A5079819010- Migraine and Headache Studies
- Cardiovascular Syncope and Autonomic Disorders
- Trigeminal Neuralgia and Treatments
- Neuroscience and Neuropharmacology Research
- Cellular transport and secretion
- Diabetes Treatment and Management
- Hippo pathway signaling and YAP/TAZ
- Respiratory and Cough-Related Research
- Cell Adhesion Molecules Research
- Pharmacology and Obesity Treatment
- Retinal Development and Disorders
- Pancreatic function and diabetes
- Glycosylation and Glycoproteins Research
- Chronic Lymphocytic Leukemia Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Immune Cell Function and Interaction
- Sympathectomy and Hyperhidrosis Treatments
- Acute Lymphoblastic Leukemia research
- Nicotinic Acetylcholine Receptors Study
- Protein Kinase Regulation and GTPase Signaling
- Neurobiology and Insect Physiology Research
- Complement system in diseases
- Wnt/β-catenin signaling in development and cancer
- Chronic Myeloid Leukemia Treatments
- Endoplasmic Reticulum Stress and Disease
Ono Pharmaceutical (United States)
2023
Eli Lilly (United States)
2019-2022
Accadis Hochschule Bad Homburg
2021
University of Florida
2020
Columbus Oncology and Hematology Associates
2020
Institute of Molecular and Cell Biology
2009-2017
Agency for Science, Technology and Research
2015-2017
Duke University
2006
Duke University Hospital
2006
Duke Medical Center
2006
Abstract Hepatocellular carcinoma (HCC) is one of the leading causes cancer-related deaths globally. The identity and role cell surface molecules driving complex biological events to HCC progression are poorly understood, hence representing major lacunae in therapies. Here, combining SILAC quantitative proteomics biochemical approaches, we uncover a critical oncogenic Agrin, which overexpressed secreted HCC. Agrin enhances cellular proliferation, migration signalling. Mechanistically,...
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 GluA1 trafficking is unclear. Here we report that enriched dendrites and spines, along with endosomes. Significantly, mobilization endosomes into spines observed. Mechanistically, interacts K-ras GTPase via RA domain; following chemical LTP stimuli, recruited SNX27-enriched through...
Phox (PX) domain-containing sorting nexins (SNXs) are emerging as important regulators of endocytic trafficking. Sorting nexin 27 (SNX27) is unique, it contains a PDZ (Psd-95/Dlg/ZO1) domain. We show here that SNX27 primarily targeted to the early endosome by interaction its PX domain with PtdIns(3)P. Although ablation gene in mice did not significantly affect growth and survival during embryonic development, plays an essential role postnatal survival. N-Methyl-d-aspartate (NMDA) receptor 2C...
The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires internalization into endosomes, which then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor couples retromer trafficking complex. SNX27 binds directly C-terminal PDZ-binding motif PTHR, wiring it for endosomal sorting. structure bound reveals a high-affinity interface involving conserved electrostatic...
Coat protein II (COPII)-mediated export from the endoplasmic reticulum (ER) involves sequential recruitment of COPII complex components, including Sar1 GTPase, Sec23/Sec24 subcomplex, and Sec13/Sec31 subcomplex. p125A was originally identified as a Sec23A-interacting protein. Here we demonstrate that also interacts with C-terminal region Sec31A. The Sec31A-interacting domain is between residues 260-600, therefore distinct required for interaction Sec23A. Gel filtration immunodepletion...
To study the efficacy and safety of lasmiditan for acute treatment migraine in patients using preventive medications.While has been proven to be an effective migraine, its effectiveness not examined when used concurrently with preventives.SAMURAI SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies 18 years or older 3 8 attacks per month. Patients randomized treat a attack oral 50 mg (SPARTAN only), 100 mg, 200 placebo. Migraine preventives allowed as long doses...
