A5063166319- Acute Myeloid Leukemia Research
- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- HER2/EGFR in Cancer Research
- Acute Lymphoblastic Leukemia research
- Functional Brain Connectivity Studies
- Advanced MRI Techniques and Applications
- Neonatal and fetal brain pathology
- Cancer, Hypoxia, and Metabolism
- Gene expression and cancer classification
- Medical Image Segmentation Techniques
- Cancer-related gene regulation
- Cancer Genomics and Diagnostics
- Neural dynamics and brain function
- Multiple Myeloma Research and Treatments
- Estrogen and related hormone effects
- Hemispheric Asymmetry in Neuroscience
- Growth Hormone and Insulin-like Growth Factors
- Vascular Tumors and Angiosarcomas
- Cancer Research and Treatments
- Voice and Speech Disorders
Astellas Pharma (United States)
2017-2025
Thomas Jefferson University
2025
The University of Texas MD Anderson Cancer Center
2019
Texas Tech University
2013-2016
Ipsen (United States)
2016
Washington University in St. Louis
2009-2015
NewYork–Presbyterian Hospital
2014
Arqule (United States)
2007-2013
Boston Biomedical (United States)
2010
IQVIA (United States)
2010
The cerebral cortex of the human infant at term is complexly folded in a similar fashion to adult but has only one third total surface area. By comparing 12 healthy infants born with young adults, we demonstrate that postnatal cortical expansion strikingly nonuniform: regions lateral temporal, parietal, and frontal expand nearly twice as much other insular medial occipital cortex. This differential may reflect regional differences maturity dendritic synaptic architecture birth and/or...
Application of resting state functional connectivity magnetic resonance imaging (fcMRI) to the study prematurely born infants enables assessment earliest forms cerebral and characterization its early development in human brain. We obtained 90 longitudinal fcMRI data sets from a cohort preterm aged 26 weeks postmenstrual age (PMA) through term equivalent at PMA-specific time points. Utilizing seed-based correlation analysis, we identified networks involving varied cortical regions, thalamus,...
The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy this class cancer therapeutics. Little is known about mechanism(s) these agents. Here we establish a model N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2 (methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (lapatinib), an inhibitor and ErbB1 kinases by chronically exposing lapatinib-sensitive ErbB2-overexpressing breast cells lapatinib, simulating clinic where lapatinib...
The met proto-oncogene is functionally linked with tumorigenesis and metastatic progression. Validation of the receptor tyrosine kinase c-Met as a selective anticancer target has awaited emergence inhibitors. Herein, we report ARQ 197 first non-ATP-competitive small molecule that selectively targets kinase. Exposure to resulted in inhibition proliferation c-Met-expressing cancer cell lines well induction caspase-dependent apoptosis constitutive activity. These cellular responses were...
We have established a population average surface-based atlas of human cerebral cortex at term gestation and used it to compare infant adult cortical shape characteristics. Accurate surface reconstructions for each hemisphere 12 healthy infants were generated from structural magnetic resonance imaging data using novel segmentation algorithm. Each was inflated, flattened, mapped standard spherical configuration, registered target sphere that reflected characteristics all 24 contributing...
Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible intensive chemotherapy are disappointing. This multicenter, open-label, phase trial randomized (2:1) untreated adults FLT3mut+ AML induction to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 were treatment...
Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of
Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying p53-responsive reporter. Among the compounds isolated were derivatives 9-aminoacridine (9AA), including antimalaria drug quinacrine, strongly induced p53 function and other types cancer cells....
Genes that are characteristic of only certain strains a bacterial species can be great biologic interest. Here we describe PCR-based subtractive hybridization method for efficiently detecting such DNAs and apply it to the gastric pathogen Helicobacter pylori . Eighteen specific monkey-colonizing strain (J166) were obtained by against an unrelated whose genome has been fully sequenced (26695). Seven J166-specific clones had no DNA sequence match 26695 genome, 11 other mixed, with adjacent...
