Browsing by Author "Nelson, Robert P."

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    Hypogammaglobulinemia in Adolescents and Young Adults with Acute Lymphoblastic Leukemia
    (Mary Ann Liebert, Inc., 2020-12) Lange, Cassandra S.; Rahrig, April; Althouse, Sandra K.; Nelson, Robert P.; Batra, Sandeep; Medicine, School of Medicine
    Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15–39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin–Frankfurt–Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.
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    An Integrative multi-lineage model of variation in leukopoiesis and acute myelogenous leukemia
    (BMC, 2017-08-25) Sarker, Joyatee M.; Pearce, Serena M.; Nelson, Robert P.; Kinzer-Ursem, Tamara L.; Umulis, David M.; Rundell, Ann E.; Medicine, School of Medicine
    Background Acute myelogenous leukemia (AML) progresses uniquely in each patient. However, patients are typically treated with the same types of chemotherapy, despite biological differences that lead to differential responses to treatment. Results Here we present a multi-lineage multi-compartment model of the hematopoietic system that captures patient-to-patient variation in both the concentration and rates of change of hematopoietic cell populations. By constraining the model against clinical hematopoietic cell recovery data derived from patients who have received induction chemotherapy, we identified trends for parameters that must be met by the model; for example, the mitosis rates and the probability of self-renewal of progenitor cells are inversely related. Within the data-consistent models, we found 22,796 parameter sets that meet chemotherapy response criteria. Simulations of these parameter sets display diverse dynamics in the cell populations. To identify large trends in these model outputs, we clustered the simulated cell population dynamics using k-means clustering and identified thirteen ‘representative patient’ dynamics. In each of these patient clusters, we simulated AML and found that clusters with the greatest mitotic capacity experience clinical cancer outcomes more likely to lead to shorter survival times. Conversely, other parameters, including lower death rates or mobilization rates, did not correlate with survival times. Conclusions Using the multi-lineage model of hematopoiesis, we have identified several key features that determine leukocyte homeostasis, including self-renewal probabilities and mitosis rates, but not mobilization rates. Other influential parameters that regulate AML model behavior are responses to cytokines/growth factors produced in peripheral blood that target the probability of self-renewal of neutrophil progenitors. Finally, our model predicts that the mitosis rate of cancer is the most predictive parameter for survival time, followed closely by parameters that affect the self-renewal of cancer stem cells; most current therapies target mitosis rate, but based on our results, we propose that additional therapeutic targeting of self-renewal of cancer stem cells will lead to even higher survival rates. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0469-2) contains supplementary material, which is available to authorized users.
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    Prognostic biomarkers for acute graft-versus-host disease risk after cyclophosphamide-fludarabine nonmyeloablative allotransplantation
    (Elsevier, 2014-11) Nelson, Robert P.; Khawaja, Muhammad Rizwan; Perkins, Susan M.; Elmore, Lindsey; Mumaw, Christen L.; Orschell, Christie M.; Paczesny, Sophie; Department of Pediatrics, IU School of Medicine
    Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3α [REG3α], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Rα]) were measured at specific time points after cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14 (c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3α concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Rα were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3α, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort.
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    A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency
    (Elsevier, 2014-04) Lee, Yu Nee; Frugoni, Francesco; Dobbs, Kerry; Walter, Jolan E.; Giliani, Silvia; Gennery, Andrew R.; Al-Herz, Waleed; Haddad, Elie; LeDeist, Francoise; Bleesing, Jack H.; Henderson, Lauren A.; Pai, Sung-Yun; Nelson, Robert P.; El-Ghoneimy, Dalia H.; El-Feky, Reem A.; Reda, Shereen M.; Hossny, Elham; Soler-Palacin, Pere; Fuleihan, Ramsay L.; Patel, Niraj C.; Massaad, Michel J.; Geha, Raif S.; Puck, Jennifer M.; Palma, Paolo; Cancrini, Caterina; Chen, Karin; Vihinen, Mauno; Alt, Frederick W.; Notarangelo, Luigi D.; Department of Medicine, Division of Hematology and Oncology, IU School of Medicine
    Background The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T−B− severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods We have developed a flow cytometry–based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1−/− pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.