Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes
Parkin J.D.,University of Melbourne |
San Antonio J.D.,Malvern Inc. |
Pedchenko V.,Vanderbilt University |
Hudson B.,Vanderbilt University |
And 2 more authors.
Human Mutation | Year: 2011
Collagen IV is the major protein found in basement membranes. It comprises three heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity. We constructed linear maps of the collagen IV heterotrimers ("interactomes") that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype-phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin, and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection, and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases, and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example, for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms, and muscle Cramps [HANAC] syndrome, and early-onset Alport syndrome, respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets. © 2011 Wiley-Liss, Inc.
Chieffo C.,Malvern Inc. |
Cook D.,Oregon Health And Science University |
Xiang Q.,Malvern Inc. |
Frohman L.A.,University of Illinois at Chicago
Journal of Clinical Endocrinology and Metabolism | Year: 2013
Context: Acromegaly is caused by excessive GH secretion and IGF-I overproduction. The goals of treatment are to reduce GH and IGF-I values to normal and relieve the associated symptoms. Objective: The purpose of this article was to demonstrate that an octreotide implant (84 mg) is safe and efficacious in patients with acromegaly who were responsive to prior monthly octreotide long-acting release (LAR) injections. Design: This was a phase 3, open-label study. Before treatment, subjects received a stable monthly dose of octreotide LAR injections (10-40 mg) for >;3 months. Randomization was in a 3: 1 ratio to either a 6-month octreotide implant or monthly octreotide LAR injections. Setting: This was a multicenter, international study conducted in private or institutional practices. Subjects: Enrollment included 163 subjects (aged >;18 years) with acromegaly. Main Outcome Measure: The efficacy, safety, and tolerability of the octreotide implant during 24 weeks of treatment was evaluated. Results: After 24 weeks, the success rate of the implant for maintenance of IGF-I and GH levels was 86% (95% confidence interval, 80.3%) compared with a rate of 84% (95% confidence interval, 73.8%) for octreotide LAR. Serum octreotide concentrations after implant insertion increased within 8 days and peaked between days 14 and 28. The overall safety of the octreotide implant and octreotide LAR were similar. Diarrhea and headache were more frequent with the implant, whereas cholecystitis and hypertension were more frequent with octreotide LAR. Conclusions: In this pivotal phase 3 study, the octreotide implant maintained reduced blood levels of GH and IGF-I with continuous octreotide release over 6 months, which was well tolerated. Copyright © 2013 by The Endocrine Society.
Ma L.,Malvern Inc. |
Danoff T.M.,Malvern Inc. |
Borish L.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2014
Background Anaphylaxis is a serious allergic reaction that can cause death; however, the actual risk of death is unclear. Objective We sought to estimate the case fatality rate among hospitalizations or emergency department (ED) presentations for anaphylaxis and the mortality rate associated with anaphylaxis for the general population. Methods This was a population-based epidemiologic study using 3 national databases: the Nationwide Inpatient Sample (NIS; 1999-2009), the Nationwide Emergency Department Sample (NEDS; 2006-2009), and Multiple Cause of Death Data (MCDD; 1999-2009). Sources for these databases are hospital and ED discharge records and death certificates, respectively. Results Case fatality rates were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients. The rate of anaphylaxis-related hospitalizations increased from 21.0 to 25.1 per million population between 1999 and 2009 (annual percentage change, 2.23%; 95% CI, 1.52% to 2.94%), contrasting with a decreasing case fatality rate among hospitalizations (annual percentage change, -2.35%; 95% CI, -4.98% to 0.34%). Overall mortality rates ranged from 0.63 to 0.76 per million population (186-225 deaths per year, MCDD) and appeared stable in the last decade (annual percentage change, -0.31%; 95% CI, -1.54% to 0.93%). Conclusion From 2006 to 2009, the overwhelming majority of hospitalizations or ED presentations for anaphylaxis did not result in death, with an average case fatality rate of 0.3%. Anaphylaxis-related hospitalizations increased steadily in the last decade (1999-2009), but this increase was offset by the decreasing case fatality rate among those hospitalized; both inpatient and overall mortality rates associated with anaphylaxis appeared stable and were well under 1 per million population. Although anaphylactic reactions are potentially life-threatening, the probability of dying is actually very low. With the prevalence of anaphylaxis on the increase, practitioners need to stay vigilant and follow the treatment guidelines to further reduce anaphylaxis-related deaths. © 2013 American Academy of Allergy, Asthma & Immunology.
Amin S.,Malvern Inc. |
Barnett G.V.,University of Delaware |
Pathak J.A.,MedImmune |
Roberts C.J.,University of Delaware |
Current Opinion in Colloid and Interface Science | Year: 2014
In this review, we attempt to give a concise overview of recent progress made in mechanistic understanding of protein aggregation, particulate formation and protein solution rheology. Recent advances in analytical techniques and methods for characterizing protein aggregation and the formed protein particles as well as advancements, technique limitations and controversies in the field of protein solution rheology are discussed. The focus of the review is primarily on biotherapeutics and proteins/antibodies that are relevant to that area. As per the remit of Current Opinion in Colloid and Interface Science, here we attempt to stimulate interest in areas of debate. While the field is certainly not mature enough that all problems may be considered resolved and accepted by consensus, we wish to highlight some areas of controversy and debate that need further attention from the scientific community. © 2014.
