A5032939076- Advanced biosensing and bioanalysis techniques
- Cutaneous lymphoproliferative disorders research
- Nonmelanoma Skin Cancer Studies
- Migraine and Headache Studies
- Cancer-related Molecular Pathways
- DNA and Nucleic Acid Chemistry
- Ubiquitin and proteasome pathways
- Signaling Pathways in Disease
- Neuroscience of respiration and sleep
- RNA and protein synthesis mechanisms
- Trigeminal Neuralgia and Treatments
- Eosinophilic Disorders and Syndromes
- Autoimmune Bullous Skin Diseases
- Autoimmune and Inflammatory Disorders
- Cancer and Skin Lesions
- Drug-Induced Adverse Reactions
- Skin and Cellular Biology Research
- Urologic and reproductive health conditions
- Cutaneous Melanoma Detection and Management
- Chemical synthesis and alkaloids
- Synthesis and Biological Activity
- Sarcoidosis and Beryllium Toxicity Research
- Infectious Diseases and Mycology
- Dermatological and Skeletal Disorders
- Cell death mechanisms and regulation
Bristol-Myers Squibb (Germany)
2024
Bristol-Myers Squibb (United States)
2007-2022
Scripps Research Institute
2018
Icahn School of Medicine at Mount Sinai
2010-2015
SUNY Upstate Medical University
2002-2014
National Instruments (United States)
2013
Mount Sinai Medical Center
2009-2012
Royal Children's Hospital
2011
Murdoch Children's Research Institute
2011
Salford Royal Hospital
2009
Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation this chiral motif has long been hampered by the systemic use phosphorus(III) [P(III)]-based reagent systems sole practical means assembly. A fundamentally different approach is described herein: invention a...
Stress signals activate the SAPK/JNK and p38 MAPK classes of protein kinases, which mediate cellular responses, including steps in apoptosis maturation some cell types. We now show that stress initiated by transforming growth factor-β1 (TGF-β1) induce G1 arrest through stabilization CDK inhibitor p21Cip1. TGF-β1 was previously shown to increase p21 levels, turn mediated inactivation CDK2-cyclin E complex HD3 cells (Yan, Z., Kim, G.-Y., Deng, X., Friedman, E. (2002) J. Biol. Chem. 277,...
The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food Drug Administration approvals for therapeutic oligonucleotides, by far most which contain modified phosphate linkages. These unnatural linkages have desirable biological physical properties but are often accessed difficulty using phosphoramidite chemistry. We report a flexible efficient [P(V)]–based platform that can install wide variety will into...
Elevated levels of the cyclin-dependent kinase (CDK) inhibitor p27 block cell in G0/G1 until mitogenic signals activate G1 cyclins and initiate proliferation. Post-translational regulation by different phosphorylation events is critical allowing cells to proceed through cycle. We now demonstrate that arginine-directed kinase, Mirk/dyrk1B, maximally active G0 NIH3T3 cells, when it stabilizes phosphorylating at Ser-10. The phospho-mimetic mutant p27-S10D was more stable, non-phosphorylatable...
Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still developing area of research. We have observed that some can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use combination vitro, vivo, bioinformatics approaches to identify sequence design algorithm, which reduce the number acutely toxic molecules synthesized tested find cellular assay measuring...
The phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3beta (GSK3beta) has been shown to be required for the ubiquitination and nuclear export its subsequent degradation in proteasome. mutation nearby residue, 288, nonphosphorylatable alanine also reduce D1, suggesting that 288 may lead D1. We now demonstrate G(0)/G(1)-active arginine-directed protein Mirk/dyrk1B binds phosphorylates vivo D1-T288A construct is more stable than wild-type Transient overexpression Mirk...
