tbuckley/cabot-search huggingface dataset:
Abstract LB309: Differential DNA methylation analysis and functional insights in luminal A and triple-negative breast cancer using FFPE samples
Authors: Yangbo Sun, Khyobeni Mozhui, Jay H. Fowke, Saunak Sen, Karen C. Johnson
Journal: Cancer Research (2025)

Abstract Background: Epigenetic modifications, such as DNA methylation, play a critical role in breast cancer heterogeneity, influencing tumor progression and therapeutic responses. This study investigates differential methylation patterns between luminal A (LumA) and triple-negative breast cancer (TNBC) subtypes using formalin-fixed, paraffin-embedded (FFPE) samples. Functional insights are derived through gene ontology and pathway analyses to understand subtype-specific epigenetic mechanisms. Methods: Genome-wide methylation profiling was performed on FFPE samples of LumA (n=3) and TNBC (n=5) cases using the Illumina Infinium EPIC array. Differentially methylated CpG sites were identified, and gene ontology analysis and pathway enrichment analyses were conducted on genes annotated to differentially methylated CpG sites to identify biological processes and pathways driving subtype differences. Results: Among the 937,690 original probes, 319,514 probes failed in at least one sample and were excluded from further analysis, thus, 618,176 probes were kept for analysis. A total of 28,801 differentially methylated CpG sites were identified between LumA and TNBC cases, with a threshold on methylation differences of 10%. A total of 12,772 genes were associated with the 28,801 significant differentially methylated probes identified between LumA and TNBC. Key enriched gene oncology terms included "small GTPase-mediated signal transduction ", " regulation of trans-synaptic signaling”, and “actin filament organization”, highlighting subtype-specific epigenetic regulation of tumor biology. Pathway analysis revealed significant enrichment of pathways such as "RHO GTPase cycle" and “RAC1 GTPase cycle” in TNBC, consistent with their distinct tumor microenvironments. Conclusions: This study highlights distinct methylation patterns in LumA and TNBC subtypes, reflecting their divergent biological and clinical behaviors. The identified pathways provide insights into potential therapeutic targets and biomarkers for precision oncology and the ability to obtain DNA methylation data from formalin-fixed, paraffin-embedded (FFPE) samples. Future work will validate these findings in larger, independent cohorts and explore their clinical applicability. Citation Format: Yangbo Sun, Khyobeni Mozhui, Jay H. Fowke, Saunak Sen, Karen C. Johnson. Differential DNA methylation analysis and functional insights in luminal A and triple-negative breast cancer using FFPE samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB309.
Abstract LB311: Dissecting and targeting EZH2’s non-canonical oncogenic activity in cancers
Authors: Arum Kim, G Greg Wang
Journal: Cancer Research (2025)

