Medicine and Health Sciences Commons^™

Impact Of Copper And Iron Binding Properties On The Anticancer Activity Of 8-Hydroxyquinoline Derived Mannich Bases., Veronika F.S. Pape, Nóra V. May, G. Tamás Gál, István Szatmári, Flóra Szeri, Ferenc Fülöp, Gergely Szakács, Éva A. Enyedy

Department of Dermatology and Cutaneous Biology Faculty Papers

The anticancer activity of 8-hydroxyquinolines relies on complex formation with redox active copper and iron ions. Here we employ UV-visible spectrophotometry and EPR spectroscopy to compare proton dissociation and complex formation processes of the reference compound 8-hydroxyquinoline (Q-1) and three related Mannich bases to reveal possible correlations with biological activity. The studied derivatives harbor a CH2-N moiety at position 7 linked to morpholine (Q-2), piperidine (Q-3), and chlorine and fluorobenzylamino (Q-4) substituents. Solid phase structures of Q-3, Q-4·HCl·H2O, [(Cu(HQ-2)2)2]·(CH3OH)2·Cl4·(H2O)2, [Cu(Q-3)2]·Cl2 and [Cu(HQ-4)2(CH3OH)]·ZnCl4·CH3OH were characterized by single-crystal X-ray diffraction analysis. In addition, the redox properties of the copper and iron complexes …

The Genomic Landscape Of Cutaneous Scc Reveals Drivers And A Novel Azathioprine Associated Mutational Signature., Gareth J. Inman, Jun Wang, Ai Nagano, Ludmil B. Alexandrov, Karin J. Purdie, Richard G. Taylor, Victoria Sherwood, Jason Thomson, Sarah Hogan, Lindsay C. Spender, Andrew P. South, Michael Stratton, Claude Chelala, Catherine A. Harwood, Charlotte M. Proby, Irene M. Leigh

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure …

The Dermatologist And Color, Andrzej Grzybowski, Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

The idea for an issue on color and the skin was initiated by the 2017 exhibit “Breathing Color” that had been created by the new Design Museum in London, England. While variations in color may play a significant role in diagnosing a skin disease, little attention has been directed towards the influence that color may be used to identify a dermatologic disease and even monitor a therapeutic agent. The reader need only to recall how early dermatology atlases were hand colored to provide a more realistic picture of a disease.

In Vitro Transport Of Methotrexate By Drosophila Multidrug Resistance-Associated Protein., Agnes Karasik, András Váradi, Flóra Szeri

Department of Dermatology and Cutaneous Biology Faculty Papers

Methotrexate (MTX) is a widely used chemotherapeutic agent, immune suppressant and antimalarial drug. It is a substrate of several human ABC proteins that confer multidrug resistance to cancer cells and determine compartmentalization of a wide range of physiological metabolites and endo or xenobiotics, by their primary active transport across biological membranes. The substrate specificity and tissue distribution of these promiscuous human ABC transporters show a high degree of redundancy, providing robustness to these key physiological and pharmacological processes, such as the elimination of toxins, e.g. methotrexate from the body. A similar network of proteins capable of transporting methotrexate has been …

The Human Cib1-Ever1-Ever2 Complex Governs Keratinocyte-Intrinsic Immunity To Β-Papillomaviruses., Sarah Jill De Jong, Amandine Créquer, Irina Matos, David Hum, Vignesh Gunasekharan, Lazaro Lorenzo, Fabienne Jabot-Hanin, Elias Imahorn, Andres A. Arias, Hassan Vahidnezhad, Leila Youssefian, Janet G. Markle, Etienne Patin, Aurelia D'Amico, Claire Q.F. Wang, Florian Full, Armin Ensser, Tina M. Leisner, Leslie V. Parise, Matthieu Bouaziz, Nataly Portilla Maya, Xavier Rueda Cadena, Bayaki Saka, Amir Hossein Saeidian, Nessa Aghazadeh, Sirous Zeinali, Peter Itin, James G. Krueger, Lou Laimins, Laurent Abel, Elaine Fuchs, Jouni Uitto, Jose Luis Franco, Bettina Burger, Gérard Orth, Emmanuelle Jouanguy, Jean-Laurent Casanova

Department of Dermatology and Cutaneous Biology Faculty Papers

Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are …

The Role Of Human Papillomaviruses And Polyomaviruses In Braf-Inhibitor Induced Cutaneous Squamous Cell Carcinoma And Benign Squamoproliferative Lesions, Karin J. Purdie, Charlotte M. Proby, Hasan Rizvi, Heather Griffin, John Doorbar, Mary Sommerlad, Mariet C. Feltkamp, Els Van Der Meijden, Gareth J. Inman, Andrew P. South, Irene M. Leigh, Catherine A. Harwood

