organ damage accumulation in adult patients with moderately to severely active SLE compared to real-world (RW) external controls from the University of Toronto Lupus Clinic (UTLC) cohort who received SOC only. Patients who initiated 300 mg anifrolumab in the TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) trials were included in the anifrolumab arm; key eligibility criteria were applied to the UTLC to create the RW SOC arm. Propensity score and censoring weighting were used to account for baseline confounding and loss to follow-up. The primary endpoint was change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to week 208, and the secondary endpoint was time to first SDI score increase. 354 patients were included in the anifrolumab arm, and 561 patients were included in the RW SOC arm. Following weighting, mean change in SDI was 0.416 points lower (95% CI: -0.582, -0.249; P < .001) in the anifrolumab arm than in the RW SOC arm. Patients in the anifrolumab arm were 59.9% less likely (hazard ratio: 0.401; 95% CI: 0.213, 0.753, P = .005) to experience an increase in SDI within 208 weeks. Patients who received anifrolumab accumulated significantly less organ damage after 208 weeks than patients who received RW SOC. The addition of anifrolumab to SOC is effective at preventing and/or delaying organ damage in patients with moderately to severely active SLE.
Trogocytosis of chimeric antigen receptors between T cells is regulated by their transmembrane domains
Authors: Stefano Barbera, Matthijs J. A. Schuiling, Nathaniel A. Sanjaya, Ilkka Pietilä, Tina Sarén, Magnus Essand, Anna Dimberg
Journal: Science Immunology (2025)

Trogocytosis is an exchange of membrane-associated molecules between cells that can either halt or boost immune responses. However, the mechanism that regulates trogocytosis in T cells and its consequences are not yet clear. Here, we demonstrate that T cells can exchange chimeric antigen receptors (CARs) by trogocytosis, thereby arming recipient T cells with the capacity to respond to tumor antigens by up-regulating proteins associated with a cytotoxic response and killing of target cells. We demonstrate that although trogocytosis is dependent on cell-cell contact, the exchange of a specific cell membrane protein does not require a cognate binding partner on the surface of recipient cells. Instead, the probability that a protein is exchanged by trogocytosis is determined by its transmembrane domain. This finding opens new avenues for modulating this process in CAR-T cells.
Annexin A1 in neurological disorders: Neuroprotection and glial modulation
Authors: Luiz Philipe de Souza Ferreira, Rafael André da Silva, Pâmela Pacassa Borges, Luana Filippi Xavier, Pablo Scharf, Silvana Sandri, Sonia M Oliani, Sandra H P Farsky, Cristiane D Gil
Journal: Pharmacology & Therapeutics (2025)
Endocrine dysfunction in primary mitochondrial diseases
Authors: Rachel Varughese, Shamima Rahman
Journal: Endocrine Reviews (2025)

Primary mitochondrial disorders (PMD) are genetic disorders affecting the structure or function of the mitochondrion. Mitochondrial functions are diverse, including energy production, ion homeostasis, reactive oxygen species regulation, antioxidant defence, and biosynthetic responsibilities, notably including steroidogenesis. Mitochondria provide the energy to drive intracellular production and extracellular secretion of all hormones. The understanding of the endocrine consequences of PMD is key to timely identification of both endocrine complications in PMD patients, and PMD presenting primarily with endocrine disease. This is a narrative review on the endocrine manifestations of PMD, underlying disease mechanisms and current and emerging approaches to diagnosing and treating these complex disorders. Diabetes is the most frequent endocrine manifestation of PMD, but growth hormone deficiency, adrenal insufficiency, hypogonadism and parathyroid dysfunction may occur. Despite the intricate involvement of the thyroid gland in metabolic regulation, there is little evidence for a causal relationship between thyroid dysfunction and PMD. In conclusion, endocrine dysfunction is observed in PMD with varying incidence depending on the specific mitochondrial disorder and the endocrine organ in question. Diagnosis of PMD in a patient with endocrine presenting features requires a high level of clinical suspicion, particularly when apparently unrelated co-morbidities co-exist. Similarly, endocrine pathology may be subtle in patients with known PMD and thorough consideration must be given to ensure timely diagnosis and treatment. The scope for novel therapeutics for this group of devastating conditions is enormous, however, several challenges remain to be overcome before hopes of curative treatments can be brought into clinical practice.
Genetics of human handedness: microtubules and beyond
Authors: Sebastian Ocklenburg, Annakarina Mundorf, Jutta Peterburs, Silvia Paracchini
Journal: Trends in Genetics (2025)