Abstract In many human cancer types, expression of Enhancer of Zeste Homolog 2 (EZH2) is well correlated with poorer outcomes. Furthermore, ∼20-25% of patients with diffuse large B-cell lymphoma (DLBCL) contain somatic mutation of EZH2 at the Tyr-646 residue within its catalytic SET domain, leading to EZH2 gain-of- function (GOF). Thus, EZH2 represents a prominent onco-target and small-molecule inhibitors targeting its enzymatic activity are under clinical evaluation, with some (i.e. tazemetostat) FDA-approved for the treatment of lymphoma and epithelial sarcoma. However, these EZH2 enzymatic inhibitors often face issues, such as ineffectiveness or resistance, and new treatment strategies targeting EZH2 are urgently needed. Traditionally, EZH2 is viewed as a catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which induces trimethylation of histone H3 lysine 27 (H3K27me3) for repressing the target gene expression such as tumor-suppressive and immune-related genes. We recently have shown that EZH2’s oncogenic functions go well beyond PRC2 and its enzymatic function for H3K27me3 deposition and has the new PRC2-independent activity (non-canonical) to sustain oncogenesis. We show that the non-canonical function of EZH2 partly rely on transcriptional activation domains (tADs) of EZH2, which physically interacts with oncogene (co)activators, to turn on the oncogenic signaling. Our unpublished data point to increased Myc signaling as well as cancer metabolism enhancement such as lipid metabolism. We demonstrate such non-canonical oncogenic activity of EZH2 in blood cancers (including DLBCL) and solid tumors, which may explain why the current enzymatic inhibitors of EZH2 have rather limited antitumor effect. To develop a more effective therapeutic strategy in which both the canonical and noncanonical activities of EZH2 can be targeted, we employ the Proteolysis Targeting Chimera (PROTAC) technology and developed novel EZH2-targeted PROTAC degraders. EZH2-targeted PROTACs induced the EZH2 degradation and target the aberrant gene expression from both canonical and non-canonical activities of EZH2, leading to more effective, more consistent growth inhibition in tumors, and to a much greater degree when compared to EZH2 methyltransferase inhibitors. Collectively, this work uncovers an unexplored function of EZH2 in sustaining tumorigenesis via enhancing non-canonical oncogenic signaling. Indeed, our data support EZH2 PROTAC to be an attractive therapeutic candidate for cancer treatments. Citation Format: Arum Kim, G Greg Wang. Dissecting and targeting EZH2’s non-canonical oncogenic activity in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB311.
Abstract LB213: Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy
Authors: Shushu Zhao, Yeqing Chen, Pratik S. Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel Park, Meenhard Herlyn, David B. Weiner
Journal: Cancer Research (2025)

Abstract Melanoma is a highly aggressive skin cancer, especially diagnosed in advanced stages. While current treatments such as targeted therapies and immunotherapies have made promising progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is crucial. In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13Rα2) in melanoma patient-derived xenograft (PDX) models. Our findings revealed heterogeneous expression of IL13Rα2, particularly in samples from advanced stages of melanoma. Then we investigated IL13Rα2 as a potential target for melanoma treatment by employing an IL13Rα2-CD3 bispecific T cell engager (BTE). We tested the effect of IL13Rα2-CD3 BTE to T cells activity by flow cytometry. The IL13Rα2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T-cells. We studied the potency of IL13Rα2-CD3 BTE in tumor killing assay in vitro. We also observed the ability of IL13Rα2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. For in vivo studies, we administered DNA expression constructs encoding IL13Rα2-CD3 BTE (IL13Rα2-CD3 dBTE) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL13Rα2-CD3 dBTE versus control and reconstituted with human PBMCs or T cells. Tumor development was monitored, and T cells infiltration in tumor was analyzed through flow cytometry. IL13Rα2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor microenvironment. These promising findings underscore the potential of targeting IL13Rα2 as a relevant target for the development of biologics including dBTE aimed at treating specific subsets of melanoma. Citation Format: Shushu Zhao, Yeqing Chen, Pratik S. Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel Park, Meenhard Herlyn, David B. Weiner. Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB213.
Abstract LB209: Dynamic STING repression orchestrates immune cell functionality across development and maturation
Authors: Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan
Journal: Cancer Research (2025)

