A5060742220- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- HIV Research and Treatment
- Multiple Myeloma Research and Treatments
- Advanced Breast Cancer Therapies
- Neuroinflammation and Neurodegeneration Mechanisms
- Inflammation biomarkers and pathways
- HIV-related health complications and treatments
- Peptidase Inhibition and Analysis
- Diet and metabolism studies
- Diabetes Treatment and Management
- Hepatitis C virus research
- Urinary Bladder and Prostate Research
- Cardiovascular Function and Risk Factors
- Immune Cell Function and Interaction
- Atherosclerosis and Cardiovascular Diseases
- Cytomegalovirus and herpesvirus research
- Crystallization and Solubility Studies
- Immunotherapy and Immune Responses
- Tryptophan and brain disorders
- Epigenetics and DNA Methylation
- Complement system in diseases
- Diabetes and associated disorders
- HIV/AIDS Research and Interventions
- Neuropeptides and Animal Physiology
Resverlogix (Canada)
2016-2018
University of California, San Francisco
2013-2015
San Francisco VA Medical Center
2008-2014
Veterans Health Administration
2011
Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified microglia thought to phagocytose damaged cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore both vitro vivo models identify potential endogenous ligand. knockdown reduced microglial activation amoeboid phenotype decreased the...
BackgroundHIV-1 infection dysregulates the immune system and alters gene expression in circulating monocytes. Differential analysis of CD14+ monocytes from subjects infected with HIV-1 revealed increased sialoadhesin (Sn, CD169, Siglec 1), a cell adhesion molecule first described subset macrophages activated chronic inflammatory diseases.Methodology/Principal FindingsWe analyzed on by flow cytometry found significantly higher elevated viral loads compared to undetectable loads. In cultured...
HIV-1 infection dysregulates the innate immune system and alters leukocyte-gene expression. The objectives were two fold: to characterize impact of on peripheral monocyte gene expression identify predominant factor(s) responsible for altered expression.In a cross-sectional study (n = 55), CD14 monocytes isolated from 11 seronegative controls, 22 seropositive individuals with low-viral loads (LVL) high-viral (HVL). Monocyte data collected control, LVL HVL using high-density microarrays. We...
Apabetalone (RVX-208) is an epigenetic regulator developed to treat cardiovascular disease (CVD) that targets BET proteins. Through transcriptional regulation RVX-208 modulates pathways underlie CVD including reverse cholesterol transport, vascular inflammation, coagulation, and complement. Using transcriptomics proteomics we show complement one of the top downregulated by in primary human hepatocytes (PHH) plasma from patients. reduces basal cytokine-driven expression factors PHH chimeric...
BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and factors bromodomains (BDs). The disruption this interaction with small molecule bromodomain inhibitors is a promising approach treat various diseases including cancer, autoimmune cardiovascular diseases. Covalent can potentially offer more durable target inhibition leading improved in vivo pharmacology. Here we describe the design covalent BRD4(BD1)...
Hypothermia is neuroprotective against many acute neurological insults, including ischemic stroke. We and others have previously shown that protection by hypothermia partially associated with an anti-inflammatory effect. Phagocytes are thought to play important role in the clearance of necrotic debris, paving way for endogenous repair mechanisms commence, but effect cooling phagocytosis has not been extensively studied. Triggering receptor expressed on myeloid cells-2 (TREM2) a newly...
Coinfection with human immunodeficiency virus (HIV) and hepatitis C (HCV) challenges the immune system two viruses that elicit distinct responses. Chronic activation is a hallmark of HIV infection an accurate indicator disease progression. Suppressing viremia by antiretroviral therapy (ART) effectively prolongs life significantly improves function. HIV/HCV coinfected individuals have peripheral despite effective ART control viral load. Here we examined freshly isolated CD14 monocytes for...
