A5009069418- Microtubule and mitosis dynamics
- Lung Cancer Treatments and Mutations
- Ubiquitin and proteasome pathways
- Acute Myeloid Leukemia Research
- Hematopoietic Stem Cell Transplantation
- Molecular Biology Techniques and Applications
- CRISPR and Genetic Engineering
- Acute Lymphoblastic Leukemia research
- CAR-T cell therapy research
- Advanced Breast Cancer Therapies
- HIV Research and Treatment
- Lung Cancer Research Studies
- RNA modifications and cancer
- RNA Research and Splicing
- Immune Cell Function and Interaction
- Pluripotent Stem Cells Research
- Venous Thromboembolism Diagnosis and Management
- Cytomegalovirus and herpesvirus research
- Cancer Mechanisms and Therapy
- Chronic Myeloid Leukemia Treatments
- Viral-associated cancers and disorders
- interferon and immune responses
- Monoclonal and Polyclonal Antibodies Research
- Single-cell and spatial transcriptomics
- Chronic Lymphocytic Leukemia Research
Fred Hutch Cancer Center
2016-2025
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2005-2024
Institut thématique Génétique, génomique et bioinformatique
2023
Clinical Research Management
2022
Cancer Research Center
2012-2018
Seattle University
2018
The Evergreen State College
2012
University College London
2012
Colorado State University
2012
Samsung Medical Center
2012
Epigenetic therapy may induce tumor-suppressive Notch signaling in patients with small cell lung cancer.
AbstractThe yeast Isw2 chromatin remodeling complex functions in parallel with the Sin3-Rpd3 histone deacetylase to repress early meiotic genes upon recruitment by Ume6p. For many of these genes, effect an isw2 mutation is partially masked a functional complex. To identify full range repressed or activated factors and uncover hidden targets Isw2-dependent regulation, we performed genome expression analyses using cDNA microarrays. We find that mainly repression transcription pathway In...
To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, genes required their vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered GSCs (e.g., oncogenic drivers). In vivo validation GSC-specific revealed several strong hits, including wee1-like...
Too Much Tolerance? In the immune system, loss of tolerance to self can have devastating consequences, such as development autoimmune diseases. some cases, however, we may wish be able break tolerance, for example, activate cells fight tumors. Schietinger et al. (p. 723 , published online 19 January; see Perspective by Lee and Jameson ) used a combination genetic mouse models adoptive cell transfers better understand mechanisms regulating in T lymphocytes. contrast prevailing paradigm,...
Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced restriction factors, we assembled a CRISPR sgRNA library of Stimulated Genes (ISGs) into modified lentiviral vector that allows for packaging sgRNA-encoding genomes in trans budding HIV-1 particles. We observed knockout Zinc Antiviral Protein (ZAP) improved the performance screen due to ZAP-mediated inhibition vector. A small panel including MxB, IFITM1, Tetherin/BST2 and...
To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, compared with untransformed neural (NSCs) fibroblasts. Given PHF5A's known involvement facilitating interactions between U2 snRNP complex ATP-dependent helicases, examined...
Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) frequently amplified in human SCLC, but its roles SCLC progression are poorly understood. We isolated preneoplastic cells from mouse model of and found that ectopic expression L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. focused on which promoted pre-rRNA synthesis transcriptional programs associated with ribosomal biogenesis. Deletion Mycl two genetically engineered models resulted strong...
Small cell lung cancer (SCLC) is an aggressive neuroendocrine characterized by initial chemosensitivity followed emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model -overexpressing SCLC. In treatment-naïve mice, overexpression promoted cycle progression, suppressed infiltration cytotoxic T cells, accelerated also response to cisplatin–etoposide chemotherapy, with similar findings...
Abstract To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and network modeling to kinases required the growth of patient-derived brain tumor–initiating cells (BTIC) but that are dispensable proliferating human neural stem (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as top-scoring lethal kinase. Knockdown BUB1B inhibited expansion BTIC isolates, both in vitro vivo, without affecting...
Nucleosome-free regions (NFRs) at the 5' and 3' ends of genes are general sites transcription initiation for mRNA noncoding RNA (ncRNA). The presence NFRs within transcriptional regulatory conserved location start strongly suggest that regulation profoundly affects initiation. To date, multiple factors known to facilitate by positively regulating formation and/or size in vivo. However, mechanisms repress negatively have not been identified. We identified four distinct classes located genes,...
Abstract Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators erythropoiesis, we utilize a functional genomic screen for genes affecting expression erythroid marker CD235a/GYPA. Among validating hits are coding N 6 -methyladenosine (m A) mRNA methyltransferase (MTase) complex, including, METTL14 , METTL3 WTAP . We demonstrate that m A MTase activity promotes gene programs through selective...
The mouse brain contains about 75 million neurons interconnected in a vast array of neural circuits. identities and functions individual neuronal components most circuits are undefined. Here we describe method, termed “Connect-seq,” which combines retrograde viral tracing single-cell transcriptomics to uncover the molecular upstream specific circuit signaling molecules they use communicate. Connect-seq can generate map that be superimposed on neuroanatomical permit genetic interrogation how...
CD19-directed chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial (NCT01865617), we observed anti-CAR immune associated impaired vivo CAR expansion after second infusions. Because these CD8+ were predominantly directed at peptides derived from the murine single chain variable fragment (scFv)...
Abstract Background The emergence and rapid spread of SARS-CoV-2 since 2019 caused substantial global morbidity mortality continues to burden healthcare systems worldwide. Public health measures implemented reduce also reduced circulation other seasonal respiratory viruses, likely causing gaps in population-level immunity. Whether infection may dampen immune responses against pathogens is highly debated not well understood.Figure 1.VirScan analyses serum samples pre- post- clinically...