Abstract Stimulator of Interferon Genes (STING) is a critical component of the innate immune system. Mechanisms of STING-mediated type I interferon (IFN-I) signaling during infection are well studied in myeloid cells. However, homeostatic STING expression patterns and their regulation, particularly in lymphoid cells, are unknown. We established a Sting1IRES-EGFP reporter mouse to systematically characterize STING expression spatially in tissues and temporally along development of immune cells. Using this reporter and conditional Sting1 transgenic mouse models, we show that STING expression is repressed in neutrophils and forced STING signaling and expression drives systemic inflammatory disease due to secretion of cytokines and chemokines by neutrophils. Additionally, we show that STING expression is temporally restricted during T lymphocyte development at the double positive stage. Forced STING expression and signaling severely impairs T lymphocyte development and reduces thymopoiesis independent of the type I IFN receptor (IFNAR1). Mechanistically, STING expression in the thymus is controlled via epigenetic silencing by DNA methyltransferase 1 (DNMT1). Forced STING signaling in the thymus favors lineage commitment to innate-like γδ T cells rather than adaptive αβ T cells, revealing a previously unanticipated role of STING in T lymphocyte fate choice. Using two syngeneic tumor models and a cohort of human colorectal cancer patients, we found that tumor-infiltrating CD8+ T lymphocytes gradually repress STING expression as a tumor grows and loss of STING expression strongly correlates with CD8+ T cell exhaustion. Together, our data demonstrates the physiological importance of controlled, rather than ubiquitous STING expression and uncovers STING expression dynamics as an important new dimension of STING pathobiology. Citation Format: Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan. Dynamic STING repression orchestrates immune cell functionality across development and maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB209.
Drivers and mechanisms of cognitive decline in chronic kidney disease
Authors: Giovambattista Capasso, Casper F M Franssen, Alessandra F Perna, Ziad A Massy, Robert I Menzies, Carmine Zoccali, Alessandro Tessitore, Maiken Nedergaard, Mark D Okusa, Alberto Ortiz, Carsten A Wagner, Robert J Unwin
Journal: Nature Reviews Nephrology (2025)
Is the Current Lifestyle Modification Approach to Diabetes Prevention in the U.S. a Success?
Authors: Justin B. Echouffo-Tcheugui, Rosette J. Chakkalakal, Mohammed K. Ali
Journal: Diabetes Care (2025)

Prediabetes is an intermediate stage between normal glycemia and diabetes and is highly prevalent, especially in adults, but is also increasingly common in young individuals. Randomized clinical trials have demonstrated that lifestyle modification is cost-effective in preventing diabetes. Implementation studies showed the feasibility of delivering real-world structured lifestyle modification programs adapted from the U.S. Diabetes Prevention Program trial. However, the current approach to diabetes prevention in the U.S. has been largely inadequate thus far, as evidenced by the stagnant numbers of people with prediabetes and the growing number of those with diabetes. The many gaps in the implementation of the National Diabetes Prevention Program (NDPP) can be characterized as due to macro-level barriers (failures of pay-for-performance reimbursement, an undersupply of lifestyle change programs), micro-level barriers (low and disparate reach, low referral and retention rates in the program), variable fidelity in implementation, and limitations of a one-size-fits-all intervention. All of these issues point to a need for reexamining strategies for diabetes prevention in the U.S., which is yet to show benefits or value at the population level. This article details how prediabetes is currently suboptimally addressed in clinical practice and communities in the U.S. and articulates why there is an urgent need to rethink our approach to addressing prediabetes, possibly through integration of synergistic individual- and societal-levels approaches.
Capillary Ketone Level and Future Ketoacidosis Risk in Patients With Type 1 Diabetes Using Sodium–Glucose Cotransporter Inhibitors
Authors: Priya Bapat, Sharon Dhaliwal, Cimon Song, Yucheng Zhang, Daniel Scarr, Abdulmohsen Bakhsh, Dalton Budhram, Natasha J. Verhoeff, Alanna Weisman, Michael Fralick, Noah M. Ivers, David Z.I. Cherney, George Tomlinson, Doug Mumford, Leif Erik Lovblom, Bruce A. Perkins
Journal: Diabetes Care (2025)