HighlightsHuman handedness is a moderately heritable trait.Large-scale genome-wide association and exome sequencing studies have identified multiple genes associated with handedness and highlighted a role of tubulin genes.Axon guidance, axon growth, and forming the inner structure of motile cilia are key processes regulated by tubulin genes that may also be relevant for handedness,Tubulin genes are associated with several psychiatric disorders which may offer insights into biological pathways mediating the link between handedness, brain asymmetries, and psychiatric disorders.AbstractHandedness (i.e., the preference to use either the left or the right hand for fine motor tasks) is a widely investigated trait. Handedness heritability is consistently estimated to be 25%. After decades of research, recent large-scale genome-wide association and exome sequencing studies have identified multiple genes associated with handedness and highlighted tubulin genes. Tubulin genes play a role in several processes during brain development that may be relevant for handedness ontogenesis, including axon guidance, axon growth, and forming the inner structure of motile cilia. Moreover, tubulin genes are associated with several psychiatric disorders. This finding therefore may offer insights into biological pathways mediating the link between handedness, brain asymmetries, and psychiatric traits.
Dysfunctional KLRB1+CD8+ T-cell responses are generated in chronically inflamed systemic sclerosis skin
Authors: Alyxzandria M Gaydosik, Tracy Tabib, Jishnu Das, Adriana Larregina, Robert Lafyatis, Patrizia Fuschiotti
Journal: Annals of the Rheumatic Diseases (2025)

To analyse the immune mechanisms of diffuse cutaneous systemic sclerosis (dcSSc) skin disease focusing on CD8+ T-cell responses in the affected skin of patients because chronic inflammation, vasculopathy, and extensive cutaneous fibrosis are prominent features of dcSSc skin disease, causing pain and disability in patients, with no effective therapy. Single-cell transcriptomics and epigenomics were applied to well-characterised patient skin samples to identify transcriptomes and key regulators of skin-resident CD8+ T-cell subsets. Multicolor immunofluorescence miscoscopy was used to validate molecular findings. Ex vivo skin explant assays were used to functionally characterise dysfunctional CD8+ T-cell subsets on nonlesional autologous skin. We identified 2 major developmentally connected CD8+ T-cell subpopulations that were expanded in SSc skin lesions compared with healthy control skin. The first was a heterogeneous subset of effector-memory CD8+KLRB1+IL7R+ cells characterised by increased cytolytic and Tc2/Tc17 effector functions that appear to induce tissue damage and fibrosis in early-stage dcSSc skin lesions. The second, found primarily in patients with late-stage disease, was an exhausted CD8+KLRG1+IL7R- subset that exhibited transcriptional features of long-lived effector cells, likely contributing to chronic inflammation. Significantly, both subsets were also expanded in other benign dermatoses, implicating these cell populations in the pathogenesis of chronic human skin inflammation. This study provides new insight into core regulatory programmes modulating skin-resident CD8+ T-cell plasticity and identifies distinct CD8+ T-cell subpopulations that contribute to initiation and chronicity of inflammatory responses in systemic sclerosis skin lesions. These findings reveal prospective molecular targets for new therapeutic strategies against this incurable disease.
Post hoc comparison of the effectiveness of tocilizumab, rituximab, mycophenolate mofetil, and cyclophosphamide in patients with SSc-ILD from the EUSTAR database
Authors: Qingran Yan, Cosimo Bruni, Alexandru Garaiman, Carina Mihai, Suzana Jordan, Mike Oliver Becker, Muriel Elhai, Rucsandra Dobrota, Petelytska Liubov, Joerg Henes, Eric Hachulla, Elise Siegert, Alexandra Balbir-Gurman, Giovanna Cuomo, Gabriela Riemekasten, Stefan Heitmann, Davide Mohammad Reza Beigi, Susanne Ullman, Petros Sfikakis, Francesca Ingegnoli, Vera Bernardino, Marie-Elise Truchetet, Madelon Vonk, Francesco Del Galdo, Anna-Maria Hoffmann-Vold, Ye Shuang, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2025)

