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Search Results: 1 - 10 of 290341 matches for " David B O’Gorman "
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Molecular mechanisms and treatment strategies for Dupuytren’s disease
David B OGorman, Linda Vi, Bing Siang Gan
Therapeutics and Clinical Risk Management , 2010, DOI: http://dx.doi.org/10.2147/TCRM.S9165
Abstract: lecular mechanisms and treatment strategies for Dupuytren’s disease Review (3400) Total Article Views Authors: David B O’Gorman, Linda Vi, Bing Siang Gan Published Date August 2010 Volume 2010:6 Pages 383 - 390 DOI: http://dx.doi.org/10.2147/TCRM.S9165 David B O’Gorman1,2,3,4, Linda Vi1,2,5, Bing Siang Gan1,2,3,5,6 1Cell and Molecular Biology Laboratory, 2The Hand and Upper Limb Centre, St. Joseph’s Health Care London, Schulich School of Medicine and Dentistry, 3Departments of Surgery, 4Biochemistry, 5Physiology and Pharmacology, 6Medical Biophysics, The University of Western Ontario, London, OT, Canada Abstract: Dupuytren’s disease (DD) is a common disease of the hand and is characterized by thickening of the palmar fascia and formation of tight collagenous disease cords. At present, the disease is incurable and the molecular pathophysiology of DD is unknown. Surgery remains the most commonly used treatment for DD, but this requires extensive postoperative therapy and is associated with high rates of recurrence. Over the past decades, more indepth exploration of the molecular basis of DD has raised the hopes of developing new treatment modalities. This paper reviews the clinical presentation and molecular pathophysiology of this disease, as well as current and emerging treatment. It also explores the implications of new findings in the laboratory for future treatment.
Update on the management of Dupuytren’s contracture
Linda Vi, David B OGorman, Bing Siang Gan
Orthopedic Research and Reviews , 2010, DOI: http://dx.doi.org/10.2147/ORR.S8592
Abstract: ate on the management of Dupuytren’s contracture Review (4979) Total Article Views Authors: Linda Vi, David B O’Gorman, Bing Siang Gan Published Date August 2010 Volume 2010:2 Pages 35 - 43 DOI: http://dx.doi.org/10.2147/ORR.S8592 Linda Vi1, David B O’Gorman2, Bing Siang Gan3 1Department of Physiology and Pharmacology, 2Hand and Upper Limb Centre, Lawson Health Research Institute, Departments of Surgery and Biochemistry, 3Hand and Upper Limb Centre, Lawson Health Research Institute, Departments of Surgery and Medical Biophysics, University of Western Ontario, London, Ontario, Canada Abstract: Dupuytren’s disease (DD) is a pathological condition of the palmar fascia that is characterized by the formation of tight collagenous disease cords leading to permanent finger contractures. The disease is most prevalent in Caucasian men, and its incidence increases with age advancement. The most common complaint from patients having DD is the impairment of normal hand function. At present, the disease is incurable and the pathophysiology of DD is unknown. The most common treatment for DD is surgery; however, this treatment is associated with a high rate of recurrence. More recently, researchers have begun to explore the molecular basis of DD in the hopes of developing new, more effective treatment for DD. This review will summarize the history and clinical presentation of the disease, highlight current and emerging molecular treatments, and explore the implications of these advancements for future work.