OBJECTIVE We aimed to determine if routine capillary blood ketone testing on well days predicts future diabetic ketoacidosis (DKA) in type 1 diabetes (T1D) using sodium–glucose cotransporter inhibitors (SGLTi). RESEARCH DESIGN AND METHODS We examined previously collected data from empagliflozin-assigned participants in a T1D trial that included weekly fasted ketone levels. Over 6–12 months, ketone levels were subdivided into 28-day periods, and the outcome was subsequent adjudicated DKA or severe ketosis. RESULTS Among 1,194 participants, 325 had 49 DKA and 568 severe ketosis events. On-treatment maximum ketone levels were higher in the 28 days before an outcome compared with levels in those without an outcome, with area under receiver operating characteristic curve of 0.76 (95% CI 0.71–0.82). Maximum ketone level ≥0.8 mmol/L had sensitivity of 66.0%, specificity of 79.6%, and diagnostic odds ratio of 7.6. CONCLUSIONS Routine surveillance of capillary ketone levels in T1D using SGLTi may represent a DKA mitigation strategy and implies a potential threshold for continuous ketone monitoring.
Selective JAK1 inhibition remits multiorgan autoimmunity in a patient with refractory autoimmune polyendocrine syndrome type 1
Authors: Yannis Hadjiyannis, Madison N Martinez, Joseph Pechacek, Ibrahim Abukhiran, Deanna Riley, Stefania Pittaluga, Elena M Morariu, Michail S Lionakis, David G Binion, Reed Van Deusen
Journal: Journal of Allergy and Clinical Immunology (2025)
Youth-Onset Type 2 Diabetes: What We’ve Learned From Key Youth-Onset Type 2 Diabetes Studies, What We Still Don’t Know, and Why It Is Important
Authors: Kristen J. Nadeau, Elizabeth J. Mayer-Davis, Rose Gubitosi-Klug, Philip S. Zeitler, Steven E. Kahn, Dana Dabelea
Journal: Diabetes Care (2025)

In this review, we describe the epidemiology, pathophysiology, pediatric-specific treatment response data, morbidity, and mortality of youth-onset type 2 diabetes. In recognition of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 75th anniversary, the focus is primarily on data from three landmark youth-onset type 2 diabetes studies funded by the NIDDK in the last 20+ years. We discuss the now-recognized aggressive clinical course of youth-onset type 2 diabetes, which only recently became appreciated as a pediatric disease among health care providers. We highlight the similarities and differences between youth-onset and adult-onset type 2 diabetes, in particular how type 2 diabetes in youth appears to have an accelerated clinical course with earlier onset of complications in comparison with adult-onset type 2 diabetes; how these findings influenced the care and treatment recommendations for youth with type 2 diabetes; and how the many lessons from these studies, in turn, highlight remaining unanswered questions. We feature recent findings regarding long-term follow-up of diabetes complications in these youth, and how they differ from youth with type 1 diabetes. Finally, we conclude with an overview of emerging studies and topics in type 2 diabetes research that have potential to inform effective preventive action strategies.
The NIDDK Takes on the Complications of Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
Authors: Barbara H. Braffett, Ionut Bebu, Gayle M. Lorenzi, Catherine L. Martin, Bruce A. Perkins, Rose Gubitosi-Klug, David M. Nathan
Journal: Diabetes Care (2025)

In the Diabetes Control and Complications Trial (DCCT) (1983–1993), intensive therapy aimed at near-normal glycemia was compared with conventional therapy in 1,441 adolescent and adult participants with type 1 diabetes (T1D) over a mean follow-up of 6.5 years. The primary DCCT results, reported in 1993, demonstrated the benefits of intensive therapy (mean HbA1c ∼7%) compared with conventional therapy (HbA1c ∼9%) in reducing the risk of development and progression of microvascular complications by 35%–76%. HbA1c &amp;lt;7% was adopted worldwide as the therapeutic target for T1D. Subsequently, the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994–present) was initiated as the observational follow-up of the DCCT cohort. EDIC has shown that the early beneficial effects of intensive versus conventional therapy on complications persisted for ∼10 years after the convergence of HbA1c levels in the two groups during EDIC—a novel concept termed “metabolic memory.” During EDIC, prior intensive therapy was also shown to reduce the risk of severe microvascular complications, cardiovascular disease, mortality, and, recently, of age-related outcomes including cognitive impairment, bone loss, and reduced mobility. The DCCT/EDIC cohort is the most extensively studied T1D cohort in history. The participants have been followed and deeply phenotyped for 95% of their diabetes durations and 65% of their lifespans. Throughout its 40+ years, funded by and in close collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases, DCCT/EDIC has generated results that have guided treatment priorities in T1D and led to improved survival and quality of life for millions of people with T1D worldwide.
Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multiancestry Population Cohorts
Authors: Amber M. Luckett, Richard A. Oram, Aaron J. Deutsch, Hector I. Ortega, Diane P. Fraser, Kaavya Ashok, Alisa K. Manning, Josep M. Mercader, Manuel A. Rivas,, Miriam S. Udler, Michael N. Weedon, Anna L. Gloyn, Seth A. Sharp
Journal: Diabetes Care (2025)
Lipidomic Markers of Processed Meat and Unprocessed Red Meat Intake and Risk of Diabetes in American Indians
Authors: Xiaoxiao Wen, Guanhong Miao, Amanda M. Fretts, Mingjing Chen, Ying Zhang, Jason G. Umans, Shelley A. Cole, Lyle G. Best, Oliver Fiehn, Jinying Zhao
Journal: Diabetes Care (2025)

