A5084465421- Hematopoietic Stem Cell Transplantation
- Acute Myeloid Leukemia Research
- Congenital Heart Disease Studies
- Cardiovascular and Diving-Related Complications
- Kruppel-like factors research
- Cell death mechanisms and regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Pluripotent Stem Cells Research
- Immune Cell Function and Interaction
- Autophagy in Disease and Therapy
- Epigenetics and DNA Methylation
- Mesenchymal stem cell research
- Cancer-related Molecular Pathways
- Immune Response and Inflammation
- Zebrafish Biomedical Research Applications
- Retinoids in leukemia and cellular processes
- Cytokine Signaling Pathways and Interactions
- ATP Synthase and ATPases Research
- Galectins and Cancer Biology
- Mitochondrial Function and Pathology
- Cancer, Hypoxia, and Metabolism
- Hemoglobinopathies and Related Disorders
- Inflammatory mediators and NSAID effects
- Immune cells in cancer
- Heterotopic Ossification and Related Conditions
Gilead Sciences (United States)
2015-2025
University of California, San Francisco
2010-2023
Broad Center
2010-2023
University of Technology Sydney
2017
Palmetto Hematology Oncology
2013
McGill University
2005-2011
Toronto General Hospital
2003-2005
University Health Network
2005
University of Toronto
2003-2004
Epigenetic regulation serves as the basis for stem cell differentiation into distinct types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested hypothesis that chromatin organization affects lineage potential of cells and manipulation dynamics influences function. Using nuclease sensitivity assays, found a progressive decrease in digestion among pluripotent embryonic (ESCs), multipotent hematopoietic (HSCs), mature cells. Quantitative...
MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged an attractive approach restoring those cancers that retain functional p53. However, the consequences acute systemic inhibition normal adult tissues remain unknown. To determine directly effects tumors, we crossed mdmX −/− mice into p53ER TAM knockin background. In place wild-type express variant ,...
Abstract Outcomes of device closure large and small secundum atrial septal defects (ASDs) as related to rim anatomy with the Amplatzer occluder were compared. Rim adequacy (≥ 5mm) anterior, inferior, posterior, superior rims was determined using transesophageal echocardiography. Balloon‐stretched defect size defined patients into two groups: group 1, ≤ 25 mm (n = 138); 2, > 34). deficiency 62) more frequent in 2 compared 1 (50% vs. 33%; P 0.07), especially inferior (35% 2%; 0.005). Device...
A genome wide search for new BH3‐containing Bcl‐2 family members was conducted using position weight matrices (PWM) and identified a large (480 kDa), novel BH3‐only protein, originally called LASU1 (now also known as Ureb‐1, E3 histone , ARF‐BP1, Mule). We demonstrated that is an ligase ubiquitinated Mcl‐1 in vitro required its proteasome‐dependent degradation HeLa cells. Of note, the BH3 domain of interacted with but not or Bcl‐Xl. competing BH3‐ligand derived from Bim prevented interaction...
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and activin A receptor type 1 (ACVR1), is in clinical development for the treatment myeloproliferative neoplasms. The pharmacokinetics disposition [<sup>14</sup>C]MMB were characterized single-dose, human mass-balance study. Metabolism pharmacologic activity key metabolites elucidated multiple vitro vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% radioactivity recovered, primarily...
Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production control myelopoiesis on demand. Recent lineage tracing analyses revealed MPPs to be major functional contributors steady-state hematopoiesis. However, we still lack a precise resolution of myeloid differentiation trajectories cellular heterogeneity in the MPP compartment. Here, found that myeloid-biased MPP3 are functionally molecularly heterogeneous, with distinct subset...
Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery GS-5718 (edecesertib), a potent, selective, orally bioavailable inhibitor. Key to this endeavor were efforts undertaken improve chemical series' profile after significant hERG...
Mcl-1, a pro-survival member of the Bcl-2 family located at mitochondrial outer membrane, is subject to constitutive ubiquitylation by homology 3-only E3 ligase, Mule/Lasu1, resulting in rapid steady-state degradation via proteasome. Insertion newly synthesized Mcl-1 into membrane dependent on its C-terminal transmembrane segment, but once inserted, N terminus portion molecules can be proteolytic processing. Remarkably, this processing requires an intact electrochemical potential across...
Abstract The objective of this study was to determine the feasibility device closure patent foramen ovale (PFO) for presumed paradoxical emboli without echocardiographic guidance or balloon sizing and clinical outcome after closure. Closure PFO has been proposed as an alternative anticoagulation in patients with emboli. At present, most centers perform transesophageal defect. Between May 1998 April 2002, 92 consecutive underwent a using fluoroscopic monitoring only. Procedural success major...
Dynamic protein-protein interactions between proapoptotic and pro-survival Bcl-2 family members regulate outer-mitochondrial membrane permeabilization cytochrome c release, key events in the path to apoptosis. Their relative levels often dictate fate of a cell following an apoptotic stimulus. However, cancer cells, are frequently upregulated, thereby creating constitutive block apoptosis resulting continued survival under conditions that normally result death. Because many chemotherapeutics...