Tocilizumab (TCZ), rituximab (RTX), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) are the immunosuppressants (IS) most frequently used for systemic sclerosis-associated interstitial lung disease (SSc-ILD). This post hoc study aimed to compare their effectiveness in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database. We included radiologically confirmed SSc-ILD patients with treatment records for TCZ, RTX, MMF, or CYC. The primary endpoint was the change in forced vital capacity (FVC) percent predicted from baseline to follow-up. Analyses were adjusted for clinical and demographic characteristics, cotreatments, and follow-up duration using propensity score-based inverse probability of treatment weighting (IPTW). Nine hundred fifty-five patients with 997 treatment observations were included in the study. The median follow-up time was 11 months (IQR, 8-14 months). After IPTW, the changes in FVC percent predicted were not significantly different in the multigroup comparison (P = .101). Paired comparisons showed no significant difference. CYC was associated with stable FVC in logistic regression. For subgroup analysis, the treatment differences in change of FVC percent predicted among the 4 groups were not significant in patients with combination IS or previous exposure to TCZ, RTX, or conventional IS, as well as in current smokers or nonsmokers, and regardless of whether observations started either at the initiating or noninitiating stage of the treatment. In this first large real-world study, the effectiveness of TCZ, RTX, MMF, and CYC on FVC change in SSc-ILD patients was not statistically different.
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions
Authors: Isabel Lam, Alain Ndayisaba, Amanda J. Lewis, YuHong Fu, Giselle T. Sagredo, Anastasia Kuzkina, Ludovica Zaccagnini, Meral Celikag, Jackson Sandoe, Ricardo L. Sanz, Aazam Vahdatshoar, Timothy D. Martin, Nader Morshed, Toru Ichihashi, Arati Tripathi, Nagendran Ramalingam, Charlotte Oettgen-Suazo, Theresa Bartels, Manel Boussouf, Max Schäbinger, Erinc Hallacli, Xin Jiang, Amrita Verma, Challana Tea, Zichen Wang, Hiroyuki Hakozaki, Xiao Yu, Kelly Hyles, Chansaem Park, Xinyuan Wang, Thorold W. Theunissen, Haoyi Wang, Rudolf Jaenisch, Susan Lindquist, Beth Stevens, Nadia Stefanova, Gregor Wenning, Wilma D.J. van de Berg, Kelvin C. Luk, Rosario Sanchez-Pernaute, Juan Carlos Gómez-Esteban, Daniel Felsky, Yasujiro Kiyota, Nidhi Sahni, S. Stephen Yi, Chee Yeun Chung, Henning Stahlberg, Isidro Ferrer, Johannes Schöneberg, Stephen J. Elledge, Ulf Dettmer, Glenda M. Halliday, Tim Bartels, Vikram Khurana
Journal: Neuron (2025)
Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation
Authors: Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D’Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M. Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M. Casey, ChakShun Yu, Siva Swapna Kasarla, Karl William Smith, Ayten Kalfe-Yildiz, Martin Stenzel, Antonio Miranda-Vizuete, Roland Hergenröder, Prasad Phapale, Olivera Stanojlovic, Ivana Ivanovic-Burmazovic, Marija Vlaski-Lafarge, Sofia-Iris Bibli, Michael P. Murphy, Vesna Otasevic, Milos R. Filipovic
Journal: Cell Metabolism (2025)
Lipidomics unravels lipid changes in osteoarthritis articular cartilage
Authors: Qiongfei Zhou, Mohan Ghorasaini, Frederique M F Cornelis, Reem Assi, Astrid de Roover, Martin Giera, Silvia Monteagudo, Rik J Lories
Journal: Annals of the Rheumatic Diseases (2025)

