A5048375394- Osteoarthritis Treatment and Mechanisms
- Inflammatory mediators and NSAID effects
- Rheumatoid Arthritis Research and Therapies
- Hepatitis B Virus Studies
- Cell Adhesion Molecules Research
- Total Knee Arthroplasty Outcomes
- Hepatitis C virus research
- Liver Disease Diagnosis and Treatment
- Knee injuries and reconstruction techniques
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Proteoglycans and glycosaminoglycans research
- Computational Drug Discovery Methods
- Mental Health and Patient Involvement
- Virus-based gene therapy research
- Dental Implant Techniques and Outcomes
- Systemic Lupus Erythematosus Research
- Protease and Inhibitor Mechanisms
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Metabolomics and Mass Spectrometry Studies
- Respiratory and Cough-Related Research
- Bone Metabolism and Diseases
- Temporomandibular Joint Disorders
- Chemokine receptors and signaling
University of Oulu
2024
GlaxoSmithKline (United States)
2012-2023
GlaxoSmithKline (United Kingdom)
2014-2022
GlaxoSmithKline (Netherlands)
2019
Target (United States)
2012-2015
Eli Lilly (United States)
2003-2006
Indiana University School of Medicine
2006
Indiana University – Purdue University Indianapolis
2006
Thomas Jefferson University
1995-2001
Transient receptor potential vanilloid 4 (TRPV4) channels are expressed in human heart failure lungs, which can be blocked to prevent and resolve failure–induced pulmonary edema.
Objectives Osteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline analysed using a machine learning approach order study OA-dominant phenotypes driven by endotype-related clusters discover driving features their disease-context meaning. Method Data quality assessment was performed appropriate data preprocessing...
The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection small molecule binders from complex mixtures by DNA tagging. Selection against four-billion member ELT led to novel inhibitor scaffold not containing classical zinc-binding functionality. One exemplar,...
Objective/MethodAggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated vitro, ex vivo systems utilized assess target engagement, aggrecanase inhibition modulation of disease-related endpoints with the intent selecting a candidate for clinical development osteoarthritis (OA).ResultsStructural mapping predicts potent mAbs employ unique mode by cross-linking catalytic...
The key metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25-D3), induces rapid cellular responses that constitute a so-called "non-genomic" response. This effect is distinguished from its "classic" genomic role in calcium homeostasis involving the nuclear 1,25-D3 receptor. Evidence presented protein kinase C (PKC) directly activated by at physiological concentrations (EC50 = 16 ± 1 nM). was demonstrable with single PKC-α, -γ, and -∊ isoform preparations, assayed system containing only...
Abstract Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective selecting patients who would benefit from a therapy being tested. Typically majority of selected show no or limited disease progression during trial period. As consequence, the effect tested treatment cannot be observed, and efforts resources invested running rewarded. This could avoided, if selection were more predictive future progression. In this article, we formulated patient problem as...
Purpose The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, biochemical markers, support OA drug development. Participants APPROACH is a prospective cohort study including 297 tibiofemoral OA, according the American College of Rheumatology classification criteria. Patients were (pre)selected from...
Based on marked differences in the enzymatic properties of diacylglycerols compared with phorbol ester-activated protein kinase C (PKC), we recently proposed that activation induced by these compounds may not be equivalent (Slater, S. J., Kelly, M. B., Taddeo, F. Rubin, E., and Stubbs, C. D. (1994) J. Biol. Chem. 269, 17160-17165). In present study, direct evidence is provided showing esters bind simultaneously to PKC alpha. Using a novel binding assay employing fluorescent ester,...
The key signal transduction enzyme protein kinase C (PKC) contains a hydrophobic binding site for alcohols and anesthetics (Slater, S. J., Cox, K. J. A., Lombardi, V., Ho, C., Kelly, M. B., Rubin, E., Stubbs, C. D. (1993) Nature 364, 82-84). In this study, we show that interaction of n-alkanols general with PKCalpha results in dramatically different effects on membrane-associated compared lipid-independent activity. Furthermore, the differ markedly depending whether activity is induced by...
Objective To investigate the association of lipidomic profile with osteoarthritis (OA) severity, considering outcomes radiographic knee and hand OA, pain function. Design We used baseline data from Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons OA fulfilling clinical American College Rheumatology classification criteria. Radiographic severity was quantified Kellgren–Lawrence sum scores. Knee function were assessed validated...
The use of type I interferon (IFN), in combination with ribvirin, to treat chronic hepatitis C virus (HCV) infection has many drawbacks that prevent widespread application, ultimately leading a significant unmet clinical need. Potential improvements IFN therapy through targeted delivery, molecular alteration, and other agents are ongoing an attempt decrease adverse effects increase efficacy. In this report, the HCV replicon cell culture system was used assess potential synergistic antiviral...
Objectives Osteoarthritis (OA) patients with a neuropathic pain (NP) component may represent specific phenotype. This study compares joint damage, and functional disability between knee OA likely NP component, those without component. Methods Baseline data from the Innovative Medicines Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway cohort were used. Patients painDETECT score ≥19 (with n=24) matched on 1:2 ratio to ≤12 (without component), similar general...
A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed rapid and low-cost screening of crystal polymorphism (i.e. molecular crystallographic arrangement or internal structure) habit shape external structure). The involves a ternary solvent system consisting dispersed phase two miscible fluids, one which the active pharmaceutical ingredient (API) is soluble (solvent) API insoluble (antisolvent). immiscible with...
Epidemiologic observations show a higher frequency of hepatitis B virus (HBV) serologic markers in chronic alcoholics compared with the general population. This may be result an increased susceptibility to infection and/or ethanol-mediated stimulation HBV gene expression and replication. To test latter hypothesis, transgenic SCID mice, which support consistent levels replication, were fed standard Lieber-DiCarli or isocaloric diet for 5 weeks. In ethanol-fed surface antigen (HBsAg) viral DNA...
Abstract NK T (NKT) cells are an important component of the innate immune system and recognize MHC class I-like CD1d molecule. NKT possess significant immunoregulatory activity due to their rapid secretion large quantities pro- anti-inflammatory cytokines following CD1d-dependent stimulation. Because is programmed respond a multitude diverse stimuli must be able quickly differentiate between pathogenic endogenous signals, we hypothesized that, apart from stimulation via TCR (e.g.,...
Abstract Osteoarthritis (OA) is the most common form of arthritis and a major source pain disability in adult population. There significant unmet medical need for development effective pharmacological therapies treatment OA. In addition to spontaneously occurring animal models OA, many experimental have been developed provide insights into mechanisms pathogenesis progression. Many these are also being used drug pipeline. Here, we an overview commonly emerging preclinical small OA highlight...
Abstract The effect of variation the degree cis ‐unsaturation on cell membrane protein functioning was investigated using a model lipid bilayer system and kinase C (PKC). This is key element signal transduction. Furthermore it representative class extrinsic proteins that show dependent interactions with membranes. To test for dependence activity phospholipid unsaturation, experiments were devised vesicle assay consisting phosphatidylcholine (PC) phosphatidylserine (PS) in which unsaturation...