Dermatology Commons^™

Effect Of Oxidative Stress On Protein Tyrosine Phosphatase 1b In Scleroderma Dermal Fibroblasts., Pei-Suen Tsou, Nadine N. Talia, Adam J. Pinney, Ann Kendzicky, Sonsoles Piera-Velazquez, Sergio A. Jimenez, James R. Seibold, Kristine Phillips, Alisa E Koch

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: Platelet-derived growth factor (PDGF) and its receptor, PDGFR, promote fibrosis in systemic sclerosis (SSc; scleroderma) dermal fibroblasts, and such cells in scleroderma skin lesions produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and is dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. This study was undertaken to determine whether the thiol-sensitive PTP1B is affected by ROS in SSc dermal fibroblasts, thereby enhancing the phosphorylation of PDGFR and synthesis of type I collagen. This study also sought to investigate the effect of a thiol antioxidant, N-acetylcysteine (NAC), in SSc.

METHODS: Fibroblasts were isolated from the skin …

A Role For Caveolin-1 In Desmoglein Binding And Desmosome Dynamics., D Brennan, S Peltonen, A Dowling, W Medhat, K J Green, J K Wahl, F Del Galdo, M G Mahoney

Department of Dermatology and Cutaneous Biology Faculty Papers

Desmoglein-2 (Dsg2) is a desmosomal cadherin that is aberrantly expressed in human skin carcinomas. In addition to its well-known role in mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote cancer development and progression. However, the mechanisms by which Dsg2 activates these signaling pathways and the relative contribution of its signaling and adhesion functions in tumor progression are poorly understood. In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major protein of specialized membrane microdomains called caveolae, which functions in both membrane protein turnover and intracellular signaling. Sequence analysis revealed that Dsg2 contains a putative …

Lymph Node Ratio Is An Important And Independent Prognostic Factor For Patients With Stage Iii Melanoma, Adam C. Berger, Michael Fierro, John C. Kairys, David Berd, Takami Sato, Jocelyn Andrel, Terry Hyslop, Michael J. Mastrangelo

Kimmel Cancer Center Faculty Papers

INTRODUCTION:

The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients.

METHODS:

We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model.

RESULTS:

The median survival time of …

Preoperative Fdg-Pet/Ct Is An Important Tool In The Management Of Patients With Thick (T4) Melanoma., Rodrigo Arrangoiz, Pavlos Papavasiliou, Carrie A Stransky, Jian Q Yu, Li Tianyu, Elin R Sigurdson, Adam C. Berger, Jeffrey M Farma

Department of Surgery Faculty Papers

The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in …

Keratinocyte-Targeted Expression Of Human Laminin Γ2 Rescues Skin Blistering And Early Lethality Of Laminin Γ2 Deficient Mice., Tracy L Adair-Kirk, Gail L Griffin, Michelle J Meyer, Diane G Kelley, Jeffrey H Miner, Douglas R Keene, M Peter Marinkovich, J Michael Ruppert, Jouni Uitto, Robert M Senior

Department of Dermatology and Cutaneous Biology Faculty Papers

Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early …

Abca12-Mediated Lipid Transport And Snap29-Dependent Trafficking Of Lamellar Granules Are Crucial For Epidermal Morphogenesis In A Zebrafish Model Of Ichthyosis., Qiaoli Li, Michael Frank, Masashi Akiyama, Shiu-Ying Ho, Hiroshi Shimizu, Christine Thisse, Bernard Thisse, Eli Sprecher, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

Zebrafish (Danio rerio) can serve as a model system to study heritable skin diseases. The skin is rapidly developed during the first 5-6 days of embryonic growth, accompanied by expression of skin-specific genes. Transmission electron microscopy (TEM) of wild-type zebrafish at day 5 reveals a two-cell-layer epidermis separated from the underlying collagenous stroma by a basement membrane with fully developed hemidesmosomes. Scanning electron microscopy (SEM) reveals an ordered surface contour of keratinocytes with discrete microridges. To gain insight into epidermal morphogenesis, we have employed morpholino-mediated knockdown of the abca12 and snap29 genes, which are crucial for secretion of lipids and …

Mechanisms Of Resistance To Raf Inhibitors In Melanoma., A E Aplin, Fred M Kaplan, Yongping Shao

Department of Cancer Biology Faculty Papers

The recent RAF inhibitor trial with PLX4032/RG7204 in late-stage mutant B-RAF melanoma patients has been lauded as a success story for personalized cancer therapy since short-term clinical responses were observed in the majority of patients. However, initial responses were followed by subsequent tumor re-growth, and a subset of patients showed intrinsic resistance. Bi-directional translational efforts are now essential to determine the mechanisms underlying acquired/secondary and intrinsic resistance to RAF inhibitors.