Type-1 Collagen differentially alters β-catenin accumulation in primary Dupuytren's Disease cord and adjacent palmar fascia cells
Linda Vi, Anna Njarlangattil, Yan Wu, Bing Gan, David B O'Gorman
BMC Musculoskeletal Disorders , 2009, DOI: 10.1186/1471-2474-10-72
Abstract: Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-β1. β-catenin and α-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy.DD cells display a rapid depletion of cellular β-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-β1 to DD cells in collagen culture negates the loss of β-catenin accumulation. Transforming Growth Factor-β1-induced α-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells.Our findings implicate type-1 collagen as a previously unrecognized regulator of β-catenin accumulation and a modifier of TGF-β1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of in vitro models for research into the molecular mechanisms of DD.Dupuytren's contracture, or Dupuytren's Disease, (DD) [1-3] is a common, benign palmar fibromatosis of unknown etiology that results in finger contracture and loss of hand function. The most widely accepted treatment is surgical resection of the disease cord, an approach associated with prolonged post-operative rehabilitation and high recurrence rates [4,5]. Recently, minimally invasive treatment alternatives such as clostridial collagenase injection [6,7] and needle aponeurotomy [8-10] have gained popularity. While these approaches require relatively little post-treatment rehabilitation, their long-term efficacy and disease recurrence rates relative to fasciectomy are yet to be clearly established.We and others have identified dysregulated genes in primary cultures of DD cells [11] or DD cord and nodule tissue [12-14]. Many of these gene transcripts encode extrac
Wnt expression is not correlated with β-catenin dysregulation in Dupuytren's Disease
David B O'Gorman, Yan Wu, Shannon Seney, Rebecca D Zhu, Bing Gan
Journal of Negative Results in BioMedicine , 2006, DOI: 10.1186/1477-5751-5-13
Abstract: The Wnt expression profile of patient-matched DD and unaffected control palmar fascia tissue was determined by a variety of complimentary methods; Affymetrix Microarray analysis, specific Wnt and degenerative primer-based Reverse Transcriptase (RT)-PCR, and Real Time PCR. Microarray analysis identified 13 Wnts associated with DD and control tissues. Degenerate Wnt RT-PCR analysis identified Wnts 10b and 11, and to a lesser extent 5a and 9a, as the major Wnt family members expressed in our patient samples. Competitive RT-PCR analysis identified significant differences between the levels of expression of Wnts 9a, 10b and 11 in tissue samples and in primary cell cultures grown as monolayer or in FPCL, where the mRNA levels in tissue > FPCL cultures > monolayer cultures. Real Time PCR data confirmed the down-regulation of Wnt 11 mRNA in DD while Wnt 10b, the most frequently isolated Wnt in DD and control palmar fascia, displayed widely variable expression between the methods of analysis.These data indicate that changes in Wnt expression per se are unlikely to be the cause of the observed dysregulation of β-catenin expression in DD.Dupuytren's contracture or disease (DD) is a benign fibro-proliferative disease of the hand that causes permanent finger flexion contractures [1,2]. Despite its long medical history and high prevalence among Caucasians of Northern European ancestry, reportedly as high as 30–40% [3], the underlying genetic etiology of the disease remains unknown [4]. Numerous risk factors have been reported for DD, including alcoholism, trauma, diabetes, smoking, and epilepsy, but their exact role in the disease is not clear [5]. Epidemiological studies show an increased total mortality and cancer mortality rates among men with established DD [6], suggesting the pathophysiology of this disease may overlap with that of certain cancers.β- catenin, the central component of the 'canonical' Wnt signalling pathway (herein referred to as Wnt/β-catenin) has been implic
Update on the management of Dupuytren’s contracture
Linda Vi,David B OGorman,Bing Siang Gan
Orthopedic Research and Reviews , 2010,