Department of Dermatology and Cutaneous Biology Faculty Papers

Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested …

Psoriasiform Sarcoidosis Presenting In Pregnancy And Treatment Considerations, Christian A. Albornoz, Jordan Wang, Matthew Keller

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous sarcoidosis is a common presentation for patients with sarcoidosis. Rarely, patients can present with psoriasiform lesions mimicking chronic plaque psoriasis. Here, we present a case of psoriasiform sarcoidosis in a pregnant patient. Pregnancy represents a unique challenge to systemic treatments if topical management fails. Tumor necrosis factor alpha inhibitors warrant special consideration during pregnancy.

Trametinib Prevents Mesothelial-Mesenchymal Transition And Ameliorates Abdominal Adhesion Formation, Edward J. Macarak, Christine Lotto, Deepika Koganti, Xiaoling Jin, Pete J. Wermuth, Anna-Karin Olsson, Matthew Montgomery, Joel Rosenbloom

Department of Dermatology and Cutaneous Biology Faculty Papers

Background

Intra-abdominal adhesions are a major cause of morbidity after abdominal or gynecologic surgery. However, knowledge about the pathogenic mechanism(s) is limited, and there are no effective treatments. Here, we investigated a mouse model of bowel adhesion formation and the effect(s) of an Federal Drug Administration-approved drug (trametinib) in preventing adhesion formation.

Materials and methods

C57BL/6 mice were used to develop a consistent model of intra-abdominal adhesion formation by gentle cecal abrasion with mortality rates ofEDA) which arises from alternative splicing of the fibronectin messenger RNA resulting in different protein isoforms. Trichrome staining assessed collagen deposition. Quantitative polymerase chain reaction …

Cadaveric Simulation For Improving Surgical Training In Dermatology., Ezra Hazan, Richard Torbeck, Deirdre Connolly, Jordan V. Wang, Thomas Griffin, Matthew Keller, Joshua Trufant

Department of Dermatology and Cutaneous Biology Faculty Papers

Simulation models are rapidly changing medical education, especially the training of dermatology residents. Various models are available, including cadaveric simulations. Our study evaluates the impact of a cadaveric simulation on the training of dermatology residents. Over a period of three years, cadaveric simulation was shown to increase the surgical knowledge of residents. Residents were more confident in their knowledge of surgical anatomy and also surgical skills. Cadaveric simulation may offer a positive impact on resident training in dermatology.

Epidermodysplasia Verruciformis: Inborn Errors Of Immunity To Human Beta-Papillomaviruses, Sarah J. De Jong, Elias Imahorn, Peter Itin, Jouni Uitto, Gerard Orth, Emmanuelle Jouanguy, Jean-Laurent Casanova, Bettina Burger

Department of Dermatology and Cutaneous Biology Faculty Papers

Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in …

The Genetic Basis Of Hyaline Fibromatosis Syndrome In Patients From A Consanguineous Background: A Case Series., Leila Youssefian, Hassan Vahidnezhad, Andrew Touati, Vahid Ziaee, Amir Hossein Saeidian, Sara Pajouhanfar, Sirous Zeinali, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare heritable multi-systemic disorder with significant dermatologic manifestations. It is caused by mutations in ANTXR2, which encodes a transmembrane receptor involved in collagen VI regulation in the extracellular matrix. Over 40 mutations in the ANTXR2 gene have been associated with cases of HFS. Variable severity of the disorder in different patients has been proposed to be related to the specific mutations in these patients and their location within the gene.

CASE PRESENTATION: In this report, we describe four cases of HFS from consanguineous backgrounds. Genetic analysis identified a novel homozygous frameshift deletion c.969del …

Extragenital Blaschkoid Lichen Sclerosus Et Atrophicus In A Child, Christian A. Albornoz, Jordan Wang, Sherry Yang

Department of Dermatology and Cutaneous Biology Faculty Papers

Lichen sclerosus et atrophicus is a chronic inflammatory skin disease that typically affects prepubertal girls and peri- or post-menopausal women in genital and perineal areas. In some cases, it can also manifest as extragenital lesions. Extragenital Blaschkoid lesions have infrequently been reported. Here, we report a case of extragenital Blaschkoid lichen sclerosus et atrophicus in a child.

