A5034544407- Glioma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Acute Myeloid Leukemia Research
- Hippo pathway signaling and YAP/TAZ
- Antimicrobial Peptides and Activities
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Amino Acid Enzymes and Metabolism
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Neuropeptides and Animal Physiology
- Monoclonal and Polyclonal Antibodies Research
- Hypothalamic control of reproductive hormones
- Estrogen and related hormone effects
- Menopause: Health Impacts and Treatments
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Click Chemistry and Applications
- 14-3-3 protein interactions
- Retinoids in leukemia and cellular processes
- Hematopoietic Stem Cell Transplantation
- Nerve injury and regeneration
- Immunotherapy and Immune Responses
Fred Hutch Cancer Center
2008-2024
Rensselaer Polytechnic Institute
2016
University of Washington Bothell
2013-2016
Albany Molecular Research (United States)
2014
University of Washington
2005-2008
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2007-2008
Cancer Research Center
2008
TNFα levels are elevated in the marrows of patients with myelodysplastic syndrome (MDS) and associated high rates apoptosis, which contributes to hematopoietic failure. We observed that exposure human marrow stroma cell lines HS5 HS27a increases IL-32 mRNA. IL-32, turn, induces TNFα. Marrow from MDS expressed 14- 17-fold higher mRNA than healthy controls. In contrast, cells chronic myelomonocytic leukemia (CMML) only one tenth level measured Human KG1a underwent apoptosis when cocultured...
Protein:protein interactions are among the most difficult to treat molecular mechanisms of disease pathology. Cystine-dense peptides have potential disrupt such interactions, and used in drug-like roles by every clade life, but their study has been hampered a reputation for being produce, owing complex disulfide connectivity. Here we describe platform identifying target-binding cystine-dense using mammalian surface display, capable interrogating high quality diverse scaffold libraries with...
Abstract Background Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics identified few promising drugs, HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant models to identify validate other effective HDACi their biomarkers...
The G-protein-coupled receptor (GPCR) GPR54 is essential for the development and maintenance of reproductive function in mammals. A point mutation (L148S) second intracellular loop (IL2) causes idiopathic hypogonadotropic hypogonadism, a disorder characterized by delayed puberty infertility. Here, we characterize molecular mechanism which L148S disease address role IL2 Class GPCR function. Biochemical, immunocytochemical, pharmacological analysis demonstrates that does not affect expression,...
A scorpion-derived peptide-steroid conjugate accumulates in cartilage and reverses inflammation a rat model of arthritis without steroid toxicity.
The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes treatment central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drug-delivery vehicles. Found throughout phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities...
Summary Aberrant regulation of the tumour necrosis factor alpha gene ( TNF ) and stroma‐derived signals are involved in pathophysiology myelodysplasia. Therefore, KG1a, a myeloid leukaemia cell line, was exposed to Tnf absence or presence either HS‐5 HS‐27a cells, two human stroma lines. While KG1a cells were resistant Tnf‐induced apoptosis Tnf‐promoted co‐culture experiments with cells. To investigate from we examined expression changes after exposure. DNA microarray studies found both...
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. describe herein further structure-activity relationship exploration this series via an optimization strategy that primarily focused on sulfonamide benzamide appendages scaffold. These efforts led to identification advanced leads possessing a desirable balance excellent in vitro GlyT-1...
Estradiol can protect the brain from a variety of insults by activating membrane-initiated signaling pathways, and thereby modulate gene expression lead to functional changes in neurons. These direct neuronal effects hormone have been well documented; however, it is less understood what estradiol may on nonneuronal cells central nervous system. There evidence that levels induce release glial-derived growth factors other cytokines, suggesting both directly indirectly To determine whether...
Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, not as developed those small-molecule antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) Rosetta protein modeling software prediction of 4298 CDP scaffolds performed in silico prescreening binders to interest. Mammalian...
While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development robust cell-based assays relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present modified gene trap approach efficiently generate pathway-specific reporters that result "on" signal when the pathway interest is inhibited. In proof-of-concept study, used vemurafenib...
Diffuse intrinsic pontine glioma (DIPG) remains a universally fatal childhood cancer with median survival of less than 1 year. Focal radiation the standard care as surgical resection is impossible and conventional cytotoxic chemotherapy has very limited efficacy. Building on success other autopsy-derived DIPG cell cultures, we have created novel patient-derived culture, PBT-14FHTC, characterized by mutations in H3FA3, TP53, amplifications PDGFRα cKIT. Previous work demonstrated efficacy...
Abstract Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration local therapeutic delivery. However, clinical hydrogels encounter challenges related inconsistent exposure, unmodifiable release windows, difficulties subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible as a depot, utilizing poly(ethylene glycol)...
Abstract Glioblastoma multiforme (GBM) is one of the most aggressive and invasive types brain cancer, but targeted treatment options remain elusive. The standard care (surgery chemotherapy radiation) falls far short where it should be with two-year survival rates less than 10%. Using stem cell isolates from GBM patients, we found that perturbing PHF5A, a component spliceosome machinery, was lethal caused hundreds genes to mis-spliced. These mis-splicing events included both exon skipping...
Abstract Antibody-drug conjugates (ADCs) have been FDA approved for the targeted delivery of chemotherapy to cancer. However, ADCs are limited solid tumors and brain cancer by their poor penetration inability cross blood-brain-barrier. A number groups shown that cystine-knot peptides (knottins) can be modified in ways allow them target cells. Our lab demonstrated an optide (optimized knottin-peptides) conjugate such as chlorotoxin-Cy5.5 able accumulate throughout intact blood-brain barrier....
Abstract The HIPPO pathway plays a critical role in contact inhibition, that is commonly dysregulated many human cancers (including liver, colon, ovarian, and lung) which relies on the intranuclear interaction of transcriptional coactivator YAP transcription factor TEAD(1-4). This also crucial recovery from injury; for example, its regulated repression allows hepatocytes to divide replace tissue lost partial hepatectomy, after activation suppresses cell growth prevents overgrowth. While...