A5108833386- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Macrophage Migration Inhibitory Factor
- Enzyme function and inhibition
- Mechanisms of cancer metastasis
- Mitochondrial Function and Pathology
- interferon and immune responses
- Neuroblastoma Research and Treatments
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Multilevel Inverters and Converters
- Phagocytosis and Immune Regulation
- Cancer Research and Treatments
- Cytomegalovirus and herpesvirus research
- Animal Behavior and Reproduction
- Cell death mechanisms and regulation
- Intensive Care Unit Cognitive Disorders
- Telomeres, Telomerase, and Senescence
- Endoplasmic Reticulum Stress and Disease
- Neurobiology and Insect Physiology Research
- Immune cells in cancer
- Synthesis and Biological Evaluation
- Sepsis Diagnosis and Treatment
- Epigenetics and DNA Methylation
- RNA Research and Splicing
Salk Institute for Biological Studies
2019-2025
Yale University
2017-2024
University of New Haven
2018
University of Arizona
2016
Williams College
2001
Abstract Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP) 1 . Mitochondria are major regulators SASP; however, underlying mechanisms have not been elucidated 2 often essential for apoptosis, cell fate distinct from cellular senescence. During widespread mitochondrial outer membrane permeabilization (MOMP) commits to die 3 Here we find that MOMP occurring in subset mitochondria is feature This...
Although tumor growth requires the mitochondrial electron transport chain (ETC), relative contribution of complex I (CI) and II (CII), gatekeepers for initiating flow, remains unclear. In this work, we report that loss CII, but not CI, reduces melanoma by increasing antigen presentation T cell-mediated killing. This is driven succinate-mediated transcriptional epigenetic activation major histocompatibility complex-antigen processing (MHC-APP) genes independent interferon signaling....
Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes ER and binds inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK necessary for baseline mitochondrial calcium levels stimulus-induced mitochondria. Murine embryonic fibroblasts deficient have decreased proximity of altered protein composition mitochondria-associated membranes (MAMs), which form essential...
Intratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it highly correlated with metastasis, therapeutic resistance, disease recurrence in cancer patients. As result, there an urgent need develop effective therapies that target hypoxic cells within tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent prosurvival pathway upregulated response hypoxia, HIF-1-independent manner. We demonstrate...
Purpose: Patients develop resistance to antiangiogenic drugs, secondary changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival and their expression increases The goal of this study was determine whether targeting hypoxia-induced kinase is effective combination with VEGF-targeting agents. rationale for therapeutic approach based on fact that drugs can make tumors hypoxic, thus more sensitive inhibitors.Experimental Design: Xenograft orthotopic models prostate...
Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have “intergenomic signaling” that sense amount mitochondrial DNA (mtDNA) independently oxidative phosphorylation (OXPHOS), primary function genes encoded by mtDNA. However, MRS mtDNA mammalian cells remain poorly understood. We found mtDNA-depleted IMR90 can sustain OXPHOS for a significant time, providing robust...
Increased plasma mitochondrial DNA concentrations are associated with poor outcomes in multiple critical illnesses, including COVID-19. However, current methods of cell-free quantification time-consuming and lack reproducibility. Here, we used next-generation sequencing to characterize the size genome location circulating critically ill subjects COVID-19 develop a facile optimal method by droplet digital PCR. Sequencing revealed large percentage small fragments wide variability coverage...
Abstract Angiogenesis is known to play an important role in prostate cancer pathogenesis. Although the addition of VEGF-targeting agents (i.e., bevacizumab) docetaxel improved response rates mCRPC patients, it failed improve overall survival. Patients can develop resistance antiangiogenic drugs due changes tumor microenvironment, including hypoxia. PIM kinases are prosurvival whose expression increased hypoxia and advanced cancer. The goal this study was determine whether targeting...
Summary Angiogenesis is essential for sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) a master regulator angiogenesis and constitutive activation HIF-1 frequently observed in human cancers. Thus, understanding mechanisms governing the critical successful therapeutic targeting tumor angiogenesis. Herein, we establish new regulatory mechanism responsible HIF-1α cancer, irrespective oxygen tension. PIM1 kinase directly phosphorylates at threonine 455, previously...
Abstract Prostate cancer (PCa) is the leading cause of death in men worldwide. Patients diagnosed with metastatic prostate initially respond to androgen deprivation therapy, but this response not durable, and all patients develop hormone-refractory disease that ultimately leads death. Current treatment options for PCa are limited (e.g., cytotoxic chemotherapy or radiation), these agents invariably temporary does improve survival. A significant obstacle successful advanced tumor hypoxia....
<p>Loss of PIM blunts hypoxia-induced stabilization HIF-1/2 and the expression HIF-1 target genes</p>
<p>PIM inhibition blunts the expression of HIF-1 target genes in hypoxia</p>
<p>Supplemental Figure legends</p>
<p>Combinatorial inhibition of PIM and VEGF produces synergistic anti-tumor activity in xenograft models prostate colon cancer</p>
<p>Simultaneous inhibition of PIM and VEGF reduces colon cancer metastasis</p>
<p>Treatment with anti-angiogenic agents increases CAIX expression</p>
<p>Metastases arising from prostate tumors show significant regions of hypoxia</p>
<p>Dose response curves for bevacizumab</p>
<p>PIM1 expressing tumors maintain vasculature during treatment with anti-angiogenic agents</p>
<p>Combinatorial inhibition of PIM and VEGF produces synergistic anti-tumor activity in xenograft models prostate colon cancer</p>