Internal tandem duplications in fms-like tyrosine kinase 3 (FLT3-ITDs) are common acute myeloid leukemia (AML) and confer a poor prognosis. A sensitive specific assay for the detection of minimal residual disease (MRD) FLT3-ITD mutated AML could guide therapy decisions. Existing assays MRD have not been particularly useful because limited sensitivity. We developed mutations using next-generation sequencing. The initial validation this was performed by spiking fixed amounts mutant DNA into...
Abstract The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) patients with FLT3-mutated relapsed refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, treatment-emergent mutations were analyzed ADMIRAL trial. comutations...
Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction consolidation chemotherapy, maintenance therapy adult patients with newly diagnosed, non-favorable-risk AML.In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened 80 allocated to treatment. The was divided four parts:...
BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint determine the impact on survival pre- and/or post-HCT measurable residual disease (MRD), determined using highly sensitive assay FLT3-ITD mutations. Generally, associated improved relapse-free (RFS) participants detectable...
Abstract Background The GOSSAMER phase 2 study assessed the FMS ‐like tyrosine kinase 3 (FLT3) inhibitor gilteritinib as maintenance therapy in patients with FLT3 –internal tandem duplication ( ‐ITD) acute myeloid leukemia (AML) first complete remission without previous hematopoietic stem cell transplantation (HSCT). Methods Patients had to be within months of their last consolidation cycle and have completed recommended number cycles per local practice. inhibitors were allowed only during...
The human EGF receptor (HER) 2 tyrosine kinase is a survival factor for cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with anti-HER2 monoclonal antibody trastuzumab (Genentech, South San Francisco, CA), particularly in patients prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF inhibitor), but not trastuzumab, activates AMP-activated protein (AMPK), initiating metabolic stress response...
This paper describes the implementation of a biochemical and biophysical screening strategy to identify optimize small molecule Akt1 inhibitors that act through mechanism distinct from observed for kinase domain ATP-competitive inhibitors. With aid an unphosphorylated cocrystal structure 12j solved at 2.25 Å, it was possible confirm as consequence binding these novel inhibitors, ATP cleft contained number hydrophobic residues occlude expected. These Akt potently inhibit intracellular...
This study was undertaken to evaluate the influence of preterm birth and other factors on cerebral cortical maturation.We have evaluated effects folding by applying cartography methods a cohort 52 infants (<31 weeks gestation, mild or no injury conventional magnetic resonance imaging) 12 term-born control infants. All were at term-equivalent postmenstrual age.Preterm had lower values for global measures gyrification index (GI; 2.06 ± 0.07 vs 1.80 0.12, p < 0.001; preterm) surface area (CSA;...
Abstract Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 domain (TKD) mutations. Sequencing studies patients have uncovered less common, noncanonical (NC) mutations implicated secondary TKD TKI resistance. We report that gilteritinib active against NC resistance-causing vitro. A mutagenesis screen identified F691L, Y693C/N, G697S confer moderate resistance to...
Abstract Renal cell carcinoma (RCC) rarely acquires mutations in p53 tumor suppressor gene, suggesting that signaling this type might be repressed by some other mechanism. In fact, all four RCC-derived lines we tested maintained wild-type but were not capable of transactivating p53-responsive reporters and endogenous genes. protein RCC showed normal response to genotoxic stress, including accumulation, nuclear translocation, activation specific DNA binding. Functional expression analysis...
The aim of the Finland-United States Investigation NIDDM Genetics (FUSION) study is to identify genes that predispose type 2 diabetes or are responsible for variability in diabetes-related traits via a positional cloning and candidate gene approach. In previously published genome-wide scan 478 Finnish affected sibling pair (ASP) families (FUSION 1), strongest linkage results were on chromosomes 20 11. We now report second using an independent set 242 ASP 2), detailed analysis combined 737...
Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary tumors (PitNET). Their therapeutic effects mainly mediated by somatostatin receptors SST2 SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, either nonselective or activate SST2. However, nonfunctioning (NFPTs), the most common PitNET type, express SST3 finding peptides that this particular receptor has been very challenging. Therefore, main objective study...
Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status AML monocytic differentiation are implicated resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein RNA/protein profiling patients treated on a clinical trial the inhibitor venetoclax gilteritinib (Ven/Git) to characterize immunophenotypic,...