Abstract: Linda Vi1, David B O’Gorman2, Bing Siang Gan31Department of Physiology and Pharmacology, 2Hand and Upper Limb Centre, Lawson Health Research Institute, Departments of Surgery and Biochemistry, 3Hand and Upper Limb Centre, Lawson Health Research Institute, Departments of Surgery and Medical Biophysics, University of Western Ontario, London, Ontario, CanadaAbstract: Dupuytren’s disease (DD) is a pathological condition of the palmar fascia that is characterized by the formation of tight collagenous disease cords leading to permanent finger contractures. The disease is most prevalent in Caucasian men, and its incidence increases with age advancement. The most common complaint from patients having DD is the impairment of normal hand function. At present, the disease is incurable and the pathophysiology of DD is unknown. The most common treatment for DD is surgery; however, this treatment is associated with a high rate of recurrence. More recently, researchers have begun to explore the molecular basis of DD in the hopes of developing new, more effective treatment for DD. This review will summarize the history and clinical presentation of the disease, highlight current and emerging molecular treatments, and explore the implications of these advancements for future work.Keywords: Dupuytren’s disease, etiology, clinical presentation, treatment
Molecular mechanisms and treatment strategies for Dupuytren’s disease
David B OGorman,Linda Vi,Bing Siang Gan
Therapeutics and Clinical Risk Management , 2010,
Abstract: David B O’Gorman1,2,3,4, Linda Vi1,2,5, Bing Siang Gan1,2,3,5,61Cell and Molecular Biology Laboratory, 2The Hand and Upper Limb Centre, St. Joseph’s Health Care London, Schulich School of Medicine and Dentistry, 3Departments of Surgery, 4Biochemistry, 5Physiology and Pharmacology, 6Medical Biophysics, The University of Western Ontario, London, OT, CanadaAbstract: Dupuytren’s disease (DD) is a common disease of the hand and is characterized by thickening of the palmar fascia and formation of tight collagenous disease cords. At present, the disease is incurable and the molecular pathophysiology of DD is unknown. Surgery remains the most commonly used treatment for DD, but this requires extensive postoperative therapy and is associated with high rates of recurrence. Over the past decades, more indepth exploration of the molecular basis of DD has raised the hopes of developing new treatment modalities. This paper reviews the clinical presentation and molecular pathophysiology of this disease, as well as current and emerging treatment. It also explores the implications of new findings in the laboratory for future treatment.Keywords: Dupuytren’s contracture, Dupuytren’s disease, fibrosis
A novel mass spectrometry-based assay for GSK-3β activity
Erin Bowley, Erin Mulvihill, Jeffrey C Howard, Brian J Pak, Bing Siang Gan, David B O'Gorman
BMC Biochemistry , 2005, DOI: 10.1186/1471-2091-6-29
Abstract: Synthetic peptide substrates designed with a GSK-3β phosphorylation site were assayed with both recombinant enzyme and GSK-3β immunoprecipitated from NIH 3T3 fibroblasts. A molecular weight shift equal to that of a single phosphate group (80 Da.) was detected by surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) in a GSK-3β target peptide (2B-Sp). Not only was there a dose-dependent response in molecular weight shift to the amount of recombinant GSK-3β used in this assay, this shift was also inhibited by lithium chloride (LiCl), in a dose-dependent manner.We present here a novel method to sensitively measure peptide phosphorylation by GSK-3β that, due to the incorporation of substrate controls, is applicable to either purified enzyme or cell extracts. Future studies using this method have the potential to elucidate the activity of GSK-3β in vivo, and to screen enzyme activity in relation to a variety of GSK-3β related disorders.Phosphorylation is believed to be the most common protein post-translational covalent modification and is known to occur in the processing of as many as 1/3 of eukaryotic gene products [1]. That the mammalian genome is predicted to encode as many as 1000 different protein phosphatases and twice as many kinases underlines the importance of protein phosphorylation in cellular function [2,3]. One of the most diverse protein kinases studied to-date is the constitutively active serine/threonine kinase, Glycogen Synthase Kinase-3beta (GSK-3β). Originally identified for its role in the regulation of glycogen metabolism [4], it is now known that GSK-3β plays a key role in cellular processes as diverse as cytoskeletal regulation [5], cell cycle progression [6,7], apoptosis [8], cell fate and specification [9], and transcriptional/translational initiation [10,11]. Therefore, functional kinase activity of GSK-3β is important in a variety of biological and biochemical processes and altered GSK-3β activity can con
Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren's Contracture
Latha Satish, William A LaFramboise, Sandra Johnson, Linda Vi, Anna Njarlangattil, Christina Raykha, John Michael Krill-Burger, Phillip H Gallo, David B O'Gorman, Bing Gan, Mark E Baratz, Garth D Ehrlich, Sandeep Kathju
BMC Medical Genomics , 2012, DOI: 10.1186/1755-8794-5-15