Background Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine adults with moderate/severe disability two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated efficacy lasmiditan patients who reported a good or insufficient response triptans those were triptan naïve. Methods Subgroups reporting an overall “good” “poor/none” most recent use at baseline (defined as responders, respectively) triptan-naïve subpopulation...
Migraine is recognized as the second leading cause of disability globally. Lasmiditan a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment migraine. Here we analyzed effects lasmiditan on migraine assessed with Disability Assessment (MIDAS) scale interim data from long-term safety study.Completers two single-attack parent studies were offered participation in 1 year GLADIATOR study, that randomized participants to 100 mg or 200 taken needed attacks at least...
Abstract CTL clear virus‐infected cells and tumorigenic by releasing potent cytotoxic enzymes stored in preformed lytic granules. The exocytosis process includes polarization of granules toward the immunological synapse, tethering to plasma membrane finally fusion with release enzymes. Although much is known about molecular machineries necessary for earlier steps granule exocytosis, machinery governing final step has not been identified. Here, we show using control VAMP8 KO mice that...
Abstract Lasmiditan is a centrally penetrant, highly selective 5‐hydroxytryptamine (serotonin) receptor 1F (5HT ) agonist under development as novel therapy for acute treatment of migraine. A phase 1 randomized, placebo‐ and positive‐controlled crossover study assessed the abuse potential lasmiditan in adult recreational polydrug users. Following qualification phase, subjects were randomized into sequences, each consisting 5 treatments: placebo, alprazolam 2 mg, 100, 200 (lasmiditan 100 mg...
We studied the efficacy and safety of a second dose lasmiditan for acute treatment migraine. SAMURAI SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine randomized to oral 50 mg (SPARTAN only), 100 mg, 200 or placebo. Study drug was be taken within 4 h (h) onset attack (moderate severe pain). A study provided rescue (patient not pain-free at 2 took 2-24 post-first dose) recurrence h, but experienced mild, moderate, pain after first dose)....
Abstract Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation metabolic reprogramming. limits the of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). silencing human cells enhanced cell receptor (TCR)-stimulated activator...
Previous work demonstrated that a brief, sublethal excitotoxic insult strikingly increased the sensitivity of cortical neurons to cytotoxic effects terminal pathway complement, process termed “excitotoxic sensitization.” Here, we sought elucidate cellular mechanism sensitization in embryonic rat vitro . Excitotoxic did not increase membrane attack complex deposition on and produced only small reduction removal, because selective decrease endocytic elimination. Membrane complexes other...
To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared placebo in patients a baseline HbA1c less than 7% versus or higher.
Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled metformin 0.75 or 1.5 of dulaglutide. Effects such as nausea vomiting are commonly reported dulaglutide other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, stepwise dose-escalation scheme 4-week intervals between dose increments was suggested to mitigate gastrointestinal...
Abstract Background While pain freedom at 2 h is a key primary outcome for current trials acute treatment of migraine, the relationship between degree head and other efficacy measures has rarely been explored. Following lasmiditan migraine attack with moderate or severe pain, we contrast those who achieve mild but not post dosing. Methods Patient-level data were pooled across studies arms from two Phase 3 comparing placebo, SAMURAI SPARTAN. This hoc analysis assessed most bothersome symptom...
Dulaglutide (DU) 3 mg and 4.5 once weekly (QW) doses were recently approved for additional glycemic control in adult patients with type 2 diabetes. If needed, a dose-escalation scheme from 1.5 to then can be applied after at least 4-weeks on each dose. For GLP-1 receptor agonists, such as DU, common gastrointestinal (GI) side effects include nausea (N) vomiting (V). These GI are dose-dependent but attenuate over time chronic dosing. To enhance prescriber understanding of following dose...
Abstract Background We studied the efficacy and safety of a second dose lasmiditan for acute treatment migraine. Methods SAMURAI SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine randomized to oral 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was be taken within 4 hours (h) onset attack (moderate severe pain). A study provided rescue (patient not pain-free at 2h took 2-24h post-first dose) recurrence 2h, but experienced mild,...