Bell M.R.,Malvern Inc. |
Engleka M.J.,Malvern Inc. |
Malik A.,Malvern Inc. |
Strickler J.E.,Malvern Inc.
Protein Science | Year: 2013
Since the dawn of time, or at least the dawn of recombinant DNA technology (which for many of today's scientists is the same thing), investigators have been cloning and expressing heterologous proteins in a variety of different cells for a variety of different reasons. These range from cell biological studies looking at protein-protein interactions, post-translational modifications, and regulation, to laboratory-scale production in support of biochemical, biophysical, and structural studies, to large scale production of potential biotherapeutics. In parallel, fusion-tag technology has grown-up to facilitate microscale purification (pull-downs), protein visualization (epitope tags), enhanced expression and solubility (protein partners, e.g., GST, MBP, TRX, and SUMO), and generic purification (e.g., His-tags, streptag, and FLAGTM-tag). Frequently, these latter two goals are combined in a single fusion partner. In this review, we examine the most commonly used fusion methodologies from the perspective of the ultimate use of the tagged protein. That is, what are the most commonly used fusion partners for pull-downs, for structural studies, for production of active proteins, or for large-scale purification? What are the advantages and limitations of each? This review is not meant to be exhaustive and the approach undoubtedly reflects the experiences and interests of the authors. For the sake of brevity, we have largely ignored epitope tags although they receive wide use in cell biology for immunopreciptation. © 2013 The Protein Society.
Constantine G.D.,Malvern Inc.
Menopause | Year: 2016
OBJECTIVE:: To examine the effect of ospemifene 60?mg/d on vasomotor symptoms in postmenopausal women using clinical safety and efficacy data from five phase 2 and 3 studies. METHODS:: The incidence of hot flush treatment-emergent adverse events (TEAEs) was compiled from five randomized, placebo-controlled clinical studies; baseline parameters associated with hot flush incidence were also identified. Ospemifeneʼs effects on the frequency and severity of hot flushes were evaluated in a previously unpublished, 6-week, placebo-controlled study. RESULTS:: Analysis of pooled hot flush TEAE data for 2,166 women showed an incidence of hot flush of 8.5% for ospemifene and 3.2% for placebo (P?0.0001). Hot flushes were most frequent during the first 4 weeks of ospemifene treatment and decreased in frequency thereafter. Logistic regression analysis revealed that hormone therapy within 6 months before study start (P?=?0.0234), longer study treatment duration (P?=?0.0234), and more hot flush days per month at baseline (P?=?0.0313) were associated with more hot flushes. Ospemifene 60?mg/d did not worsen the frequency and severity of existing hot flushes in a 6-week, placebo-controlled trial of 198 postmenopausal women who were experiencing moderate to very severe hot flushes. CONCLUSIONS:: In randomized trials, hot flush TEAEs were more frequent with ospemifene 60?mg/d than with placebo, particularly among women with prior history of hormone therapy use. The majority of hot flushes, however, waned after 4 weeks of ospemifene treatment. Ospemifene did not worsen existing hot flushes in women experiencing moderate to very severe hot flushes. © 2016 by The North American Menopause Society.
Barber W.P.F.,Malvern Inc.
Water Research | Year: 2016
A review concerning the development and applicability of sewage sludge thermal hydrolysis especially prior to anaerobic digestion is presented. Thermal hydrolysis has proven to be a successful approach to making sewage sludge more amenable to anaerobic digestion. Currently there are 75 facilities either in operation or planning, spanning several continents with the first installation in 1995. The reported benefits of thermal hydrolysis relate to: increased digestion loading rate due to altered rheological properties, improved biodegradation of (especially activated) sludge and enhanced dewaterability. In spite of its relative maturity, there has been no attempt to perform a critical review of the pertinent literature relating to the technology. Closer look at the literature reveals complications with comparing both experimental- and full-scale results due to differences in experimental set-up and capability, and also site-specific conditions at full-scale. Furthermore, it appears that understanding of thermodynamic and rheological properties of sludge is key to optimizing the process, however these parameters are largely overlooked by the literature. This paper aims to bridge these complexities in order to elucidate the benefits of thermal hydrolysis for sewage treatment, and makes recommendations for further development and research. © 2016 Elsevier Ltd
Robertson D.S.,Malvern Inc.
Biomedicine and Preventive Nutrition | Year: 2013
Biochemical reactions, which give rise to the conversion of triglycerides to carbohydrates and the conversion of carbohydrates to triglycerides, along with identification of the metabolic cells in which these processes take place are detailed. The relationship of these processes to the condition of obesity in humans is considered and it is shown that the development of obesity is a malfunction of the metabolism. Possible treatments to limit the induction of obesity are proposed and the link of obesity to relevant chemical compounds in the diet is discussed. © 2012 Elsevier Masson SAS.
Robertson D.S.,Malvern Inc.
Clinical Biochemistry | Year: 2011
The imidazole structure is involved in the formation of several compounds in the human metabolism including methyl imidazole, imidazole acetic acid, histidine, histamine, carnosine and homocarnosine. A number of these compounds are widely distributed metabolites such as histamine which is present in basophil and mast cells as well as being present in muscle and brain cells. This work advances detailed proposals on the metabolic chemical reactions which produce and decompose the compounds. The activity of these compounds in detrimental allergic medical conditions is discussed and the origin of the medical observations of the imidazole based medical compound known as cimetidine is discussed. © 2011 The Canadian Society of Clinical Chemists.