Dermatology Commons^™

Increased Expression Of Napdh Oxidase 4 In Systemic Sclerosis Dermal Fibroblasts: Regulation By Transforming Growth Factor Β., Sonsoles Piera-Velazquez, Alma Makul, Sergio A. Jimenez

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: Systemic sclerosis (SSc) is characterized by severe and often progressive fibrosis of the skin and multiple internal organs. The mechanisms responsible for these alterations remain obscure, although excessive reactive oxygen species (ROS)-mediated oxidative stress has been implicated. NOX-4 is 1 of 7 isoforms of NADPH oxidase responsible for the generation of ROS. The purpose of this study was to examine NOX-4 expression in skin and cultured dermal fibroblasts from SSc patients and to examine its regulation by transforming growth factor β1 (TGFβ1).

METHODS: NOX-4 was assessed in normal and SSc skin by immunohistologic analysis and in normal and SSc …

Lysyl Hydroxylase 3 Localizes To Epidermal Basement Membrane And Is Reduced In Patients With Recessive Dystrophic Epidermolysis Bullosa., Stephen A Watt, Jasbani H S Dayal, Sheila Wright, Megan Riddle, Celine Pourreyron, James R Mcmillan, Roy M Kimble, Marco Prisco, Ulrike Gartner, Emma Warbrick, W H Irwin Mclean, Irene M Leigh, John A Mcgrath, Julio C Salas-Alanis, Jakub Tolar, Andrew P South

Department of Dermatology and Cutaneous Biology Faculty Papers

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 …

Rac1 P29s Regulates Pd-L1 Expression In Melanoma., Ha Linh Vu, Sheera Rosenbaum, Timothy J. Purwin, Michael A. Davies, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 …

Nf-Κb Regulation Of C-Flip Promotes Tnfα-Mediated Raf Inhibitor Resistance In Melanoma., Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients. Although most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors. Here, we show that in cutaneous BRAF V600E melanoma, the cytokine tumor necrosis factor-α (TNFα) blocks RAF inhibitor-induced apoptosis via activation of NF-κB. Several NF-κB-dependent factors are upregulated following TNFα and RAF inhibitor treatment. Of these factors, we show that death receptor inhibitor cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNFα-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF …

Do I Buy It? How Aidettm Training Changes Residents’ Values About Communication Skills In Doctor-Patient Interactions, Andrea Braverman, Phd, Austin Katona, B.Sc., Elisabeth Kunkel, Md, Leo Katz, Md, Matthew Keller, Md, Constantine Daskalakis, Sc.D, Jennifer Jasmine Arfaa, Phd, Mhsa

Department of Obstetrics and Gynecology Presentations and Grand Rounds

OBJECTIVES

Acquiring communication and interpersonal skills is an important part of providing patient-centered care and improving patient satisfaction. This study explores whether residents’ own values about patient communication change over time.

Genetic Heterogeneity Of Pseudoxanthoma Elasticum: The Chinese Signature Profile Of Abcc6 And Enpp1 Mutations., Liang Jin, Qiujie Jiang, Zhengsheng Wu, Changxia Shao, Yong Zhou, Luting Yang, Jouni Uitto, Gang Wang

Department of Dermatology and Cutaneous Biology Faculty Papers

Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization, is caused by mutations in the ABCC6 gene. We examined clinically 29 Chinese PXE patients from unrelated families, so far the largest cohort of Asian PXE patients. In a subset of 22 patients, we sequenced ABCC6 and another candidate gene, ENPP1, and conducted pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being, to our knowledge, previously unreported, including 5 frameshift and 10 missense variants. In addition, a missense mutation in combination with a recurrent nonsense mutation in ENPP1 was …

Spontaneous Asj-2j Mutant Mouse As A Model For Generalized Arterial Calcification Of Infancy: A Large Deletion/Insertion Mutation In The Enpp1 Gene., Qiaoli Li, C Herbert Pratt, Louise A Dionne, Heather Fairfield, Son Yong Karst, John P Sundberg, Jouni Uitto, Yin Tintut