The kinase Mirk/dyrk1B is essential for the differentiation of C2C12myoblasts. Mirk reinforces G0/G1 arrest state inwhich occurs by directly phosphorylating and stabilizingp27Kip1 destabilizing cyclin D1. We now demonstrate that Mirkis anti-apoptotic in myoblasts. Knockdown endogenous RNAinterference activated caspase 3 decreased myoblast survival 75%,whereas transient overexpression increased cell survival. exertsits effects during muscle at least partthrough on cycle inhibitor pro-survival...
ObjectiveHuman genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA fibrosis model, several ASO and approaches are being tested clinically as potential therapies non-alcoholic steatohepatitis (NASH).. The aim this study was to assess the therapeutic advanced NASH-like hepatic vivo...
Mirk/dyrk1B is a member of the dyrk/minibrain family serine/threonine kinases that mediate transition from growth to differentiation in lower eukaryotes and mammals. Depletion endogenous Mirk C2C12 myoblasts by RNA interference blocks skeletal muscle (Deng, X., Ewton, D., Pawlikowski, B., Maimone, M., Friedman, E. (2003) J. Biol. Chem. 278, 41347-41354). We now demonstrate knockdown transcription regulatory factor myogenin. Co-expression with MEF2C, but not MyoD or Myf5, enhanced activation...
Abstract Ductal adenocarcinoma of the pancreas is almost uniformly lethal as this cancer invariably detected at an advanced stage and resistant to treatment. The serine/threonine kinase Mirk/Dyrk1B has been shown be antiapoptotic in rhabdomyosarcomas. We have now investigated whether Mirk might mediate survival another which widely expressed, pancreatic ductal adenocarcinoma. was active each cell line where it detected. knockdown by RNA interference (RNAi) reduced clonogenicity Panc1 cells...
Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to family secreted proteins expressed within normal cells. GKN2 expression frequently lost during GC progression, suggesting an inhibitory role; however, causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice investigate the functional impact loss in...
Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification potent and orally bioavailable compounds has challenging. Herein, we describe conceptualization, synthesis, preclinical characterization a potent, active CGRP antagonist 5 (BMS-846372). Compound good oral bioavailability rat, dog, cynomolgus monkeys overall attractive properties including strong (>50% inhibition) exposure-dependent vivo...
Abstract Rhabdomyosarcoma is the most common sarcoma in children and difficult to treat if primary tumor nonresectable or disease presents with metastases. The function of serine/threonine kinase Mirk was investigated this cancer. has both growth arrest survival functions terminally differentiating skeletal myoblasts. Maintenance properties would cause down-regulation transformed Alternatively, expression be retained rhabdomyosarcoma cells used capability. significant 12 16 clinical cases...
Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, spectrum neurodegenerative disorders characterized by accumulation hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, pragmatic therapeutic approach may to intervene at level transcript, as it makes no assumptions mechanisms toxicity. Here we performed large library screen locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where...
Acquired Perforating Dermatosis (APD) is a perforating disease characterized by transepidermal elimination of dermal material [1,2]. This usually develops in adulthood. APD has been reported to occur association with various diseases, but most commonly associated dialysis-dependent chronic renal failure (CRF) or diabetes mellitus (DM) [1,2,3,4]. Morton et al found that occurs up 10% patients undergoing hemodialysis [5]. Additionally, Saray sixteen twenty-two cases were CRF [3].
In 68 patients with anorectal malformations cardiovascular anomalies (CVA) were seen in 15 and genitourinary (GU) 30. CVA more frequent (33%) whenever there was a GU anomaly. Ventricular septal defect the most lesion. All but 1 occurred type III malformation. The complexity of cardiac lesion did not parallel that
We report a 50-year-old woman who presented with six-month history of recurrent retiform purpura uncertain etiology. Laboratory findings included neutropenia, positive anticardiolipin IgM antibody, and weakly p-ANCA. Histopathology revealed leukocytoclastic vasculitis intravascular thrombi. Urine toxicology screen was for cocaine. These are similar to recent reports agranulocytosis induced by levamisole-tainted A review the clinical histopathological associated levamisole-induced will be discussed.