J. Graham Smith Jr, Md (November 22, 1926-May 18, 2010)., Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

With the passing of J. Graham Smith, Jr. on May 18, 2010, following a short illness, dermatology lost one of its most distinguished envoys. (Figure 1) Skee*, as he was known by his many friends, held the important offices in American dermatology for which he made many significant contributions.

Differential Regulation Of P53 Function By The N-Terminal Δnp53 And Δ113p53 Isoforms In Zebrafish Embryos., William R Davidson, Csaba Kari, Qing Ren, Borbala Daroczi, Adam P Dicker, Ulrich Rodeck

Department of Radiation Oncology Faculty Papers

BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the …

Granuloma Annulare: Not As Simple As It Seems., Lawrence Charles Parish, Joseph A. Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Human Papillomavirus And Survival Of Patients With Oropharyngeal Cancer., K Kian Ang, Jonathan Harris, Richard Wheeler, Randal Weber, David I Rosenthal, Phuc Felix Nguyen-Tân, William H Westra, Christine H Chung, Richard C Jordan, Charles Lu, Harold Kim, Rita S. Axelrod, Md, C Craig Silverman, Kevin P Redmond, Maura L Gillison

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.

METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive …

Updating The Dermatologic Nomenclature: Names That Are Good Or Bad., Lawrence Charles Parish, Joseph A. Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

Dermatology probably has the largest vocabulary of any of the medical specialties,¹ a statement to which we can attest when we reviewed aspects of the Dermatology Lexicon project. Some terms are derived from the Latin or Greek and present spelling problems to all but a select few. Examples include acrokeratosis verruciformis and pterigium. Other diseases carry names that are such a mouthful that few can call them out without the interruption of breathing. These might include erosio interdigitalis blastomycetica and dermatitis exudative discoid and lichenoid of Sulzberger and Garbe. No wonder the former is now referred to simply as …

Reducing The Effects Of Intracellular Accumulation Of Thermolabile Collagen Ii Mutants By Increasing Their Thermostability In Cell Culture Conditions., Katarzyna Gawron, Deborah A. Jensen, Andrzej Steplewski, Andrzej Fertala

Department of Dermatology and Cutaneous Biology Faculty Papers

Mutations in collagen II are associated with spondyloepiphyseal dysplasia, a group of heritable diseases whose common features include aberrations of skeletal growth. The mechanisms through which mutations in collagen II affect the cartilaginous tissues are complex and include both intracellular and extracellular processes. One of those mechanisms involves cellular stress caused by excessive accumulation of misfolded collagen II mutants. We investigated whether stabilizing the structure of thermolabile R789C and R992C collagen II mutants would improve their secretion from cells, thereby reducing cellular stress and apoptosis. Employing glycerol and trimethylamine N-oxide (TMAO), chemicals that increase the thermostability of collagen triple helices, …

Biomarkers In Systemic Sclerosis., Susan V. Castro, Sergio A. Jimenez

Scleroderma Center Faculty Papers

Systemic sclerosis is an autoimmune inflammatory disorder of unknown etiologycharacterized b y pronounced fibroproliferative alterations in the microvasculature, and frequent cellular and humoral immunity abnormalities, culminating in a severe and often progressive fibrotic process. Numerous biomarkers reflecting the three main pathogenetic mechanisms in systemic sclerosis have been described; however, aside from several disease-specific autoantibodies, other biomarkers have not been thoroughly validated and require further study. Thus, there is an unmet need for validated biomarkers for diagnosis, disease classification, and evaluation of organ involvement and therapeutic response in systemic sclerosis.