Invasive Trichosporonosis Treated With Voriconazole, Vaibhav Garg, Elizabeth Jones, Ben J. Friedman, Jason B. Lee, Sherry Yang

Department of Dermatology and Cutaneous Biology Faculty Papers

Introduction

Trichosporon is a genus of yeast-like fungi. It is perhaps most widely known as the cause of white piedra, a benign superficial mycosis seen in immunocompetent individuals in tropical and subtropical regions. However, the incidence of invasive trichosporonosis has increased in immunocompromised patients, most notably those with hematologic malignancies. The following case illustrates characteristic features of trichosporonosis fungemia.

Preclinical Comparison Of Proteasome And Ubiquitin E1 Enzyme Inhibitors In Cutaneous Squamous Cell Carcinoma: The Identification Of Mechanisms Of Differential Sensitivity, Angela Mchugh, Kenneth Fernandes, Andrew P. South, Jemima E. Mellerio, Julio C. Salas-Alanis, Charlotte M. Proby, Irene M. Leigh, Mark K. Saville

Department of Dermatology and Cutaneous Biology Faculty Papers

Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics. These agents can selectively kill …

Optimizing Visiting Clerkships In Dermatology: A Dual Perspective Approach., Jordan V. Wang, Kathleen P. Mcguinn, Matthew Keller

Department of Dermatology and Cutaneous Biology Faculty Papers

Matching into a dermatology residency program has become increasingly more challenging for medical students. As students continue to explore various methods to help them standout to programs, recent medical literature has continued to show evidence of the important role that visiting clerkships play. Visiting clerkships offer several benefits to both students and programs. In order to optimize visiting clerkships, the perspectives of both students and programs are each examined with recommendations provided to help maximize its benefits.

Layout And Flow Of Dermatology Clinics: Principles From Operations Management., Jordan V. Wang

Department of Dermatology and Cutaneous Biology Faculty Papers

Dermatology is a medical specialty that experiences high patient demand and long patient wait times. Dermatology clinics should look for ways to improve efficiency through the incorporation of principles from operations management. Addressing the layout and flow of a clinic can lead to operational efficiency. An ideal layout may lead to increased patient volume, satisfaction, and retention.

Inhibition Of Dna Methyltransferase Leads To Increased Genomic 5-Hydroxymethylcytosine Levels In Hematopoietic Cells., Borbála Vető, Pál Szabó, Caroline Bacquet, Anna Apró, Edit Hathy, Judit Kiss, János M. Réthelyi, Flóra Szeri, Dávid Szüts, Tamás Arányi

Department of Dermatology and Cutaneous Biology Faculty Papers

5-Hydroxymethylcytosine (5hmC) is produced from 5-methylcytosine (5mC) by Ten-eleven translocation (TET) dioxygenases. The epigenetic modification 5hmC has crucial roles in both cellular development and differentiation. The 5hmC level is particularly high in the brain. While 5mC is generally associated with gene silencing/reduced expression, 5hmC is a more permissive epigenetic mark. To understand its physiological function, an easy and accurate quantification method is required. Here, we have developed a novel LC-MS/MS-based approach to quantify both genomic 5mC and 5hmC contents. The method is based on the liberation of nucleobases by formic acid. Applying this method, we characterized the levels of DNA …

Gel Manicures And Ultraviolet A Light: A Call For Patient Education., Jordan V. Wang, Dorota Z. Korta, Christopher B. Zachary

Department of Dermatology and Cutaneous Biology Faculty Papers

Gel manicures have become a popular beauty trend in recent years. The specially formulated nail polish must undergo curing under light-based units. The majority of these curing lamps emit high-intensity ultraviolet A, which can cause skin damage and increase the risk for skin cancers. Incorporating relevant information in patient education endeavors can help them practice avoidance, apply broad-spectrum sunscreen prior, or use nitrile exam gloves in order to prevent photoaging and skin cancer resulting from these procedures.

Global Mapping Of Transcription Factor Motifs In Human Aging., David Alfego, Ulrich Rodeck, Andres Kriete

Department of Dermatology and Cutaneous Biology Faculty Papers

Biological aging is a complex process dependent on the interplay of cell autonomous and tissue contextual changes which occur in response to cumulative molecular stress and manifest through adaptive transcriptional reprogramming. Here we describe a transcription factor (TF) meta-analysis of gene expression datasets accrued from 18 tissue sites collected at different biological ages and from 7 different in-vitro aging models. In-vitro aging platforms included replicative senescence and an energy restriction model in quiescence (ERiQ), in which ATP was transiently reduced. TF motifs in promoter regions of trimmed sets of target genes were scanned using JASPAR and TRANSFAC. TF signatures established …