A5057334251- Hematopoietic Stem Cell Transplantation
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Melanoma and MAPK Pathways
- Immune cells in cancer
- Acute Myeloid Leukemia Research
- CAR-T cell therapy research
- Metabolism, Diabetes, and Cancer
- T-cell and B-cell Immunology
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- Cancer Cells and Metastasis
- Synthesis and biological activity
- Pancreatic function and diabetes
- Chemokine receptors and signaling
- Protein Tyrosine Phosphatases
- CRISPR and Genetic Engineering
- Hematological disorders and diagnostics
- Cancer Mechanisms and Therapy
- Prostate Cancer Treatment and Research
- Cancer, Hypoxia, and Metabolism
- Chronic Lymphocytic Leukemia Research
- Diabetes and associated disorders
- Cancer-related Molecular Pathways
- Phagocytosis and Immune Regulation
AstraZeneca (United States)
2025
Children's Hospital of Pittsburgh
2021-2024
University of Pittsburgh
2007-2024
Washington University in St. Louis
2014-2022
Duquesne University
2009-2019
Pediatrics and Genetics
2018
Abstract Toll-like receptor 2 (TLR2) is a member of the TLR family receptors that play central role in innate immunity. In addition to regulating effector immune cells, where it recognizes wide variety pathogen-associated and nonpathogen-associated endogenous ligands, TLR2 expressed hematopoietic stem cells (HSCs). Its HSCs, however, not well understood. Furthermore, augmented signaling associated with myelodysplastic syndrome, an HSC disorder characterized by ineffective hematopoiesis high...
Abstract Background: AZD2284 is a novel, targeted alpha therapeutic directed against six-transmembrane epithelial antigen of prostate-2 (STEAP2), receptor highly overexpressed in prostate cancer. comprised humanized, STEAP2-targeting rodent cross-reactive IgG1 monoclonal antibody conjugated with DOTA chelate and radiolabeled the alpha-particle emitting radionuclide, actinium-225 [225Ac]. Leveraging high STEAP2 expression cancer linear energy transfer emitter, presumed to deliver radioisotope...
Abstract Metastatic castration-resistant prostate cancer (mCRPC) continues to pose a significant clinical challenge and is associated with poor survival rates in patients who failed previous lines of androgen receptor axis-targeted therapies taxanes. Antibody drug conjugates (ADCs) provide novel approach traditional chemotherapy by targeting tumor-specific antigens deliver cytotoxic payloads while sparing normal tissue enhancing the therapeutic index. Herein, we describe preclinical...
Abstract The inflammatory response to infection or injury dramatically increases the hematopoietic demand on bone marrow replace effector leukocytes consumed in response. In setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating stem and progenitor cells proliferate produce progeny for accelerated myelopoiesis. Sterile tissue due trauma also leukocyte demand; however, effect sterile hematopoiesis is not well described. We find that alone...
Triple-negative breast cancers (TNBCs) represent 15% to 20% of all and are often associated with poor prognosis. The lack targeted therapies for TNBCs contributes higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) mitogen-activated protein kinase pathways have been linked increased cancer proliferation survival. It has proposed that these survival characteristics enhanced through compensatory signaling crosstalk mechanisms. While between PI3K extracellular...
Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). has been proposed regulate HSCs cell autonomously non-cell autonomously, but relative importance of each mechanism not directly tested. Furthermore, cytokines that activate PI3K upstream are well defined. We sought clarify whether or HSC mobilization. also tested deficiency affects response granulocyte colony-stimulating factor (G-CSF)...
Abstract The tetraspanin CD53 has been implicated in B cell development and function. is a transcriptional target of EBF1, critical transcription factor for early development. Further, human deficiency results recurrent infections reduced serum Igs. Although prior studies have indicated role regulating mature cells, its not well understood. In this study, we show that expression, which minimal on hematopoietic stem progenitor increases throughout bone marrow maturation, mice lacking...
Abstract Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process involving the cellular energy sensor adenosine monophosphate (AMP)–activated protein kinase (AMPK). Deletion of AMPK donor limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia effects. In current studies, murine knock-out (KO) decreased oxidative at early time points posttransplant lacked compensatory increase glycolysis after inhibition electron...
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, the pathogenesis of which involves enhanced immune signaling that promotes or selects for mutant and progenitor cells (HSPCs). In particular, toll-like receptor (TLR) expression in MDS, their inhibition is an attractive therapeutic strategy. Although prior studies have reported increased TLR2 its binding partners TLR1 TLR6 CD34
Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive cells. EMT implicated in cancer metastasis, chemo-resistance, progression, and generation of stem (CSCs). Inducing (MET), the reverse phenomenon EMT, proposed as novel strategy target triple negative tamoxifen-resistant breast cancer. Triple (TNBC) characterized by loss hormone receptors, highly phenotype, lack targeted therapy. Estrogen receptor-positive can be tamoxifen,...
Abstract The hematopoietic stem cell (HSC) cycle responds to inflammatory and other proliferative stressors; however, these cells must quickly return quiescence avoid exhaustion maintain their functional integrity. mechanisms that regulate this are not well understood. Here, we show tetraspanin CD53 is markedly upregulated in HSCs response a variety of stimuli the loss associated with prolonged cycling reduced HSC function context stress. Mechanistically, promotes activity dimerization...
Aging is associated with significant changes in hematopoiesis that include a shift from lymphopoiesis to myelopoiesis and an expansion of phenotypic hematopoietic stem cells (HSCs) impaired self-renewal capacity myeloid-skewed lineage differentiation. Signals commensal flora support basal young mice; however, their contribution aging largely unknown. Here, we characterize middle-aged mice housed under specific pathogen free (SPF) germ-free (GF) conditions. The marked develops during SPF...
Toll-like receptor 2 (TLR2) expression is increased on hematopoietic stem and progenitor cells (HSPCs) of patients with myelodysplastic syndromes (MDS), enhanced TLR2 signaling thought to contribute MDS pathogenesis. Notably, heterodimerizes TLR1 or TLR6, while high associated lower-risk disease, but not TLR1, correlates higher-risk disease. This raises the possibility heterodimer-specific effects in MDS, work described here, we tested specific modulation TLR1/2 versus TLR2/6 premalignant...
Cellular therapies are currently employed to treat a variety of disease processes. For T cell-based therapies, success often relies on the metabolic fitness cell product, where cells with enhanced capacity demonstrate improved in vivo efficacy. AMP-activated protein kinase (AMPK) is cellular energy sensor which combines environmental signals status enforce efficient and flexible programming. We hypothesized that increasing AMPK activity human would augment their oxidative capacity, creating...
Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined role of cellular energy sensor AMP kinase (AMPK) alloreactive during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold allogeneic cells, deficient both AMPKα1 AMPKα2 decreased...