Superficial Dsg2 Expression Limits Epidermal Blister Formation Mediated By Pemphigus Foliaceus Antibodies And Exfoliative Toxins., D Brennan, Ying Hu, Walid Medhat, A Dowling, M G Mahoney

Department of Dermatology and Cutaneous Biology Faculty Papers

Cell-cell adhesion mediated by desmosomes is crucial for maintaining proper epidermal structure and function, as evidenced by several severe and potentially fatal skin disorders involving impairment of desmosomal proteins. Pemphigus foliaceus (PF) and staphylococcal scalded skin syndrome (SSSS) are subcorneal blistering diseases resulting from loss of function of the desmosomal cadherin, desmoglein 1 (Dsg1). To further study the pathomechanism of these diseases and to assess the adhesive properties of Dsg2, we employed a recently established transgenic (Tg) mouse model expressing Dsg2 in the superficial epidermis. Neonatal Tg and wild type (WT) mice were injected with purified ETA or PF Ig. …

The Most Important Medical Source: Aunt Mabel Knows Best., Lawrence Parish, Joseph A Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

Not so long ago, one of us was consulted by a middle-aged woman with rosacea. For many years, she had had periodic flares of red papules and pustules on her nose and the adjoining areas. The confluent telangiectasia on her cheeks gave a permanent appearance of well-applied rouge. She had seen several dermatologists and had received a wide variety of medications, all of which seemed appropriate except to her as would be subsequently revealed. She wanted a new approach, but there were limitations placed upon her request: no pills or capsules; nothing odiferous; no agent that might bleach clothing; and …

Fluorescent Protein Markers To Tag Collagenous Proteins: The Paradigm Of Procollagen Vii, Hye J. Chung, Andrzej Steplewski, Jouni Uitto, Andrzej Fertala

Department of Dermatology and Cutaneous Biology Faculty Papers

Fluorescent proteins are powerful markers allowing tracking expression, intracellular localization, and translocation of tagged proteins but their effects on the structure and assembly of complex extracellular matrix proteins has not been investigated. Here, we analyzed the utility of fluorescent proteins as markers for procollagen VII, a triple-helical protein critical for the integrity of dermal-epidermal junction. DNA constructs encoding a red fluorescent protein-tagged wild type mini-procollagen VII α chain and green fluorescent protein-tagged α chains harboring selected mutations were genetically engineered. These DNA constructs were co-expressed in HEK-293 cells and the assembly of heterogeneous triple-helical mini-procollagen VII molecules was analyzed. Immunoprecipitation …

R992c (P.R1192c) Substitution In Collagen Ii Alters The Structure Of Mutant Molecules And Induces The Unfolded Protein Response., Hye Jin Chung, Deborah A. Jensen, Katarzyna Gawron, Andrzej Steplewski, Andrzej Fertala

Department of Dermatology and Cutaneous Biology Faculty Papers

We investigated the molecular bases of spondyloepiphyseal dysplasia (SED) associated with the R992C (p.R1192C) substitution in collagen II. At the protein level, we analyzed the structure and integrity of mutant molecules, and at the cellular level, we specifically studied the effects of the presence of the R992C collagen II on the biological processes taking place in host cells. Our studies demonstrated that mutant collagen II molecules were characterized by altered electrophoretic mobility, relatively low thermostability, the presence of atypical disulfide bonds, and slow rates of secretion into the extracellular space. Analyses of cellular responses to the presence of the mutant …

Freedom For The Bulgarian Nurses And A Palestinian Doctor., Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

On July 24, 2007, the five Bulgarian nurses and the Palestinian, unjustly accused of infecting Libyan children with the AIDS virus, were freed by the Libyan government. They had spent a tumultuous seven years in prison, much of the time on death row, having been accused of injecting the children with tainted blood they had brought with them. This was not only preposterous but also an impossibility as the particular strain of the AIDS virus had been found in Libya, two years prior. [1]

Mice Deficient In Involucrin, Envoplakin, And Periplakin Have A Defective Epidermal Barrier., Lisa M Sevilla, Rachida Nachat, Karen R Groot, John F Klement, Jouni Uitto, Philippe Djian, Arto Määttä, Fiona M Watt

Department of Dermatology and Cutaneous Biology Faculty Papers

The cornified envelope is assembled from transglutaminase cross-linked proteins and lipids in the outermost epidermal layers and is essential for skin barrier function. Involucrin, envoplakin, and periplakin form the protein scaffold on which the envelope assembles. To examine their combined function, we generated mice deficient in all three genes. The triple knockouts have delayed embryonic barrier formation and postnatal hyperkeratosis (abnormal accumulation of cornified cells) resulting from impaired desquamation. Cornified envelopes form but are ultrastructurally abnormal, with reduced lipid content and decreased mechanical integrity. Expression of proteases is reduced and the protease inhibitor, serpina1b, is highly upregulated, resulting in defective …

Dermatology 75 Years Ago., Lawrence Parish, Joseph A Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