Department of Dermatology and Cutaneous Biology Faculty Papers

Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder caused by mutations in the ENPP1 gene, manifests with extensive mineralization of the cardiovascular system. The affected individuals in most cases die within the first year of life, and there is currently no effective treatment for this disorder. In this study, we characterized a spontaneous mutant mouse, asj-2J, as a model for GACI. These mice were identified as part of a phenotypic deviant search in a large-scale production colony of BALB/cJ mice at The Jackson Laboratory. They demonstrated a characteristic gait due to stiffening of the joints, with phenotypic similarity …

Jewish Dermatologists In Nazi Germany., Walter H.C. Burgdorf, Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

With the development of medical specialties beginning in the 1860’s, physicians could devote their time to the study of specific organ systems or surgical approaches. Although Jews had been given full rights in the new Germany by 1871, prejudice and other restrictions often precluded hospital and university appointments. Major specialities like internal medicine and surgery were almost closed to Jews, as were obstetrics and gynecology. Dermatology with its heavy emphasis on sexually transmitted diseases evolved into a suitable domain for Jewish physicians almost by default. Even those Jews who converted to Christianity were not spared from discrimination. Paul Gerson Unna …

Steatocystoma Multiplex: Those Little Tumours., Ellen H. De Moll, W. Clark Lambert, Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Tumour-Stroma Crosstalk In The Development Of Squamous Cell Carcinoma., Yok Zuan Lim, Andrew P South

Department of Dermatology and Cutaneous Biology Faculty Papers

Squamous cell carcinoma (SCC) represents one of the most frequently diagnosed tumours and contributes significant mortality worldwide. Recent deep sequencing of cancer genomes has identified common mutations in SCC arising across different tissues highlighting perturbation of squamous differentiation as a key event. At the same time significant data have been accumulating to show that common tumour-stroma interactions capable of driving disease progression are also evident when comparing SCC arising in different tissues. We and others have shown altered matrix composition surrounding SCC can promote tumour development. This review focuses on some of the emerging data with particular emphasis on SCC …

Mouse Models For Pseudoxanthoma Elasticum: Genetic And Dietary Modulation Of The Ectopic Mineralization Phenotypes., Qiaoli Li, Haitao Guo, David W Chou, Annerose Berndt, John P Sundberg, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6(-/-) ) recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6(-/-) mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904) in the …

Human Adipose-Derived Stem Cell Transplantation As A Potential Therapy For Collagen Vi-Related Congenital Muscular Dystrophy., Vitali Alexeev, Machiko Arita, Adele Donahue, Paolo Bonaldo, Daniel A. Monti, Olga Igoucheva

Department of Dermatology and Cutaneous Biology Faculty Papers

INTRODUCTION: Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in …

Language Barriers To Informed Consent For Dermatologic Interventions., Jordan Wang, Matthew Keller

Department of Dermatology and Cutaneous Biology Faculty Papers

CASE SCENARIO

A 39-year-old Spanish-speaking woman with limited English-language proficiency presents with her 13-year-old son to your private dermatology practice. Through her son, you learn the patient is worried about a mole that has significantly grown in size over the past 3 months. After examination, you recommend the nevus be biopsied to better evaluate it. However, you are barely able to communicate with the patient, and you suspect that her son is not interpreting everything you say based on his especially brief communications with her. To proceed with the biopsy, you must first obtain informed consent.

As the dermatologist, you …

Images In Clinical Medicine. Rumpel-Leede Sign., Krystle Wang, Jason Lee

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Controversies In Dermatology: Part V., Ronni Wolf, Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

“It were not best that we should all think alike; it is difference of opinion that makes horse-races” Mark Twain (Samuel L. Clemens) in The Tragedy of Pudd’nead Wilson, Ch. 19, “Pudd’nead Wilson’s Calendar”.

