A5034504809- Acute Myeloid Leukemia Research
- RNA modifications and cancer
- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- RNA and protein synthesis mechanisms
- Hematopoietic Stem Cell Transplantation
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Hemoglobinopathies and Related Disorders
- Blood disorders and treatments
- Platelet Disorders and Treatments
- RNA Research and Splicing
- Neutropenia and Cancer Infections
- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- CRISPR and Genetic Engineering
- Bacterial Genetics and Biotechnology
- DNA Repair Mechanisms
- Genomics and Phylogenetic Studies
- Pelvic floor disorders treatments
- Genomics and Chromatin Dynamics
- Virus-based gene therapy research
- Pelvic and Acetabular Injuries
National Heart Lung and Blood Institute
2020-2025
National Institutes of Health
2015-2024
Johns Hopkins Medicine
2017-2023
Johns Hopkins University
2017-2023
National Human Genome Research Institute
2023
National Institute of Diabetes and Digestive and Kidney Diseases
2016-2022
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2015-2021
Pediatrics and Genetics
2021
University of Chicago
2007-2018
University of Otago
2007-2010
Abstract Background Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing mix drug‐inactivating hypersensitivity and noninactivating reactions. Erwinia chrysanthemi (ERW) approved for hypersensitivity, but less convenient, more expensive, yields lower serum asparaginase activity (SAA). We began policy universal...
In eukaryotes, 43S preinitiation complex (PIC) formation is a rate-determining step of translation. Ribosome recycling following translation termination produces free 40S subunits for re-assembly PICs. Yeast mutants lacking orthologs mammalian eIF2D (Tma64), and either MCT-1 (Tma20) or DENR (Tma22), are broadly impaired recycling; however, it was unknown whether this defect alters the translational efficiencies (TEs) particular mRNAs. Here, we conducted ribosome profiling yeast tma64∆/tma20∆...
Hcr1/eIF3j is a sub-stoichiometric subunit of eukaryotic initiation factor 3 (eIF3) that can dissociate the post-termination 40S ribosomal from mRNA in vitro. We examine this ribosome recycling role vivo by profiling and reporter assays find loss Hcr1 leads to reinitiation translation 3′ UTRs, consistent with defect recycling. However, appears be 60S subunit, rather than because does not require an AUG codon suppressed overexpression dissociation Rli1/ABCE1. Consistent role, cannot...
Abstract There is no standard or widely effective treatment of patients with moderate aplastic anemia (MAA) hypo-productive uni-lineage cytopenias (UC). Eltrombopag (EPAG), a small molecule thrombopoietin mimetic, has previously been shown to result in durable multi-lineage hematologic responses low toxicity refractory severe (SAA). Its safety and efficacy MAA are unknown. This prospective phase 2 study enrolled untreated treated UC clinically relevant cytopenias. EPAG was administered at...
Abstract The recycling of ribosomes at stop codons for use in further rounds translation is critical efficient protein synthesis. Removal the 60S subunit catalyzed by ATPase Rli1 (ABCE1) while removal 40S thought to require Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR). However, it remains unclear how these Tma proteins cause control reinitiation downstream translation. Here we used a ribosome footprinting strategy directly observe intermediate steps cells. Deletion genes encoding resulted...
Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation replication; however, molecular basis for instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie unusual sensitivity replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within six with highest levels breakage, and their surrounding non-fragile (NCFSs). Chromatin most...
// Bao Nguyen 1,* , Allen B. Williams David J. Young 1,2 Hayley Ma 1 Li Mark Levis Patrick Brown and Donald Small Department of Oncology, Johns Hopkins University School Medicine, Baltimore, MD, USA 2 Pediatrics * These authors have contributed equally to this work Correspondence to: Small, email: Keywords : acute myeloid leukemia, mutant FLT3, activation loop, tyrosine kinase inhibitors Received December 16, 2016 Accepted 25, Published January 06, 2017 Abstract Fms -like kinase-3 (FLT3) is...
Abstract Pathogenic/likely pathogenic (P/LP) germline variants in RUNX1 cause familial platelet disorder with associated myeloid malignancies (FPDMM), also known as RUNX1- Familial Platelet Disorder (RUNX1-FPD, or FPD), a condition characterized by qualitative and quantitative defects predisposition to hematopoietic malignancies. Here, we present follow up case of woman acute leukemia lifelong thrombocytopenia which had previously been attributed presumptive (P) GATA2 missense variants....
Vertebrate mitochondria use stop codons UAA and UAG decoded by the release factor (RF) MTRF1L two reassigned arginine codons, AGA AGG. A second highly conserved RF-like factor, MTRF1, which evolved from a gene duplication of an ancestral mitochondrial RF1 not RF2, is good candidate for recognizing nonstandard codons. MTRF1 differs other RFs having insertions in external loops important codon recognition (tip helix alpha5 loop) key substitutions that are involved interactions eubacterial...
Chromosomal common fragile sites (CFSs) are genetically unstable regions of the genome that induced by conditions impair DNA replication. In this report, we show treatment with polymerase inhibitor, aphidicolin (APH), slows replication rate throughout S phase. To investigate unusual sensitivity CFSs to APH-induced stress, examined dynamics within a 50 kb region most frequently expressed CFS, FRA3B. We mapped four origins replication, ori 1–4, using two independent methods. untreated cells,...
The programmable nuclease technology CRISPR-Cas9 has revolutionized gene editing in the last decade. Due to risk of off-target editing, accurate and sensitive methods for characterization are crucial prior applying therapeutically. Here, we utilized a rhesus macaque model compare predictive values CIRCLE-seq, an vitro prediction method, with silico (ISP) based solely on genomic sequence comparisons. We use AmpliSeq HD error-corrected sequencing validate sites predicted by CIRCLE-seq ISP CD33...
Abstract Translation of the genetic code occurs in a cycle where ribosomes engage mRNAs, synthesize protein, and then disengage order to repeat process again. The final part this process—ribosome recycling, dissociate from mRNAs—involves complex molecular choreography specific protein factors remove large small subunits ribosome coordinated fashion. Errors can lead accumulation at stop codons or translation downstream open reading frames (ORFs). Ribosome recycling is also critical when...