A5002158047- Virus-based gene therapy research
- Liver physiology and pathology
- Pluripotent Stem Cells Research
- CAR-T cell therapy research
- Liver Disease Diagnosis and Treatment
- CRISPR and Genetic Engineering
- Hematopoietic Stem Cell Transplantation
- Cancer Research and Treatments
- Sirtuins and Resveratrol in Medicine
- Veterinary Oncology Research
- RNA modifications and cancer
- Autophagy in Disease and Therapy
- Computer Graphics and Visualization Techniques
- Liver Disease and Transplantation
- Advanced Vision and Imaging
- T-cell and B-cell Immunology
- RNA Research and Splicing
- Tea Polyphenols and Effects
- RNA Interference and Gene Delivery
- Body Composition Measurement Techniques
- Acute Myeloid Leukemia Research
- Pancreatic function and diabetes
- Science Education and Perceptions
- Gene Regulatory Network Analysis
- Data-Driven Disease Surveillance
Fred Hutch Cancer Center
2014-2024
Cork University Hospital
2024
University of Washington
2010-2015
GlaxoSmithKline (United Kingdom)
2012-2014
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2014
Cancer Research Center
2014
Somerville Hospital
2012
Stanford University
2002
London School of Economics and Political Science
1986
Suntory (United Kingdom)
1986
Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how 3' splice site recognition factor U2AF1 alter its normal role splicing. We find that influence similarity programs leukemias, but do not give rise widespread failure. cause differential hundreds genes, biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), damage...
Abstract Canine embryonic stem (cES) cell lines were generated to establish a large-animal preclinical model for testing the safety and efficacy of (ES) cell-derived tissue replacement therapy. Putative cES initiated from canine blastocysts harvested natural matings. Times harvest estimated as 12–16 days after presumed surge in circulating levels luteinizing hormone. Four established at 13–14 postsurge satisfied most criteria cells, whereas day 14 did not. One line, Fred Hutchinson dog...
Chronic liver injury leads to fibrosis, cirrhosis, and loss of function. Liver cirrhosis is the 12th leading cause death in United States, it primary risk factor for developing cancer. Fibrosis result from activation hepatic stellate cells (HSCs), which are collagen producing cell type liver. Here, we show that platelet-derived growth receptor α (PDGFRα) expressed by human HSCs, PDGFRα expression elevated disease. Using a green fluorescent protein (GFP) reporter mouse strain, evaluated role...
Cirrhosis is the primary risk factor for development of hepatocellular carcinoma (HCC), yet mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood. Using a mouse model that recapitulates many aspects pathophysiology human liver disease, we explored changes in microenvironment induce dysplasia and HCC. Hepatic expression platelet-derived growth C (PDGF-C) induces progressive fibrosis, chronic inflammation, neoangiogenesis sinusoidal congestion, as well global gene...
The marrow microenvironment and vasculature plays a critical role in regulating hematopoietic cell recruitment, residence, maturation. Extensive vitro vivo studies have aimed to understand the types that contribute hematopoiesis stem environment. Nonetheless, models are limited by lack of complex multicellular interactions, cellular interactions not easily manipulated vivo. Here, we develop an engineered human vascular niche examine three-dimensional direct trafficking. Using soft...
Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease and behavioural frontotemporal dementia (FTD), whereas heterozygous increase risk late-onset Alzheimer's (AD) FTD. For over half TREM2 found families recessive defect occurs at transcript level via premature termination codons or...
An approach to heterogeneous process migration that involves building a machine-independent program specifies the current code and data state of be migrated is described. When this compiled executed on target machine, it will first reconstruct process's then continue normal execution now-migrated process. The principal advantage hides details translation in compilers for each machine.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
Chronic liver injury leads to fibrosis and cirrhosis. Cirrhosis, the end stage of chronic disease, is a leading cause death worldwide increases risk developing hepatocellular carcinoma. Currently, there lack effective antifibrotic therapies treat Development requires an in-depth understanding cellular molecular mechanisms involved in inflammation after hepatic injury. Two growth factor signaling pathways that regulate are transforming factor-β (TGFβ) platelet-derived (PDGF). However, their...
SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB HIF1α. Since it possible to make small molecule activators inhibitors Sirtuins we wished establish biochemical cellular assays assist drug discovery efforts validate whether represents a valid target for these indications. We confirmed that can deacetylate acetylated-histone H3 lysine 9 (H3K9Ac), however this deacetylase activity unusually low assays. In an effort develop alternative...
Abstract One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model naturally occurring canine sarcomas as CAR therapy. Canine CARs specific B7-H3 were constructed using single-chain variable fragment derived from B7-H3–specific antibody MGA271, which confirmed be cross-reactive with B7-H3. After refining activation, transduction, and expansion...
SIRT6 is a member of the Sirtuin family histone deacetylases that has been implicated in inflammatory, aging and metabolic pathways. Some its actions have suggested to be via physical interaction with NFκB HIF1α transcriptional regulation through deacetylase activity. Our previous studies investigated activity explored ability regulate responses an inflammatory stimulus such as TNFα. In order develop greater understanding function we sought identify interacting proteins by both...
Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors moderate the response injury create extracellular matrix at site injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) angiotensin II (AngII), increases HSC contraction, migration fibrogenesis. Regulator signaling-5 (RGS5), an inhibitor vasoactive GPCR agonists, functions control GPCR-mediated contraction hypertrophy in pericytes smooth muscle...
Abstract Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how 3′ splice site recognition factor U2AF1 alter its normal role splicing. We find that influence similarity programs leukemias, but do not give rise widespread failure. cause differential hundreds genes, biological pathways such as DNA methylation ( DNMT3B ), X chromosome inactivation H2AFY...
This manuscript illustrates a protocol for efficiently creating integration-free human induced pluripotent stem cells (iPSCs) from peripheral blood using episomal plasmids and histone deacetylase (HDAC) inhibitors. The advantages of this approach include: (1) the use minimal amount as source material; (2) nonintegrating reprogramming vectors; (3) cost effective method generating vector free iPSCs; (4) single transfection; (5) small molecules to facilitate epigenetic reprogramming. Briefly,...
Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role signalling through the cell receptor. Evidence, mainly from knockout mice, has suggested that ITK particularly important function Th2 this prompted significant efforts to discover inhibitors for treatment of allergic disease. However, known have functions outside its domain general knockouts are often not good models behaviour small molecule inhibitors. Consequently we developed transgenic mouse...
Recently, we developed a small molecule responsive hyperactive Mpl-based Cell Growth Switch (CGS) that drives erythropoiesis associated with macrophages in the absence of exogenous cytokines. Here, compare physical, cellular and molecular interaction between erythroid cells CGS expanded CD34+ harvested from cord blood, marrow or G-CSF-mobilized peripheral blood. Results indicated macrophage based islands could be generated blood but not cells. Additional studies suggest deficiency resides...
Vasculature is an interface between the circulation and hematopoietic tissue providing means for hundreds of billions blood cells to enter every day in a regulated fashion. The precise mechanisms that control interactions with vessel wall are largely undefined. Here, we report on development vitro 3D human marrow vascular microenvironment (VME) study trafficking release cells, specifically platelets. We show mature megakaryocytes from aspirated as well differentiated culture CD34+ can be...