Browsing by Subject "Molecular markers"

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    Abstract 33: Transcriptomic Identification of Functionally Potent Umbilical Cord Blood Units
    (Oxford University Press, 2024-08-21) Ropa, James; Gutch, Sarah; Beasley, Lindsay; Van't Hof, Wouter; Sun, Jessica; Capitano, Maegan; Kaplan, Mark; Medical and Molecular Genetics, School of Medicine
    Introduction: Umbilical cord blood (UCB) is an important donor source for standard of care cellular therapies as well as innovative new treatments. Universal potency criteria for cord blood unit (CBU) selection for different cellular therapy applications are still desired and efficient methods to elucidate these criteria remain elusive. Objectives: Our goal is to find molecular markers that identify potent CBUs for use in cellular therapies. Here, we utilized transcriptomics to reveal genes associated with hematopoietic stem and progenitor cell (HSC/HPC) potency in hematopoietic cell transplantation. Methods: We performed three separate transcriptomic analyses of human UCB used in mouse models of transplantation. This included bulk RNA-sequencing of HSCs/HPCs from CBUs with known engraftment capacities (n=9 CBUs), bulk RNA-sequencing of homed/early engrafted CD34+ cells (n=3 CBUs), and single cell RNA-sequencing of CD34+ cells expanded in varying oxygen tensions, which affects their transplantation potency (n=4 CBUs). Results: HSCs/HPCs enriched for dehydrogenase and cell cycle associated genes yield better repopulating cell frequency. Early homed CD34+ cells have enriched expression of immune activation and cell cycle genes compared to input transplanted cells. Distinct clusters of UCB cells marked by genes such as PRSS2 and AVP are enriched in oxygenation conditions that drive increased potency. Dehydrogenase and stress response genes are enriched in populations predicted to be more functional regardless of HSC/HPC subpopulation. Integration of all three studies reveals genes that may define highly potent CBUs, including DDIT4, a stress response gene. Indeed, DDIT4 independently predicts engraftment outcomes in mouse models of transplantation. Future work will examine a qPCR based gene panel potency assay to predict outcomes in patient transplantations. Discussion: We have identified genes associated with HSC/HPC potency using transcriptomic approaches. These findings have immediate translational implications for CBU selection for transplantation, but also provides a blueprint for finding CBUs best suited for use in developing off-the-shelf immune effector therapies or those that are best for treating non-hematologic central nervous system disorders such as cerebral palsy, among other applications. Importantly, this study highlights the importance for omics technology as a valuable tool to define potency criteria for UCB as a donor source for cellular therapies.
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    Correction to: Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research
    (Springer, 2022) Jagsi, R.; Mason, G.; Overmoyer, B.A.; Woodward, W.A.; Badve, S.; Schneider, R.J.; Lang, J.E.; Alpaugh, M.; Williams, K.P.; Vaught, D.; Smith, A.; Smith, K.; Miller, K.D.; Medicine, School of Medicine
    Erratum for: Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research. Jagsi R, Mason G, Overmoyer BA, Woodward WA, Badve S, Schneider RJ, Lang JE, Alpaugh M, Williams KP, Vaught D, Smith A, Smith K, Miller KD; Susan G. Komen-IBCRF IBC Collaborative in partnership with the Milburn Foundation. Breast Cancer Res Treat. 2022 Apr;192(2):235-243. doi: 10.1007/s10549-021-06434-x. Epub 2022 Jan 1. PMID: 34973083
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    Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research
    (Springer, 2022) Jagsi, R.; Mason, G.; Overmoyer, B.A.; Woodward, W.A.; Badve, S.; Schneider, R.J.; Lang, J.E.; Alpaugh, M.; Williams, K.P.; Vaught, D.; Smith, A.; Smith, K.; Miller, K.D.; Medicine, School of Medicine
    Purpose: Inflammatory breast cancer is a deadly and aggressive type of breast cancer. A key challenge relates to the need for a more detailed, formal, objective definition of IBC, the lack of which compromises clinical care, hampers the conduct of clinical trials, and hinders the search for IBC-specific biomarkers and treatments because of the heterogeneity of patients considered to have IBC. Methods: Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to review the state of IBC and to propose initiatives to advance the field. After literature review of the defining clinical, pathologic, and imaging characteristics of IBC, the experts developed a novel quantitative scoring system for diagnosis. Results: The experts identified through consensus several "defining characteristics" of IBC, including factors related to timing of onset and specific symptoms. These reflect common pathophysiologic changes, sometimes detectable on biopsy in the form of dermal lymphovascular tumor emboli and often reflected in imaging findings. Based on the importance and extent of these characteristics, the experts developed a scoring scale that yields a continuous score from 0 to 48 and proposed cut-points for categorization that can be tested in subsequent validation studies. Conclusion: To move beyond subjective 'clinical diagnosis' of IBC, we propose a quantitative scoring system to define IBC, based on clinical, pathologic, and imaging features. This system is intended to predict outcome and biology, guide treatment decisions and inclusion in clinical trials, and increase diagnostic accuracy to aid basic research; future validation studies are necessary to evaluate its performance.