A5039668456- Orthopedic Surgery and Rehabilitation
- Shoulder Injury and Treatment
- Musculoskeletal synovial abnormalities and treatments
- Shoulder and Clavicle Injuries
- Traumatic Ocular and Foreign Body Injuries
- Elbow and Forearm Trauma Treatment
- Tendon Structure and Treatment
- Sarcoma Diagnosis and Treatment
- Peripheral Nerve Disorders
- Testicular diseases and treatments
- Foreign Body Medical Cases
- Infectious Diseases and Tuberculosis
- Trauma Management and Diagnosis
- Orthopedic Infections and Treatments
- Urological Disorders and Treatments
- Hernia repair and management
- Bone Tumor Diagnosis and Treatments
- Bone fractures and treatments
- Nerve Injury and Rehabilitation
- Appendicitis Diagnosis and Management
- Sports injuries and prevention
- Hip disorders and treatments
- Mitochondrial Function and Pathology
- Urologic and reproductive health conditions
- Gastrointestinal disorders and treatments
AbbVie (United States)
2017-2025
Vanderbilt University
2015-2025
Washington University in St. Louis
2024
Vanderbilt University Medical Center
2019-2024
Sparsh Hospital
2024
University of South Alabama
2023
University of Liverpool
2022
Kettering University
2012-2021
AbbVie (Japan)
2018-2019
University of Illinois Chicago
2011-2019
Due to their strict maternal inheritance in most animals and plants, mitochondrial genomes are predicted accumulate mutations that beneficial or neutral females but harmful males. Although a few male-harming mtDNA have been identified, consistent with this ‘Mother’s Curse’, effect on has largely unexplored. Here, we identify COIIG177S, hypomorph of cytochrome oxidase II, which specifically impairs male fertility due defects sperm development function without impairing other female functions....
The urgent need for novel HCV antiviral agents has provided an impetus understanding the structural requisites of NS5B polymerase inhibitors at molecular level. Toward this objective, comparative field analysis (CoMFA) and similarity indices (CoMSIA) 67 were performed using two methods. First, ligand-based 3D QSAR studies based on lowest energy conformations employing atom fit alignment method. Second, receptor-based models derived from predicted binding obtained by docking all allosteric...
The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize pathways block activation the host immune response. Here, we show that recurrent antagonism has shaped evolution protein MAVS—a crucial viral-sensing pathway in primates. From sequencing and phylogenetic analyses MAVS from 21 simian primates, found evolved under strong positive selection. We focused how this selection MAVS'...
We here describe the first reported comprehensive analysis of Hsp90 paralogue affinity and selectivity in clinical inhibitor chemotypes. This has been possible through development a versatile experimental assay based on new FP-probe (16a) that we both here. The can test rapidly accurately binding all major chemotypes testing range spans low nanomolar to millimolar affinities. couple this with computational allows for rationalization defines not only modes relay pan-paralogue or, conversely,...
Anti-cancer immunotherapy is encountering its own checkpoint. Responses are dramatic and long lasting but occur in a subset of tumors largely dependent upon the pre-existing immune contexture individual cancers. Available data suggest that three landscapes best define cancer microenvironment: <b><i>immune-active</i></b>, <b><i>immune-deserted immune-excluded</i></b>. This trichotomy observable across most solid (although frequency each landscape varies depending on tumor tissue origin)...
Abstract The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers been recruited to participate cognitive, neuropsychologic, imaging, fluid biomarkers, genomic multi-omic studies. Tissue longitudinal data collected foster, facilitate, support on dementia aging....
Grp94 is involved in the regulation of a restricted number proteins and represents potential target host diseases, including cancer, septic shock, autoimmune chronic inflammatory conditions, diabetes, coronary thrombosis, stroke. We have recently identified novel allosteric pocket located N-terminal binding site that can be used to design ligands with 2-log selectivity over other Hsp90 paralogs. Here we perform extensive SAR investigations this ligand series rationalize affinity paralog...
Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies the discovery development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure–activity relationship studies first rationally designed inhibitor class that binds to a novel...
Background CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages destroy tumor stroma. Systemic administration of agonists has historically been associated with considerable toxicity, providing the rationale for development tumor-targeted immunomodulators improve clinical safety efficacy. This phase I study assessed safety, tolerability, preliminary activity, biomarkers ABBV-428, a first-in-class,...
Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin carboplatin combined etoposide [CE]) frontline treatment of extensive-stage SCLC.One cycle CE pre-enrollment permitted (later mandated). The following four cohorts were enrolled: monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); induction q6 2) followed by 21...
The discovery and development of heat shock protein 70 (Hsp70) inhibitors is currently a hot topic in cancer. In the preceding paper this issue (10.1021/jm401551n), we have described structure–activity relationship studies first Hsp70 inhibitor class rationally designed to bind novel allosteric pocket located N-terminal domain protein. These ligands contained an acrylamide take advantage active cysteine embedded acted as covalent modifiers upon binding. Here, perform chemical modifications...
Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, 16.2 The electrophilic 2-position...
Abstract Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking P‐glycoprotein moderate CYP3A verapamil, a drug commonly administered to patients hypertension, ischemic heart disease, or atrial fibrillation. Age‐matched controls normal function concurrently. Subjects’ overall mean age was 59 years. Mean creatinine clearance values 2 groups 105 71 mL/min. After single 20‐mg oral doses, area...
As fundamental units of neuronal communication, chemical synapses are composed presynaptic and postsynaptic specializations that form at specific locations with defined shape size. Synaptic assembly must be tightly regulated to prevent overgrowth the synapse size number, but molecular mechanisms inhibit poorly understood. We identified regulator synaptogenesis-1 (RSY-1) as an evolutionarily conserved molecule locally antagonized assembly. The loss RSY-1 in Caenorhabditis elegans led...
This phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. The a randomized, double-blind, placebo-controlled carried out two parts addition third part involving an open-label food/sex effect. A total 100 subjects were enrolled into as follows: I—single-dose with 10, 25, 50, 100, 150, 200, 300 mg (n = 56); II—multiple-dose every other day dosing 32); III—sex food effect 150 12; open-label)....
Cooperation and cheating are widespread evolutionary strategies. While confers an advantage to individual entities within a group, competition between groups favors cooperation. Selfish or cheater mitochondrial DNA (mtDNA) proliferates hosts while being selected against at the level of host fitness. How does environment shape dynamics across different selection levels? Focusing on food availability, we address this question using heteroplasmic Caenorhabditis elegans . We find that...
Abstract Diseases are a manifestation of how thousands proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting reversing defective chaperomes. Here we provide structural, biochemical, functional insights into the discovery epichaperome probes, with focus on their use central...