Part V of Controversies in Dermatology continues the precedent of earlier issues by providing a platform for discussion of a broad range of contemporary and controversial issues. In this issue of Clinics in Dermatology, we will forego the temptation to expose hidden agendas and witches brews, rather, we shall focus on accepted beliefs, principles, doctrines, and paradigms, which you may find even more astonishing.

Barrier-Repair Prescription Moisturizers: Do We Really Need Them? Facts And Controversies., Ronni Wolf, Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

There is now scientific evidence of genetically driven skin-barrier anomalies in atopic patients. These barrier anomalies facilitate sustained antigen ingress through the defective barrier, which can bring about a Th2-dominant response. It enhances the transepidermal water loss, resulting in dry skin and leading to the release of preformed proinflammatory cytokines and to a cascade of events ending up in inflammation.

Clinical Phenotypes And Abcc6 Gene Mutations In Brazilian Families With Pseudoxanthoma Elasticum., Caroline Silvério Faria, Qiaoli Li, Haitao Guo, Jouni Uitto, Sylvia Satomi Takeno, Marilia De Arruda Cardoso Smith, Dertia Villalba Freire-Maia

Department of Dermatology and Cutaneous Biology Faculty Papers

Pseudoxanthoma elasticum (PXE; OMIM 264800) manifests with characteristic skin lesions of yellowish papules which coalesce into plaques of inelastic and leathery skin on the predilection sites (1). The ocular findings consist of angioid streaks, choroidal neovascularization and subretinal hemorrhages resulting in loss of visual acuity and occasional blindness. Cardiovascular problems include hypertension, intermittent claudication, and occasional myocardial infarcts and stroke. The prevalence of PXE is estimated to be in the range of 1:50,000-70,000 and to be more frequent in females than in males. The diagnosis can be challenging to clinicians due to late-onset of clinical manifestations and considerable heterogeneity. PXE …

Inverse Lichen Planus, Michael D Lee, Laurel R Schwartz

Department of Dermatology and Cutaneous Biology Faculty Papers

A Case of Inverse Lichen Planus

Lichen planus (LP) is a pruritic, papular eruption characterized by its violaceous color and polygonal shape. It is most commonly found on the flexor surfaces of the upper extremities, on the genitalia, and on the mucous membranes. We herein report a classic case of LP in an inverse distribution.

Outdated Dermatologic Drug Samples And Obligations To The Patient., Jordan Wang, Matthew Keller

Department of Dermatology and Cutaneous Biology Faculty Papers

CASE SCENARIO

A 37-year-old man with a slightly raised, red, scaly patch on his left arm is seen in the clinic of an academic teaching hospital by a young dermatologist. Following examination and biopsy, he is found to have squamous cell carcinoma in situ. The patient was recently laid off from work and had lost access to his health insurance. He is struggling to make ends meet for his family, so it would be difficult for him to cover any extraneous health-related expenses. Upon relaying this information to the dermatologist, the patient is provided with a full course of 5-fluorouracil …

Strategies For Anti-Fibrotic Therapies., Joel Rosenbloom, Fabian A. Mendoza, Md, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the …

Angular Cheilitis: A Maligned Condition., Caren Campbell, Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

Why an essay on angular cheilitis, an easily recognized cutaneous entity? One suggestion rests with the observation that angular cheilitis could be one of the most maligned conditions seen in contemporary practice. The fissuring, redness, and soreness at the angles of the mouth may not be catastrophic, but the embarrassment and soreness are disconcerting. Another that is more disturbing concerns the unnecessary testing and treatment often seen in the community.