Abstract: To achieve this, total RNA was obtained from fibroblasts derived from primary DC-affected palmar fascia, patient-matched unaffected palmar fascia, and palmar fascia from non-DC patients undergoing carpal tunnel release (6 patients in each group). These cells were grown on a type-1 collagen substrate (to better mimic their in vivo environments). Microarray analyses were subsequently performed using Illumina BeadChip arrays to compare the transcriptomic profiles of these three cell populations. Data were analyzed using Significance Analysis of Microarrays (SAM v3.02), hierarchical clustering, concordance mapping and Venn diagram.We found that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected fascia of DC patients exhibited a much greater overlap than fibroblasts derived from the palmar fascia of patients undergoing carpal tunnel release. Quantitative real time RT-PCR confirmed the differential expression of select genes validating the microarray data analyses. These data are consistent with the hypothesis that predisposition and recurrence in DC may stem, at least in part, from intrinsic similarities in the basal gene expression of diseased and phenotypically unaffected palmar fascia fibroblasts. These data also demonstrate that a collagen-rich environment differentially alters gene expression in these cells. In addition, Ingenuity pathway analysis of the specific biological pathways that differentiate DC-derived cells from carpal tunnel-derived cells has identified the potential involvement of microRNAs in this fibroproliferative disorder.These data show that the transcriptomic profiles of DC-disease fibroblasts and fibroblasts from unaffected palmar fascia in DC patients are highly similar, and differ significantly from the transcriptomic profiles of fibroblasts from the palmar fascia of patients undergoing carpal tunnel release.Dupuytren's contracture (DC) is characterized by abnormal thickening of palmar fascia into collagen-ric
Identification of differentially expressed genes in fibroblasts derived from patients with Dupuytren's Contracture
Latha Satish, William A LaFramboise, David B O'Gorman, Sandra Johnson, Benjamin Janto, Bing Gan, Mark E Baratz, Fen Z Hu, J Christopher Post, Garth D Ehrlich, Sandeep Kathju
BMC Medical Genomics , 2008, DOI: 10.1186/1755-8794-1-10
Abstract: Dupuytren's contracture (DC) is the most common inherited disease of connective tissue in humans [1] and an autosomal dominant form of the disease was recently mapped to the long arm of chromosome 16 [2]. The disease is characterized by the appearance of small nodules of hyperproliferative cells within the palmar fascia that, over time, give rise to large bands of contracted, collagen-rich fibrotic tissue (diseased cords), a hallmark of the disease [3,4]. If left untreated, this disease may impose severe limitations on hand function. It is a familial disorder that is highly prevalent in individuals of Northern European extraction [5,6] and is observed less frequently among other ethnicities [7]. The manifestations of Dupuytren's are usually noticeable between the ages of 40 to 60 and with a higher incidence in men than in women [8].Although the pathogenesis of DC disease has not been fully explained it is clear that genetics plays an important role; traumatic factors may also be important and may explain the male gender bias of the disease. In addition, a number of metabolic conditions that negatively affect wound healing processes in general have been statistically associated with DC including: diabetes mellitus (8%), alcoholism (10%), smoking, and HIV infection [9-12]. Finally, there is a puzzling connection with epilepsy (2%).The mainstay of treatment is surgery, but no specific surgical approach has proved to be consistently more effective than others at curing this condition as the trauma associated with surgery itself can lead to recurrence. Possible alternatives to surgery include injection of steroids, γ-interferon [13,14], use of creams based on vitamin E, dimethylsulphoxides, drugs inducing hypo-uricaemia, ultrasonic therapy [15] and clostridial collagenase injection [16]. However, these medical treatments appear to be either temporary alternatives to surgical intervention with only limited success at best, or are still under clinical assessment.Previous s
The Intramolecular Radical Cation Induced Diels-Alder Reaction in the Diene - Diene Format
David B. Rusterholz,David B. Gorman,Paul G. Gassman
Molecules , 1997, DOI: 10.3390/20500080
Abstract: Two 1,3,8,10-undecatetraenes were synthesized to test the viability of the intramolecular radical cation induced Diels-Alder reaction in the diene - diene format. Cyclization was successful only for the substituted tetraene with the lower oxidation potential. The major hexahydroindene product possessed a trans ring juncture demonstrating a selectivity for the endo stereochemistry.
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