Osteoarthritis (OA) is linked to disrupted lipid metabolism. We aimed to profile the lipid composition of human articular cartilage, investigate OA-associated lipidome changes, and explore biological effects. Lipidomic profiling and computational analyses were performed on human articular chondrocytes (hACs) from non-OA (n = 13) and OA (n = 14) hips. Lipid changes were confirmed in the destabilisation of the medial meniscus (DMM) mouse model. The effect of specific lipids was evaluated by in vitro supplementation and gene silencing. We identified 573 lipid species covering 11 lipid classes in hACs. OA and non-OA hACs showed distinct lipid profiles. Most ceramides and dihydroceramides were increased, while cholesteryl esters, diacylglycerols, triacylglycerols, sphingomyelins, hexosylceramides, and lactosylceramides were predominantly decreased in OA chondrocytes. Most upregulated lipids in OA contained C18:1, C20:4, or C22:4 side chains. Many downregulated lipids contained C18:2 or odd-chain C17:0. Lipid profiling of articular cartilage from the DMM mouse model paralleled changes in OA hACs, including odd-chain C17:0 reduction. Further analysis showed that deficiency in enzyme 2-hydroxyacyl-CoA lyase 1 (HACL1), responsible for odd-chain fatty acid synthesis, leads to accumulation of 2-hydroxy C18:0, precursor of C17:0, which results in a shift in hACs from an anabolic to a catabolic state. Our study maps the hAC lipid composition and highlights changes in lipid profiles associated with OA. Dysregulation of certain lipids, especially odd-chain fatty acids, linked to a deficiency in the enzyme HACL1, leads to pathological changes. This understanding opens potential avenues for therapies aimed at targeting lipid imbalances to slow down or treat OA.
An antigen-capturing and lymph node-targeting nanoparticle for cancer immunotherapy
Authors: Zhen Zhang, Chen Xu, Ningqiang Gong, Guangchao Qing, Yuxuan Zhang, Yuxuan Shi, Jacob S Brenner, Fangzhou Li, Fu-Jian Xu, Xing-Jie Liang
Journal: Journal of Controlled Release (2025)
Wearable microfluidic biosensors with haptic feedback for continuous monitoring of hydration biomarkers in workers
Authors: Julia C. Spinelli, Brandon J. Suleski, Donald E. Wright, Joseph L. Grow, Gabriel R. Fagans, Maura J. Buckley, Da Som Yang, Kaitao Yang, Steven M. Beil, Jessica C. Wallace, Thomas S. DiZoglio, Jeffrey B. Model, Shirley Love, David E. Macintosh, Alan P. Scarth, Matthew T. Marrapode, Corinna Serviente, Raudel Avila, Barrak K. Alahmad, Michael A. Busa, John A. Wright, Weihua Li, Douglas J. Casa, John A. Rogers, Stephen P. Lee, Roozbeh Ghaffari, Alexander J. Aranyosi
Journal: npj Digital Medicine (2025)

Real-time monitoring of hydration biomarkers in tandem with biophysical markers can offer valuable physiological insights about heat stress and related thermoregulatory response. These metrics have been challenging to achieve with wearable sensors. Here we present a closed-loop electrochemical/biophysical wearable sensing device and algorithms that directly measure whole-body sweat loss, sweating rate, sodium concentration, and sodium loss with electrode arrays embedded in a microfluidic channel. The device contains two temperature sensors for skin temperature and thermal flux recordings, and an accelerometer for real-time monitoring of activity level. An onboard haptic module enables vibratory feedback cues to the wearer once critical sweat loss thresholds are reached. Data is stored onboard in memory and autonomously transmitted via Bluetooth to a smartphone and cloud portal. Field studies conducted in physically demanding activities demonstrate the key capabilities of this platform to inform hydration interventions in highly challenging real-world settings.