Browsing by Author "Has, Cristina"
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Item Clinical Practice Guidelines for Epidermolysis Bullosa Laboratory Diagnosis(2019) Has, Cristina; Liu, Lu; Bolling, Marieke; Charlesworth, Alexandra V.; Hachem, May El; Escámez, María José; Fuentes, Ignacia; Büche, Sarah; Hiremagalore, Ravi; Pohla-Gubo, Gabriele; Akker, Peter van den; Wertheim-Tysarowska, Katarzyna; Zambruno, GiovannaThe overall objective of this guideline is to provide the user with information on the laboratory diagnosis of inherited epidermolysis bullosa (EB) to improve outcomes (Table 1). An accurate diagnosis and subclassification of EB enables (i) early prognostication of disease severity, (ii) decision making for patient management, (iii) informed genetic counselling for the patient and family and DNA‐based prenatal or preimplantation genetic diagnosis, (iv) long‐term surveillance and management of possible complications, (v) inclusion in clinical trials and (vi) precision medicine.Item Epidermolysis bullosa simplex-generalized severe due to p.Glu477Lys mutation in keratin 5: a genotype-phenotype correlation with in silico modeling analysis(2019) Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita N.; Hovnanian, Alain; Lucky, Anne W.Background/Objectives: Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods: In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results: Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions: Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.Item Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.(2019) Atanasova, Velina S.; Pourreyron, Celine; Farshchian, Mehdi; Christian A., Brown IV; Watt, Stephen A.; Wright, Sheila; Warkala, Michael; Guttmann-Gruber, Christina; Piñón Hofbauer, Josefina; Fuentes, Ignacia; Prisco, Marco; Rashidghamat, Elham; Has, Cristina; Palisson, Francis; Hovnanian, Alain; McGrath, John A.; Mellerio, Jemima E.; Bauer, Johann; South, Andrew P.Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.Item Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic-Consensus: Recommendations by an international panel of experts(2020) Murrell, Dedee F; Lucky, Anne W; Salas-Alanis, Julio C; Woodley, David T; Palisson, Francis; Natsuga, Ken; Nikolic, Milos; Ramirez-Quizon, Mae; Paller, Amy S; Lara-Corrales, Irene; Barzegar, Mohammadreza Amir; Sprecher, Eli; Has, Cristina; Laimer, Martin; Bruckner, Anna L; Bilgic, Asli; Nanda, Arti; Purvis, Diana; Hovnanian, Alain; Murat-Sušić, Slobodna; Bauer, Johannes; Kern, Johannes S; Bodemer, Christine; Martin, Linda K; Mellerio, Jemima; Kowaleski, Cezary; Robertson, Susan J; Bruckner-Tuderman, Leena; Pope, Elena; Marinkovich, M Peter; Tang, Jean Y; Su, John; Uitto, Jouni; Eichenfield, Lawrence F; Teng, Joyce; Aan Koh, Mark Jean; Lee, Sang Eun; Khuu, Phuong; Rishel, Heather I; Sommerlund, Mette; Wiss, Karen; Hsu, Chao-Kai; Chiu, Tor Wo; Martinez, Anna E