It seems that the practicing dermatologist in 2007 is being attacked on all fronts. The Food and Drug Administration has mandated a cumbersome program for monitoring isotrentinoin usage, its analogue barely comes under scrutiny. iPledge is just a plain nightmare. The acumen of the board certified dermatologist is being challenged by Maintenance of Certification proposals because other specialties are doing it; yet, the neighborhood pharmacist is unhampered in dispensing all sorts of advice about treatment. The insurance clerk thrives on denying medication, prescribed by the physician, using flawed reasoning or else suggesting that a ten days’ supply of medicine should …

Dermatology Is A Specialty; Dermatology Is Not A Subspecialty., Lawrence Parish, Larry E Millikan

Department of Dermatology and Cutaneous Biology Faculty Papers

Specialization began in American medicine about the time of the War Between the States. Several factors spurred the direction of practitioners away from being the so-called “complete physicians. Most important were the advances in instrumentation made by the 1860’s, which allowed ophthalmology and otolaryngology to develop into distinct divisions of allopathic medicine; sometimes, they even joined together, viz eye, ear, nose, and throat specialist. Dermatology, too, became one of the early specialties for a myriad of reasons ranging from the obvious – visual inspection - to the mundane, viz. default – syphilis was too ugly and complicated for every physician …

Bibliography Of Secondary Sources On The History Of Dermatology Iii. Books, Monographs, And Chapters In English Supplemented Through 2005., Lawrence Charles Parish, John Thorne Crissey, Jennifer L Parish, Daniel H Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

Providing supplements to the history of dermatology bibliographic record has been a continuous project for the past four decades. When the endeavor was initiated, the original authors decided that only contributions in English and those directly related to dermatology, excluding sexually transmitted diseases as such, would be indexed.

There is the perennial question of whether such a manually created bibiliographic project has a need. The obvious answer remains yes. While Index Medicus has expanded the number of journals that are indexed, the number of dermatology publications currently included by Index Medicus is just over fifty. Granted, most of the papers …

Barnacles, Old Age Marks, Or Just Plain Seborrheic Keratoses., Lawrence Charles Parish, Joseph A. Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

Growing older may mean more wrinkles and creaking joints, but why does it also entail an accumulation of barnacles. These brown, somewhat friable, often warty lesions are more common on senior citizens but are not necessarily limited to the chronologically challenged. Seborrheic keratoses (SKs) can be easily recognized (fig 1), but the itching and the occasional scratch-induced dermatitis make them more than a cosmetic nuisance. (fig 2)

SKs can go by a variety of names, ranging from basal cell papillomas, senile warts, and senile keratoses to seborrheic verrucae and verrucous senilis. The various terms provide no more information on their …

Transfection Of Il-10 Expression Vectors Into Endothelial Cultures Attenuates Alpha4beta7-Dependent Lymphocyte Adhesion Mediated By Madcam-1., Makoto Sasaki, Paul Jordan, Jeff Houghton, Xianmin Meng, Makoto Itoh, Takashi Joh, J Steven Alexander

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression …

Ubinuclein, A Novel Nuclear Protein Interacting With Cellular And Viral Transcription Factors., S Aho, M Buisson, T Pajunen, Y W Ryoo, J F Giot, H Gruffat, A Sergeant, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

The major target tissues for Epstein-Barr virus (EBV) infection are B lymphocytes and epithelial cells of the oropharyngeal zone. The product of the EBV BZLF1 early gene, EB1, a member of the basic leucine-zipper family of transcription factors, interacts with both viral and cellular promoters and transcription factors, modulating the reactivation of latent EBV infection. Here, we characterize a novel cellular protein interacting with the basic domains of EB1 and c-Jun, and competing of their binding to the AP1 consensus site. The transcript is present in a wide variety of human adult, fetal, and tumor tissues, and the protein is …

Elevated Expression Of Type Vii Collagen In The Skin Of Patients With Systemic Sclerosis. Regulation By Transforming Growth Factor-Beta., Lidia Rudnicka, John Varga, Angela M. Christiano, Renato V. Iozzo, Sergio A. Jimenez, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

A hallmark of systemic sclerosis (SSc) is the development of tissue fibrosis. Excessive production of several connective tissue components normally present in the dermis, including type I, III, V, and VI collagens as well as fibronectin and proteoglycans, is a consistent finding in the skin of SSc patients. Type VII collagen is a major constituent of anchoring fibrils, present in the skin at the dermal-epidermal basement membrane zone. TGF-beta has been shown to upregulate the expression of the type VII collagen gene. In this study, we assessed the expression of type VII collagen and TGF-beta in the skin of patients …