In spite of effective antiretroviral therapy (ART), cognition is impaired in upwards 35% the HIV-infected population. We investigated a possible link between peripheral immune activation and brain metabolite concentrations.Thirty-five HIV-seropositive (HIV+) eight HIV-seronegative adults were recruited to this cross-sectional study. All HIV-positive patients on ART or treatment interruption. Participants evaluated for monocyte gene expression, cognitive status, concentrations using 4-Tesla...
Atherosclerosis is an inflammatory disease that accelerated in human immunodeficiency virus (HIV) infection. Individuals with HIV infection have activated type I interferon (IFN) monocyte phenotype, which may enhance uptake of modified low-density lipoprotein (LDL) thereby initiating a prefoam cell pathology and recruitment into atherosclerotic plaques. In sampling HIV-infected subjects, increase activation genes, MX1 CXCL10, correlated expression the scavenger receptor A (SR-A), major for...
Abstract Detection of drug activity in patients is essential to confirm its mechanism action, as well ensure proper target engagement at the selected dose elicit optimal clinical activity. Pharmacodynamic (PD) markers are often developed detect pharmacological responses and optimize dosing. Whole blood an easily attainable minimally invasive source biological material measure drugs. We designed, developed, validated a whole PD marker assay ZEN-3694, orally available inhibitor bromodomain...
Abstract ZEN-3694 is an orally bioavailable small molecule discovered and developed from a BET bromodomain inhibitor discovery platform. In vitro, selectively binds to both bromodomains of the proteins, inhibiting interaction acetylated histone peptide with IC50 values in low nM range. inhibits proliferation MV4-11 AML cells 0.2 uM, MYC mRNA expression 0.16 uM. has also demonstrated strong activity against many solid tumor hematological cell lines sub-uM values. vitro synergy Standard Care...
Abstract Metastatic castration resistant prostate cancer (mCRPC) is a major unmet medical need due to its widespread occurrence and incurable status. Current standard of care for advanced androgen-deprivation therapy (ADT), upon failure, patients are administered secondary ADT with androgen receptor (AR) antagonists such as enzalutamide abiraterone. While most display an initial response these agents, eventually all become via various mechanisms that often result in constitutive AR signaling...
Abstract More than 200,000 women are diagnosed with breast cancer every year in the United States. About 80% of these cases estrogen receptor positive (ER+), which is characterized by up-regulation ER signaling and downstream activation cyclin-dependent kinases CDK4/6 cyclin D1 (CCND1). Current lines therapies include either endocrine or inhibitors, have resulted great improvement treatment ER+ cancer. As expected, resistance to occurs over time development additional therapeutic strategies...
Clearing cellular debris after brain injury represents an important mechanism to re-attain tissue homeostasis and promote functional recovery. Triggering receptor expressed by myeloid cells-2 (TREM2) is involved in the innate immune system, carries out surveillance functions binding phagocytosing pathogens. TREM2 on macrophages microglia, promotes phagocytosis of apoptotic cells. Deficiency leads accelerated dementia, mutations gene have been linked Alzheimer’s. Here we explore significance...
Abstract Estrogen receptor positive breast cancer (ER+) remains a very prevalent disease with high mortality rate despite recent successes new therapies such as CDK4/6, PARP, and PI3K inhibitors. These have shown to significantly prolong progression free survival of metastatic patients, however resistance develops over time in all the patients need develop therapeutic strategies is pressing. The bromodomain extra-terminal domain (BET) proteins play an important role regulation transcription...
RVX-208 affects epigenetics by inhibiting bromodomain and extraterminal (BET) proteins from binding to their natural ligand, acetyl-lysine marks on histone tails thereby modulates gene activity. In SUSTAIN ASSURE phase IIb trials of CVD patients (n=499), giving 200 mg/d orally lead a 55% relative risk reduction in major adverse cardiovascular events (MACE) vs. placebo. This marked MACE is unlikely due RVX-208’s modest induction ApoA-I/HDL, thus prompting studies for its benefits beyond...