OBJECTIVE To identify lipidomic markers of habitual unprocessed red meat and processed meat intake and evaluate their associations with diabetes risk in American Indians. RESEARCH DESIGN AND METHODS We studied 1,816 participants from the Strong Heart Family Study. Using untargeted liquid chromatography-mass spectrometry, we quantified 1,542 lipids (518 known) in fasting plasma at baseline and follow-up (∼5 years apart). Meat intake was assessed via Food Frequency Questionnaires. Mixed-effects linear regression was used to identify lipids associated with meat consumption. Mixed-effects logistic regression was used to examine whether these lipids were associated with incident diabetes, independent of conventional risk factors, or with longitudinal glucose/insulin metrics. RESULTS Diabetes developed in 66 of 1,076 participants with normal baseline glucose. After multiple testing correction, 15 known lipids, primarily plasmalogens, were associated with unprocessed red meat intake. Three plasmalogens were linked to incident diabetes (odds ratio [OR] 1.32 [95% CI 1.02–1.70] to 1.39 [1.08–1.78] per SD increase in baseline levels) and higher red meat intake. Eight lipids, mainly sphingomyelins, were associated with processed meat intake. Two sphingomyelins were linked to incident diabetes (OR 1.33 [95% CI 1.02–1.75] and 1.36 [1.04–1.80]) and higher processed meat intake. Of 23 meat-related lipids, 20 were associated with altered glucose/insulin metrics, and 11 mediated positive associations between red or processed meat intake and fasting glucose. CONCLUSIONS We identified lipidomic markers of unprocessed red and processed meat consumption. Several lipids were independently associated with increased diabetes risk, potentially by mediating the association between meat intake and glucose metabolism.
Type 1 Diabetes TrialNet: Leading the Charge in Disease Prediction, Prevention, and Immunotherapeutic Mechanistic Understanding
Authors: Laura M. Jacobsen, Jamie L. Felton, Brandon M. Nathan, Cate Speake, Jeffrey Krischer, Kevan C. Herold
Journal: Diabetes Care (2025)

Established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2001, Type 1 Diabetes TrialNet (TrialNet) is an international consortium of clinical research centers that studies the development of type 1 diabetes and performs clinical studies aimed at delaying or preventing the disease. In recognition of NIDDK’s 75th anniversary, this review will summarize the major findings, accomplishments, and future opportunities of its long-running program TrialNet. More than 20 intervention, observational, and mechanism-directed clinical studies have been conducted in collaboration with thousands of people living with type 1 diabetes and their families. New and repurposed immunotherapies have been successful in stages 2 and 3 of type 1 diabetes, contributing to the U.S. Food and Drug Administration approval of the first disease-modifying therapy to delay the onset of type 1 diabetes. Mechanistic findings continue to drive ongoing and future trial designs including novel combination therapies. TrialNet has several ongoing trials, with several for early stages of type 1 diabetes in development. There are new initiatives within TrialNet for community engagement, increasing clinical trial representation, personalizing treatments, and training the next generation of translational investigators.