When a middle aged man presented with angular cheilitis on routine examination, he asked if this was due to a vitamin deficiency. Fig 1 He had been told by a …

Altered Drainage Patterns In Patients With Melanoma And Previous Axillary Dissection., Caitlyn M. Johnson, Charles Intenzo, Michael Mastrangelo, Kendra Feeney, Adam C. Berger

Department of Surgery Faculty Papers

The incidence of melanoma is increasing rapidly in the United States. Sentinel lymph node biopsy is an important diagnostic tool in the treatment and staging of melanoma. However, many patients with melanoma will have had lymph node surgery for previous melanoma or breast cancer. We set out to examine alterations in drainage patterns in patients with previous axillary dissection for breast cancer. We reviewed four patients with truncal and/or extremity melanomas and examined their lymphoscintigraphy and drainage patterns. Three patients with truncal melanoma mapped to cervical lymph nodes and a fourth patient with an arm melanoma mapped to her previously …

The Karabus Affair Speaks To Larger Issues For American Academic And Medical Centers., Leonard A Zwelling, Md, Mba, Razelle Kurzrock, Md, Philip R Cohen, Md, Bernard Levin, Md, Ch, Lawrence Parish, Md

Department of Dermatology and Cutaneous Biology Faculty Papers

Finally, on March 12, 2013, a major American newspaper, The Wall Street Journal, reported on the plight of Dr. Cyril Karabus (1,2). Dr. Karabus is the 78 year old pediatric oncologist from Claremont, Capetown, South Africa who is well known as the retired head of the Oncology and Hematology Unit of the Red Cross Children’s Hospital, University of Cape Town, as well as for his devoted service to poor children in the apartheid era. In 2002, he cared for a three-year old Yemeni girl with acute myelogenous leukemia during a locum tenens in the United Arab Emirates (UAE).

Warning Signal: Unaware Of An In Absentia Conviction, South African Cancer Specialist Jailed On Return To The United Arab Emirates., Philip R Cohen, Razelle Kurzrock, Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

In 2002, Dr. Cyril Karabus, a specialist in pediatric cancers and retired head of the Oncology and Hematology Unit of Red Cross Children's Hospital in Capetown, South Africa, spent a brief locum at Sheikh Khalifa Medical City, a hospital in Abu Dhabi in the United Arab Emirates (UAE). He was there for only 5 weeks, during which time he treated a young girl who died of acute myeloblastic leukemia. After Karabus returned home, the girl's father complained to police about his daughter's death, and Karabus was convicted of murder in absentia. Karabus knew nothing of the charges or of the …

Genodermatoses: Differential Diagnosis Of Cutaneous Elastin Disorders: Cutis Laxa Vs. Pseudoxanthoma Elasticum, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Genodermatoses, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

A Case Of Facial Pain And Vesicular Rash, Matt Baichi

The Medicine Forum

The patient is an 81 year old male with a past medical history of non-insulin dependent diabetes mellitus, hypertension, and dyslipidemia who presents with a complaint of facial pain. The pain began 3-4 days before presentation to his primary care physician. It was constant and intense. There was no history of similar head or facial pain, visual changes, jaw claudication, rash, tearing, nasal discharge, photophobia, phonophobia, sinus congestion, tooth ache, nor neurologic complaints. There was no relief with over-the-counter analgesics. A rash subsequently developed over his left forehead and scalp. At presentation, vital signs were stable. Skin examination revealed an …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways., Douglas N Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S Shaw, Jill Roberts, Gregory J Bix

Department of Dermatology and Cutaneous Biology Faculty Papers

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Dermatofibroma: A Curious Tumor., Lawrence Parish, Shideh Yazdanian, W Clark Lambert, Peter C Lambert

Department of Dermatology and Cutaneous Biology Faculty Papers

A tumor, such as a dermatofibroma, causes consternation among many patients, but it rarely creates problems on its own. Also called a histiocytoma, it remains one of the most common mesenchymal growths. Its etiology is unknown with the previous theory that it is a dermal response to injury, such as an insect bite, being challenged. As much as patients like to blame spiders or other arthropods for traumatizing an arm or leg, no definitive explanation is available for its etiology.

A Prospective Observational Study Of Mycophenolate Mofetil Treatment In Progressive Diffuse Cutaneous Systemic Sclerosis Of Recent Onset., Fabian A. Mendoza, Md, Sarah J. Nagle, Jason B. Lee, Md, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset.

METHODS: Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients.

RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR …