234 results on '"Seth J. Orlow"'
Search Results
2. Cardiovascular risk in patients with scarring and nonscarring alopecias: Assessing the current state of evidence
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Rachel Sally, Camille Robinson, Seth J. Orlow, Jerry Shapiro, Michael Garshick, and Kristen Lo Sicco
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alopecia ,alopecia areata ,androgenetic alopecia ,cardiovascular disease ,cardiovascular risk ,cicatricial alopecia ,Dermatology ,RL1-803 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Alopecia is traditionally classified into scarring and nonscarring subtypes, with etiopathologies ranging from androgen‐mediated to immuno‐inflammatory. Over 50% of men and almost 50% of women will experience some form of hair loss in their lifetime. Given this prevalence and the psychosocial significance of hair, understanding the pathophysiology and comorbidities of different types of hair loss is imperative. Other proinflammatory dermatologic disorders, such as psoriasis, are recognised to have systemic manifestations including an increased risk of cardiovascular (CV) disease, and are now considered CV risk‐enhancing conditions. With increased recognition of the importance of systemic inflammation in promoting atherosclerosis, high prevalence, and improved treatment strategies, there is increased interest in establishing whether a similar association between alopecia and cardiovascular disease (CVD) exists. In this manuscript, we aim to review the current literature regarding CV risk in androgenic alopecia (AGA) and alopecia areata (AA). Additionally, we review the literature for cicatricial alopecias and highlight the need for more research into their potential associations with CV risk. Evidence from the identified AGA publications suggests an association of AGA with CV risk factors including hypertension, dyslipidemia, and insulin resistance, as well as with coronary artery disease. For AA, most of the identified studies found an association between AA and CV risk, though the relationships were not always statistically significant. Research on cicatricial alopecias and CV risk is limited and often contradictory. There is great need for more studies regarding the association between various types of alopecia and the development of CVD, and potential mechanisms. Particularly needed are more studies of cicatricial alopecias and potential associated CV risk. While some literature suggests that patients with alopecia have an increased risk of CVD, the lack of concrete evidence represents a notable gap in our current understanding.
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- 2024
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3. Nonprofit funding in dermatology: A cross-sectional analysis in the United States, 2015 to 2019
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Aneesh Agarwal, MBA and Seth J. Orlow, MD, PhD
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Dermatology ,RL1-803 - Published
- 2023
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4. Multiple eruptive dermatofibromas in an adolescent with a history of pityriasis lichenoides et varioliformis acuta
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Jessica S. Haber, MD, Shane Meehan, MD, and Seth J. Orlow, MD, PhD
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dermatofibromas ,eruptive ,pediatric ,pityriasis lichenoides chronica ,Dermatology ,RL1-803 - Published
- 2022
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5. Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex
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Olga Lavinda, Prashiela Manga, Seth J. Orlow, and Timothy Cardozo
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tyrosinase ,oculocutaneous albinism ,computational molecular docking ,protein-protein interface ,melanosome ,pigmentary disorders ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.
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- 2021
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6. Recent advances in understanding vitiligo [version 1; referees: 3 approved]
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Prashiela Manga, Nada Elbuluk, and Seth J. Orlow
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Antigen Processing & Recognition ,Autoimmunity ,Cellular Death & Stress Responses ,Dermatologic Pathology ,Dermatologic Pharmacology ,Genetics of the Immune System ,Hair Diseases ,Immunopharmacology & Hematologic Pharmacology ,Innate Immunity ,Leukocyte Signaling & Gene Expression ,Medical Genetics ,Photodermatology & Skin Aging ,Pigmentary Disorders ,Medicine ,Science - Abstract
Vitiligo, an acquired depigmentation disorder, manifests as white macules on the skin and can cause significant psychological stress and stigmatization. Recent advances have shed light on key components that drive disease onset and progression as well as therapeutic approaches. Vitiligo can be triggered by stress to the melanin pigment-producing cells of the skin, the melanocytes. The triggers, which range from sunburn to mechanical trauma and chemical exposures, ultimately cause an autoimmune response that targets melanocytes, driving progressive skin depigmentation. The most significant progress in our understanding of disease etiology has been made on three fronts: (1) identifying cellular responses to stress, including antioxidant pathways and the unfolded protein response (UPR), as key players in disease onset, (2) characterizing immune responses that target melanocytes and drive disease progression, and (3) identifying major susceptibility genes. The current model for vitiligo pathogenesis postulates that oxidative stress causes cellular disruptions, including interruption of protein maturation in the endoplasmic reticulum (ER), leading to the activation of the UPR and expression of UPR-regulated chemokines such as interleukin 6 (IL-6) and IL-8. These chemokines recruit immune components to the skin, causing melanocytes to be targeted for destruction. Oxidative stress can further increase melanocyte targeting by promoting antigen presentation. Two key components of the autoimmune response that promote disease progression are the interferon (IFN)-γ/CXCL10 axis and IL-17-mediated responses. Several genome-wide association studies support a role for these pathways, with the antioxidant gene NRF2, UPR gene XBP1, and numerous immune-related genes including class I and class II major histocompatibility genes associated with a risk for developing vitiligo. Novel approaches to promote repigmentation in vitiligo are being investigated and may yield effective, long-lasting therapies.
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- 2016
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7. Supplementary Data from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
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Seth J. Orlow, Iman Osman, and Ming Chen
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Supplementary Data from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
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- 2023
8. Data from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
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Seth J. Orlow, Iman Osman, and Ming Chen
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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O6-methylguanine-DNA-methyltransferase, apoptosis [measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703–12)
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- 2023
9. Supplementary Figure S1 from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
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Seth J. Orlow, Iman Osman, and Ming Chen
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Supplementary Figure S1 from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
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- 2023
10. The Alopecia Areata Consensus of Experts (ACE) study part II: Results of an international expert opinion on diagnosis and laboratory evaluation for alopecia areata
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Samantha Eisman, Won Soo Lee, V. Jolliffe, Laita Bokhari, George Cotsarelis, Matthew Harries, Pascal Reygagne, Pooja Sharma, Paradi Mirmirani, Rodney Sinclair, Paul Farrant, Nekma Meah, Annika Vogt, Ulrike Blume-Peytavi, Jeff C. Donovan, Janet L. Roberts, Valerie D. Callender, Dmitri Wall, Maria K. Hordinsky, Brittany G. Craiglow, Bevin Bhoyrul, Adriana Rakowska, Elise A. Olsen, Leona Yip, Seth J. Orlow, Bianca Maria Piraccini, Katherine York, Brett A. King, Ramon Grimalt, Antonella Tosti, Martin S Wade, Vijaya Chitreddy, Alan D. Irvine, Andrew G. Messenger, Andrea Combalia, Jack Green, Abraham Zlotogorski, Jerry Shapiro, Satoshi Itami, Amy J. McMichael, Daniel Asz-Sigall, Wilma F. Bergfeld, Lidia Rudnicka, and Regina C. Betz
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medicine.medical_specialty ,Consensus ,Alopecia Areata ,Delphi Technique ,International Cooperation ,Delphi method ,Dermoscopy ,Comorbidity ,Dermatology ,Severity of Illness Index ,Global Burden of Disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Risk Factors ,Epidemiology ,medicine ,Humans ,business.industry ,Expert consensus ,Guideline ,Dermatology Life Quality Index ,Alopecia areata ,Prognosis ,medicine.disease ,030220 oncology & carcinogenesis ,Family medicine ,Expert opinion ,Practice Guidelines as Topic ,business ,Hair Follicle - Abstract
Background We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. Objective To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. Results Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). Limitations The study had low representation from Africa, South America, and Asia. Conclusion There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.
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- 2021
11. Topical corticosteroid use for atopic dermatitis in the pediatric emergency department
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Jason F. Wang, Seth J. Orlow, Trevor K. Young, Vikash S. Oza, and Laura E. Melnick
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Pediatric emergency ,medicine.medical_specialty ,Dermatology ,Topical hydrocortisone ,Dermatitis, Atopic ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Systemic antibiotics ,Adrenal Cortex Hormones ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Medical prescription ,Single institution ,Child ,Retrospective Studies ,Emollients ,business.industry ,Mean age ,Atopic dermatitis ,medicine.disease ,Topical corticosteroid ,Pediatrics, Perinatology and Child Health ,Emergency Service, Hospital ,business - Abstract
BACKGROUND/OBJECTIVES To investigate the evaluation and management of atopic dermatitis (AD) in the pediatric emergency department (PED). METHODS This retrospective chart review was performed at the PED of a single institution and examined data from 2012 to 2017. Of 335 visits from patients 18 years and younger coded for AD, 167 visits with documented findings that supported a diagnosis of AD according to guidelines from the American Academy of Dermatology were included. RESULTS The mean age of presentation was 6.3 years (standard deviation [SD]: 5.9). Of 11 patients with multiple visits, the mean between-visit interval was 31 days (SD: 41). Topical corticosteroids (TCSs) were not prescribed or recommended in 63/167 visits. In an additional 46/167 visits, over-the-counter topical hydrocortisone was recommended. Of prescribed TCS, the mean TCS class was 5.5 (SD: 1.9). 61/104 recommended or prescribed TCSs were weak (Class 7), the most likely used class (P
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- 2021
12. Skin in the Game: An Analysis of Venture Capital Investment in Dermatology from 2002 to 2021
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Aneesh Agarwal and Seth J. Orlow
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Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry - Published
- 2023
13. A Global eDelphi Exercise to Identify Core Domains and Domain Items for the Development of a Global Registry of Alopecia Areata Disease Severity and Treatment Safety (GRASS)
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Jeff C. Donovan, Cheng Zhou, Valerie D. Callender, Dmitri Wall, Ncoza C. Dlova, Leonardo Spagnol Abraham, Laita Bokhari, Martin S Wade, Sergio Vano-Galvan, Bruna Duque-Estrada, Alan D. Irvine, Wilma F. Bergfeld, Antonella Tosti, Abby Ellison, David Saceda Corralo, Jen Chambers, Pooja Sharma, Seth J. Orlow, Andrew G. Messenger, Bianca Maria Piraccini, Ulrike Blume-Peytavi, Spartak Kaiumov, Brett A. King, Roisin Adams, Rodney Sinclair, Annika Vogt, Melissa Riley, Katherine York, Rachita Dhurat, Won Soo Lee, Brittany G. Craiglow, Bevin Bhoyrul, Aida Gadzhigoroeva, Leslie Jones, Chel Campbell, V. Jolliffe, Juan Ferrando Barberá, Gang Chen, Regina C. Betz, Adriana Rakowska, Elise A. Olsen, Amy J. McMichael, Samantha Eisman, Abraham Zlotogorski, Matthew Harries, George Cotsarelis, Jerry Shapiro, Paul Farrant, Vijaya Chitreddy, Paradi Mirmirani, Leona Yip, Lidia Rudnicka, Nino Lortkipanidze, Yuliya Ovcharenko, Ramon Grimalt, Pascal Reygagne, Maria K. Hordinsky, Tatiana Silyuk, Rodrigo Pirmez, Desmond J. Tobin, Nekma Meah, Wall D., Meah N., York K., Bhoyrul B., Bokhari L., Abraham L.S., Adams R., Bergfeld W., Betz R.C., Blume-Peytavi U., Callender V., Campbell C., Chambers J., Chen G., Chitreddy V., Cotsarelis G., Craiglow B., Dhurat R., Dlova N., Donovan J., Duque-Estrada B., Eisman S., Ellison A., Farrant P., Barbera J.F., Gadzhigoroeva A., Grimalt R., Harries M., Hordinsky M., Irvine A.D., Jolliffe V., Jones L., King B., Lee W.-S., Lortkipanidze N., McMichael A., Messenger A., Mirmirani P., Olsen E., Orlow S.J., Ovcharenko Y., Piraccini B.M., Pirmez R., Rakowska A., Reygagne P., Riley M., Rudnicka L., Saceda Corralo D., Shapiro J., Sharma P., Silyuk T., Kaiumov S., Tobin D.J., Tosti A., Vano-Galvan S., Vogt A., Wade M., Yip L., Zlotogorski A., Zhou C., and Sinclair R.
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medicine.medical_specialty ,Consensus ,Internationality ,Alopecia Areata ,Delphi Technique ,Delphi method ,MEDLINE ,Redress ,Consensu ,Dermatology ,Disease ,Subspecialty ,Severity of Illness Index ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,Global network ,medicine ,Humans ,Surveys and Questionnaire ,Registries ,skin and connective tissue diseases ,Pharmaceutical industry ,integumentary system ,business.industry ,Alopecia areata ,medicine.disease ,030220 oncology & carcinogenesis ,Family medicine ,business ,Human - Abstract
Importance A recent expert consensus exercise emphasized the importance of developing a global network of patient registries for alopecia areata to redress the paucity of comparable, real-world data regarding the effectiveness and safety of existing and emerging therapies for alopecia areata. Objective To generate core domains and domain items for a global network of alopecia areata patient registries. Evidence Review Sixty-six participants, representing physicians, patient organizations, scientists, the pharmaceutical industry, and pharmacoeconomic experts, participated in a 3-round eDelphi process, culminating in a face-to-face meeting at the World Congress of Dermatology, Milan, Italy, June 14, 2019. Findings Ninety-two core data items, across 25 domains, achieved consensus agreement. Twenty further noncore items were retained to facilitate data harmonization in centers that wish to record them. Broad representation across multiple stakeholder groups was sought; however, the opinion of physicians was overrepresented. Conclusions and Relevance This study identifies the domains and domain items required to develop a global network of alopecia areata registries. These domains will facilitate a standardized approach that will enable the recording of a comprehensive, comparable data set required to oversee the introduction of new therapies and harness real-world evidence from existing therapies at a time when the alopecia areata treatment paradigm is being radically and positively disrupted. Reuse of similar, existing frameworks in atopic dermatitis, produced by the Treatment of Atopic Eczema (TREAT) Registry Taskforce, increases the potential to reuse existing resources, creates opportunities for comparison of data across dermatology subspecialty disease areas, and supports the concept of data harmonization.
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- 2021
14. Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children During the COVID-19 Pandemic
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Katharina S. Shaw, Adam J. Ratner, Vikash S. Oza, Philip Kahn, Jinal K. Shah, Gail F. Shust, Rebecca A. Betensky, Trevor K. Young, Asif Noor, Risa Ann Alperin, and Seth J. Orlow
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Male ,Conjunctival injection ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Erythema ,Adolescent ,Mucocutaneous zone ,Dermatology ,Skin Diseases ,Palmoplantar erythema ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Edema ,Pandemic ,Medicine ,Humans ,Child ,Retrospective Studies ,Mucous Membrane ,business.industry ,Brief Report ,COVID-19 ,Infant ,Retrospective cohort study ,Systemic Inflammatory Response Syndrome ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,New York City ,medicine.symptom ,business - Abstract
Importance To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms. Objective To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020. Design, Setting, and Participants A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C. Main Outcomes and Measures Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists. Results Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity. Conclusions and Relevance In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.
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- 2020
15. Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex
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Prashiela Manga, Olga Lavinda, Seth J. Orlow, and Timothy Cardozo
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0301 basic medicine ,Tyrosinase ,melanosome ,protein-protein interface ,RM1-950 ,tyrosinase ,03 medical and health sciences ,0302 clinical medicine ,Heterotrimeric G protein ,medicine ,pigmentary disorders ,Pharmacology (medical) ,TYRP1 ,Original Research ,OCA2 ,Pharmacology ,Chemistry ,molecular modeling ,medicine.disease ,Oculocutaneous albinism ,Phenotype ,Cell biology ,Transmembrane domain ,030104 developmental biology ,Docking (molecular) ,030220 oncology & carcinogenesis ,computational molecular docking ,Therapeutics. Pharmacology ,oculocutaneous albinism - Abstract
Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.
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- 2020
16. The Vitiligo (mivit) Mutant Allele of the Microphthalmia Locus, Chromosome 6
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M. Lynn Lamoreux and Seth J. Orlow
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Genetics ,Mutant allele ,medicine ,Locus (genetics) ,Vitiligo ,Biology ,medicine.disease ,Microphthalmia - Published
- 2020
17. The Adrenocortical Dysplasia (acd) Mutation, Chromosome 8
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Wesley G. Beamer, Hope O. Sweet, John P. Sundberg, and Seth J. Orlow
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Mutation ,Pathology ,medicine.medical_specialty ,integumentary system ,Polydactyly ,business.industry ,Cortical morphology ,Chromosome ,medicine.disease ,medicine.disease_cause ,Hyperpigmentation ,Dysplasia ,New mutation ,medicine ,medicine.symptom ,business ,Adrenocortical Insufficiency - Abstract
The adrenocortical dysplasia (acd) mouse mutation arose spontaneously in the dwarf strain in 1985 at the Jackson Laboratory. Both the background strain and the acd/acd mice are agouti/leaden. Mice homozygous for the adrenocortical dysplasia mutation (acd/acd) are identifiable at birth by reduced body weight and a high incidence of polydactyly of the hind feet and kinking of the tail. Examination of plucked hairs revealed the presence of dystrophic overhairs (awls and auchene hairs), but an absence of zigzag underhairs. Adrenal cortical morphology and organization were dramatically altered in the (acd/acd) mice compared to littermate controls, hence the designation of this new mutation. Adrenocortical dysplasia is due to a single autosomal recessive mutation. Hypoadrenocorticism (chronic adrenocortical insufficiency) has been recognized as a distinct, yet not uncommon disease in the dog. Dogs with these diseases develop hyperpigmentation of the skin, particularly over points of friction and wear.
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- 2020
18. The Hairy Ears (Eh) Mutation, Chromosome 15
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Seth J. Orlow and John P. Sundberg
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Genetics ,Chromosome 15 ,Mutation (genetic algorithm) ,Biology ,Hairy ears - Published
- 2020
19. The Silver (si) Mutation, Chromosome 10
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Seth J. Orlow and John P. Sundberg
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Genetics ,Chromosome (genetic algorithm) ,Mutation (genetic algorithm) ,Biology - Published
- 2020
20. The Depilated (dep) Mutation, Chromosome 4
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John P. Sundberg and Seth J. Orlow
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Genetics ,Chromosome 4 ,Mutation (genetic algorithm) ,Biology - Published
- 2020
21. Psychiatric disorders and suicidal behavior in patients with acne prescribed oral antibiotics versus isotretinoin: Analysis of a large commercial insurance claims database
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Seth J. Orlow, Elyse M. Love, Priscilla W. Wong, Randie H. Kim, Arielle R. Nagler, Evan A. Rieder, and Nkemjika Ugonabo
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medicine.medical_specialty ,Population ,Dermatology ,computer.software_genre ,Suicidal Ideation ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Insurance ,0302 clinical medicine ,Acne Vulgaris ,medicine ,Humans ,skin and connective tissue diseases ,education ,Psychiatry ,Isotretinoin ,Suicidal ideation ,Depression (differential diagnoses) ,Acne ,Retrospective Studies ,education.field_of_study ,Database ,business.industry ,Mental Disorders ,Retrospective cohort study ,Odds ratio ,medicine.disease ,Confidence interval ,United States ,Anti-Bacterial Agents ,030220 oncology & carcinogenesis ,Dermatologic Agents ,medicine.symptom ,business ,computer ,medicine.drug - Abstract
The association between isotretinoin and psychiatric disturbance, including depression and suicidal behavior, is controversial.To investigate whether acne patients prescribed isotretinoin or antibiotics were more likely to have psychiatric disorders and/or engage in suicidal behavior.Retrospective cohort study using the IBM MarketScan Research Databases, which contain commercial insurance claims in the United States, to identify acne patients who were prescribed isotretinoin or oral antibiotics between 2011 and 2017 and who were diagnosed with psychiatric disorders or suicidal behavior.A total of 72,555 patients were included in the study. Patients in the general population were 1.47 times more likely to be diagnosed with suicidal ideation or attempt compared to acne patients prescribed isotretinoin (adjusted odds ratio [OR] 1.47; confidence interval [95% CI], 1.27, 1.70; P .0001). The general population (adjusted OR 0.87; 95% CI, 0.84, 0.89; P .0001) and acne patients prescribed antibiotics (adjusted OR 0.88; 95% CI, 0.85, 0.91; P .0001) were less likely to have a psychiatric diagnosis compared to acne patients prescribed isotretinoin. The prevalence of suicidal behavior during isotretinoin treatment was lower (0.10%; P = .082) than in the year prior to isotretinoin treatment (0.22%) and in the year following treatment (0.34%; P = .004).The study excluded individuals with public insurance and those who were uninsured, and the data in the study relied on the accuracy of the medical coding.Compared to the general population, acne patients prescribed isotretinoin were less likely to engage in suicidal behavior. Further exploration into the slight increase in suicidal behavior seen in isotretinoin patients 1 year after therapy is warranted.
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- 2020
22. The Alopecia Areata Consensus of Experts (ACE) study: Results of an international expert opinion on treatments for alopecia areata
- Author
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Wilma F. Bergfeld, Valerie D. Callender, A.D. Irvine, Abraham Zlotogorski, Maria K. Hordinsky, Victoria Jolliffe, Daniel Asz Sigall, Jerry Shapiro, Jack Green, Lidia Rudnicka, Nekma Meah, Elise A. Olsen, Jeff C. Donovan, Adriana Rakowska, Dmitri Wall, Won Soo Lee, Ulrike Blume-Peytavi, Katherine York, Samantha Eisman, George Cotsarelis, Seth J. Orlow, Antonella Tosti, Satoshi Itami, Ramon Grimalt, Matthew Harries, Vijaya Chitreddy, Pooja Sharma, Pascal Reygagne, Leona Yip, Annika Vogt, Amy J. McMichael, Brittany G. Craiglow, Bevin Bhoyrul, Martin S Wade, Brett A. King, Paul Farrant, Laita Bokhari, Regina C. Betz, Paradi Mirmirani, Andrew G. Messenger, Andrea Combalia, Bianca Maria Piraccini, Janet L. Roberts, Rodney Sinclair, and Meah N, Wall D, York K, Bhoyrul B, Bokhari L, Sigall DA, Bergfeld WF, Betz RC, Blume-Peytavi U, Callender V, Chitreddy V, Combalia A, Cotsarelis G, Craiglow B, Donovan J, Eisman S, Farrant P, Green J, Grimalt R, Harries M, Hordinsky M, Irvine AD, Itami S, Jolliffe V, King B, Lee WS, McMichael A, Messenger A, Mirmirani P, Olsen E, Orlow SJ, Piraccini BM, Rakowska A, Reygagne P, Roberts JL, Rudnicka L, Shapiro J, Sharma P, Tosti A, Vogt A, Wade M, Yip L, Zlotogorski A, Sinclair R.
- Subjects
Complementary Therapies ,medicine.medical_specialty ,Alopecia Areata ,Delphi Technique ,Administration, Topical ,Delphi method ,Administration, Oral ,Topical treatment ,Dermatology ,Injections, Intralesional ,Severity of Illness Index ,Systemic therapy ,law.invention ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Adrenal Cortex Hormones ,law ,Humans ,Medicine ,Expert Testimony ,Patient registry ,business.industry ,Alopecia areata, Treatments for alopecia areata ,Age Factors ,alopecia areata, steroid, methotrexate, cyclosporin ,Expert consensus ,Phototherapy ,Alopecia areata ,medicine.disease ,Combined Modality Therapy ,Treatment Outcome ,030220 oncology & carcinogenesis ,Expert opinion ,Family medicine ,Dermatologic Agents ,business - Abstract
Background A systematic review failed to identify any systemic therapy used in alopecia areata (AA) where use is supported by robust evidence from high-quality randomized controlled trials. Objective To produce an international consensus statement on the use and utility of various treatments for AA. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Agreement of 66% or greater was considered consensus. Results In the first round, consensus was achieved in 22 of 423 (5%) questions. After a face-to-face meeting in round 3, overall, consensus was achieved for only 130 (33%) treatment-specific questions. There was greater consensus for intralesional treatment of AA (19 [68%]) followed by topical treatment (25 [43%]). Consensus was achieved in 45 (36%) questions pertaining to systemic therapies in AA. The categories with the least consensus were phototherapy and nonprescription therapies. Limitations The study included a comprehensive list of systemic treatments for AA but not all treatments used. Conclusion Despite divergent opinions among experts, consensus was achieved on a number of pertinent questions. The concluding statement also highlights areas where expert consensus is lacking and where an international patient registry could enable further research.
- Published
- 2020
23. High-value dermatology: 5 Laboratory tests to reconsider
- Author
-
Seth J. Orlow, Jason F. Wang, Oluwatobi A Ogbechie-Godec, and Hao Feng
- Subjects
Male ,medicine.medical_specialty ,Evidence-Based Medicine ,Clinical Laboratory Techniques ,Diagnostic Tests, Routine ,business.industry ,Dermatology ,Evidence-based medicine ,Sensitivity and Specificity ,Laboratory testing ,Clinical Practice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Value based healthcare ,Practice Guidelines as Topic ,medicine ,Humans ,Female ,Medical physics ,030212 general & internal medicine ,business ,Value (mathematics) - Published
- 2018
24. Characterization of Herpes Simplex Virus Infections Seen in the Pediatric Dermatology Office
- Author
-
Seth J. Orlow, Julia K. Gittler, and Euphemia W. Mu
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Population ,Herpesvirus 1, Human ,Dermatology ,medicine.disease_cause ,Virus ,Disease Outbreaks ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Recurrent herpes simplex ,medicine ,Humans ,030212 general & internal medicine ,Pediatric dermatology ,Child ,education ,Retrospective Studies ,education.field_of_study ,business.industry ,Infant ,Outbreak ,Herpes Simplex ,Herpes simplex virus ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,business - Abstract
Background/Objectives Atypical and severe clinical manifestations of primary and recurrent herpes simplex virus (HSV) infections may present to a pediatric dermatologist for evaluation. The purpose of this study was to characterize the clinical features of the population diagnosed with HSV referred to a pediatric dermatology office. Methods This retrospective case series examined patients diagnosed with HSV in a pediatric dermatology practice at an academic medical center from 2005 to 2015. Characteristics of the population were collected and analyzed. Results In this study of 48 children diagnosed with HSV, 33% presented at age 2 years or younger, with approximately half having exhibited initial symptoms before 2 years of age; 39.6% of the population had six or more outbreaks per year. The outbreaks were equally divided between unifocal and multifocal presentations, with 60% of children without any labial or mucosal involvement. Suppressive treatment was initiated in 33% of patients; the average age at initiation was 6 years. Conclusion Our data characterize a subset of immunocompetent young children who present to pediatric dermatologists with frequent HSV outbreaks that are often multifocal and involve cutaneous sites, with or without mucosal involvement.
- Published
- 2017
25. Oral Antibacterial Therapy for Acne Vulgaris: An Evidence-Based Review
- Author
-
Seth J. Orlow, Amanda Bienenfeld, and Arielle R. Nagler
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Antibiotics ,Administration, Oral ,Guidelines as Topic ,Minocycline ,Dermatology ,Placebo ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Meta-Analysis as Topic ,Acne Vulgaris ,medicine ,Humans ,030212 general & internal medicine ,Dosing ,Acne ,Randomized Controlled Trials as Topic ,Clinical Trials as Topic ,Evidence-Based Medicine ,business.industry ,General Medicine ,medicine.disease ,Trimethoprim ,Anti-Bacterial Agents ,Clinical trial ,Treatment Outcome ,Systematic review ,Tetracyclines ,Doxycycline ,Practice Guidelines as Topic ,business ,medicine.drug - Abstract
To some degree, acne vulgaris affects nearly every individual worldwide. Oral antibiotic therapy is routinely prescribed for the treatment of moderate to severe inflammatory acne; however, long-term use of oral antibiotics for acne may have unintended consequences. The aim of this study was to provide a systematic evaluation of the scientific evidence on the efficacy and appropriate use of oral antibiotics in the treatment of acne. A systematic search of MEDLINE was conducted to identify randomized controlled clinical trials, systematic reviews, and meta-analyses evaluating the efficacy of oral antibiotics for acne. Overall, 41 articles that examined oral antibiotics compared with placebo, another oral therapy, topical therapy, alternate dose, or duration were included in this study. Tetracyclines, macrolides, and trimethoprim/sulfamethoxazole are effective and safe in the treatment of moderate to severe inflammatory acne. Superior efficacy of one type or class of antibiotic could not be determined, therefore the choice of antibiotic is generally based on the side-effect profile. Although different dosing regimens have been studied, there is a lack of standardized comparator trials to determine optimal dosing and duration of each oral antibiotic used in acne. The combination of oral antibiotics with a topical therapy is superior to oral antibiotics alone. This article provides a systematic evaluation of the scientific evidence of the efficacy of oral antibiotics for acne. Due to heterogeneity in the design of the trials, there is insufficient evidence to support one type, dose, or duration of oral antibiotic over another in terms of efficacy; however, due to increasing resistance to antibiotics, dermatologists should heed consensus guidelines for their appropriate use.
- Published
- 2017
26. Acquired acrodermatitis enteropathica due to zinc‐depleted parenteral nutrition
- Author
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Lauren E. Wiznia, Yasir Al-Qaqaa, Nooshin Brinster, Seth J. Orlow, Suneet Bhansali, and Vikash S. Oza
- Subjects
Vitamin ,medicine.medical_specialty ,Respiratory distress ,business.industry ,Acrodermatitis enteropathica ,chemistry.chemical_element ,Dermatology ,Zinc ,medicine.disease ,Gastroenterology ,Enteral administration ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Parenteral nutrition ,chemistry ,Atypical pneumonia ,030220 oncology & carcinogenesis ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Zinc deficiency ,business - Abstract
Well-known causes of zinc deficiency, also referred to as acrodermatitis enteropathica (AE), include defects in intestinal zinc transporters and inadequate intake, but a rare cause of acquired zinc deficiency discussed here is an iatrogenic nutritional deficiency caused by parenteral nutrition administered without trace elements. While zinc-depleted parenteral nutrition causing dermatosis of acquired zinc deficiency was first reported in the 1990s, it is now again relevant due to a national vitamin and trace element shortage. A high index of suspicion may be necessary to diagnose zinc deficiency, particularly because early clinical findings are nonspecific. We present this case of acquired zinc deficiency in a patient admitted to a pediatric intensive care unit for respiratory distress and atypical pneumonia, who subsequently developed a severe bullous eruption due to iatrogenic zinc deficiency but was treated effectively with enteral and parenteral zinc supplementation, allowing for rapid re-epithelialization of previously denuded skin.
- Published
- 2019
27. Tinea incognito in an urban pediatric population
- Author
-
Thomas, Stringer, Julia K, Gittler, and Seth J, Orlow
- Subjects
Male ,Antifungal Agents ,Adolescent ,Urban Population ,Child Health Services ,Infant ,Medical Records ,Tinea ,Child, Preschool ,Prevalence ,Humans ,Female ,New York City ,Child ,Retrospective Studies - Abstract
Tinea incognito (TI) describes a common dermatophytosis with often atypical clinical features attributed to inappropriate use of topical immunomodulatory agents, usually corticosteroids. Given the high prevalence of TI and limited literature detailing this condition, we conducted a retrospective review of cases of pediatric dermatophytosis presenting to the Faculty Group Practice of the Ronald O. Perelman Department of Dermatology, New York University School of Medicine (New York, New York), between 2005 and 2016. Among microbiologically confirmed dermatophytosis cases, we found that even with prior treatment, TI often presented with classic features of tinea such as annularity and scale. The majority of cases were treated with oral antifungals, though some were treated with topical antifungals alone. This case series underscores the need to maintain a high clinical suspicion for TI.
- Published
- 2018
28. Inhibition of the CRAF/prohibitin interaction reverses CRAF-dependent resistance to vemurafenib
- Author
-
Nicole A. Doudican and Seth J. Orlow
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Indoles ,Cell Survival ,MAP Kinase Signaling System ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Growth factor receptor ,Rocaglamide ,Cell Line, Tumor ,Prohibitins ,Genetics ,medicine ,Animals ,Humans ,Prohibitin ,Vemurafenib ,Melanoma ,neoplasms ,Molecular Biology ,Benzofurans ,Cell Proliferation ,Sulfonamides ,Cell Cycle ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-raf ,Repressor Proteins ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Female ,Signal transduction ,Protein Binding ,medicine.drug - Abstract
Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma. Prohibitins (PHBs) are highly conserved proteins that are thought to control the cell cycle, senescence and tumor suppression. PHB1 is essential for CRAF-mediated ERK1/2 activation through direct binding to CRAF. We developed a CRAF-mediated model of vemurafenib resistance in melanoma cells to assess the importance of the interaction between CRAF and PHB1 in resistance to BRAF-targeting agents. We demonstrate that CRAF overexpression renders melanoma cells resistant to BRAF-targeting agents. Moreover, treatment with the natural compound rocaglamide A disrupts the interaction between PHB and CRAF in melanoma cells, thus reducing MEK1/2 and ERK1/2 signaling, inhibiting melanoma cell growth and inducing apoptosis. The efficacy of these compounds was also demonstrated in a human melanoma xenograft model. Taken together, these data suggest that PHB1 may serve as a novel, druggable target in CRAF-mediated vemurafenib resistance.
- Published
- 2016
29. The use of oral antibiotics before isotretinoin therapy in patients with acne
- Author
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Arielle R. Nagler, Emily C. Milam, and Seth J. Orlow
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.drug_class ,Antibiotics ,Administration, Oral ,Dermatology ,Single Center ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Antibiotic resistance ,Internal medicine ,Acne Vulgaris ,medicine ,Humans ,030212 general & internal medicine ,Young adult ,Isotretinoin ,Acne ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,Anti-Bacterial Agents ,Drug Therapy, Combination ,Female ,Dermatologic Agents ,Diagnosis code ,business ,medicine.drug - Abstract
Background Systemic antibiotics are used widely to treat moderate to severe acne, but increasing antibiotic resistance makes appropriate use a priority. Objective We sought to determine the duration of systemic antibiotic use in patients with inflammatory/nodulocystic acne who eventually required isotretinoin. Methods We performed a retrospective, single-site chart review of patients with acne diagnostic codes evaluated January 1, 2005 to December 31, 2014, at a dermatology practice in an academic medical center. Included patients were prescribed isotretinoin during the study period and received 30 days or more of antibiotics. Results The average duration of antibiotic use was 331.3 days. In all, 21 patients (15.3%) were prescribed antibiotics for 3 months or less, 88 patients (64.2%) for 6 months or more, and 46 patients (33.6%) for 1 year or longer. Patients treated only at the study site had a mean duration of antibiotic treatment of 283.1 days whereas patients who also received antibiotics from another institution had a mean duration of 380.2 days. This difference approached statistical significance (P = .054). Limitations This study was limited to a single center. Conclusion Expert guidelines recommend responsible use of antibiotics in acne in light of emerging resistance. We found that patients who eventually received isotretinoin had extended exposure to antibiotics, exceeding recommendations. Early recognition of antibiotic failure and the need for isotretinoin can curtail antibiotic use.
- Published
- 2016
30. Keratosis Pilaris and its Subtypes: Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options
- Author
-
Seth J. Orlow and Jason F. Wang
- Subjects
medicine.medical_specialty ,Keratosis pilaris rubra ,Pilosebaceous unit ,Dermatology ,Disease ,Filaggrin Proteins ,Administration, Cutaneous ,Keratosis Pilaris ,Keratosis pilaris atrophicans ,Dermatitis, Atopic ,Diagnosis, Differential ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Erythromelanosis follicularis faciei et colli ,Intermediate Filament Proteins ,Medicine ,Humans ,Abnormalities, Multiple ,Skin pathology ,Skin ,business.industry ,Ichthyosis ,General Medicine ,Phototherapy ,medicine.disease ,Treatment Outcome ,Dermabrasion ,030220 oncology & carcinogenesis ,Mutation ,Etiology ,ras Proteins ,Dermatologic Agents ,Eyebrows ,business ,Darier Disease ,Signal Transduction - Abstract
Keratosis pilaris is a common skin disorder comprising less common variants and rare subtypes, including keratosis pilaris rubra, erythromelanosis follicularis faciei et colli, and the spectrum of keratosis pilaris atrophicans. Data, and critical analysis of existing data, are lacking, so the etiologies, pathogeneses, disease associations, and treatments of these clinical entities are poorly understood. The present article aims to fill this knowledge gap by reviewing literature in the PubMed, EMBASE, and CINAHL databases and providing a comprehensive, analytical summary of the clinical characteristics and pathophysiology of keratosis pilaris and its subtypes through the lens of disease associations, genetics, and pharmacologic etiologies. Histopathologic, genomic, and epidemiologic evidence points to keratosis pilaris as a primary disorder of the pilosebaceous unit as a result of inherited mutations or acquired disruptions in various biomolecular pathways. Recent data highlight aberrant Ras signaling as an important contributor to the pathophysiology of keratosis pilaris and its subtypes. We also evaluate data on treatments for keratosis pilaris and its subtypes, including topical, systemic, and energy-based therapies. The effectiveness of various types of lasers in treating keratosis pilaris and its subtypes deserves wider recognition.
- Published
- 2018
31. The Use of Hormonal Antiandrogen Therapy in Female Patients with Acne: A 10-Year Retrospective Study
- Author
-
Arielle R. Nagler, Joyce H. Park, Seth J. Orlow, and Amanda Bienenfeld
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Antibiotics ,Dermatology ,Spironolactone ,Antiandrogen ,Drug Prescriptions ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Pharmacotherapy ,Internal medicine ,Acne Vulgaris ,medicine ,Humans ,Young adult ,Antiandrogen Therapy ,Acne ,Retrospective Studies ,business.industry ,Retrospective cohort study ,Androgen Antagonists ,General Medicine ,Middle Aged ,medicine.disease ,Anti-Bacterial Agents ,Contraceptives, Oral, Combined ,Cross-Sectional Studies ,chemistry ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Little is known about how dermatologists prescribe hormonal antiandrogen acne treatment (HAAT). The aim of this study was to investigate dermatologists’ HAAT-prescribing habits and HAAT’s impact on systemic antibiotic use in women with acne. We performed a retrospective study at an academic medical center of female patients receiving HAAT (combined oral contraceptive [COC], spironolactone) for acne from January 2005 to October 2015. Data from a control group of female acne patients who never received HAAT were also collected. A total of 672 female patients received HAAT. Out of all systemic medications for acne, antibiotics were used as first-line treatment in 39% of patients, COCs in 12%, and spironolactone in 21%. Mean antibiotic durations in patients who initiated HAAT for the first time at the study site (250.4 days) were significantly longer than in patients who received HAAT prior to presentation and continued HAAT at the study site (192.0 days) (p = 0.021). A statistically significant inverse association was found between HAAT use and mean antibiotic duration (p = 0.016). HAAT is not typically used as a first-line systemic therapy in women with acne. HAAT usage is associated with shorter cumulative antibiotic durations and early HAAT initiation can decrease systemic antibiotic use in acne treatment.
- Published
- 2018
32. Clinical evidence for washing and cleansers in acne vulgaris: a systematic review
- Author
-
Vikash S. Oza, Seth J. Orlow, Thomas Stringer, and Arielle R. Nagler
- Subjects
medicine.medical_specialty ,Benzoyl Peroxide ,business.industry ,Detergents ,Psychological intervention ,Dermatology ,medicine.disease ,Glycolates ,body regions ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Clinical evidence ,030225 pediatrics ,Face ,Acne Vulgaris ,medicine ,Anti-Infective Agents, Local ,Humans ,Propionibacterium acnes ,business ,Salicylic Acid ,Acne - Abstract
Washing and over-the-counter cleansers are common interventions in acne vulgaris (AV), but the clinical evidence for their benefit is poorly understood. This systematic review presents clinical studies of washing and cleanser efficacy in acne vulgaris to guide treatment recommendations of dermatologists.We surveyed English-language articles indexed in MEDLINE (1951-March 2017) and EMBASE (1974-March 2017). Articles were required to be prospective studies of a single over-the-counter cleanser or washing intervention in AV with an objective AV outcome measurement published in a peer-reviewed journal.Fourteen prospective studies representing 671 participants were included in this review. Modalities investigated included face washing frequency, true soap/syndet cleansing bars, antiseptic cleansers, alpha and beta-hydroxy (i.e. salicylic) acid cleansers, and several proprietary formulations. Given the low number of well-performed clinical studies of cleansers and washing, it is difficult to formulate reliable recommendations. We hope that our findings highlight the necessity of further investigation in this area.
- Published
- 2018
33. Rapid improvement of prurigo nodularis with cyclosporine treatment
- Author
-
Seth J. Orlow, David E. Cohen, Shields Callahan, and Lauren E. Wiznia
- Subjects
Adult ,Male ,medicine.medical_specialty ,Treatment outcome ,MEDLINE ,Dermatology ,Severity of Illness Index ,Drug Administration Schedule ,Cohort Studies ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Severity of illness ,Medicine ,Humans ,Aged ,Retrospective Studies ,Academic Medical Centers ,Dose-Response Relationship, Drug ,business.industry ,Follow up studies ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cyclosporine ,Female ,Dermatologic Agents ,Prurigo ,business ,Prurigo nodularis ,Cohort study ,Follow-Up Studies - Published
- 2017
34. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant response promotes melanocyte viability and reduces toxicity of the vitiligo-inducing phenol monobenzone
- Author
-
Nada Elbuluk, Omotayo Arowojolu, Prashiela Manga, and Seth J. Orlow
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cell Survival ,NF-E2-Related Factor 2 ,Dimethyl Fumarate ,Vitiligo ,Dermatology ,Melanocyte ,medicine.disease_cause ,Biochemistry ,digestive system ,environment and public health ,Antioxidants ,Article ,Cell Line ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Depigmentation ,Internal medicine ,medicine ,NAD(P)H Dehydrogenase (Quinone) ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Skin ,Hypopigmentation ,Gene knockdown ,integumentary system ,Chemistry ,respiratory system ,medicine.disease ,Oxidants ,KEAP1 ,Monobenzone ,Cell biology ,Hydroquinones ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Toxicity ,Melanocytes ,medicine.symptom ,Oxidative stress ,medicine.drug ,Peroxiredoxin VI - Abstract
Vitiligo, characterised by progressive melanocyte death, can be initiated by exposure to vitiligo-inducing phenols (VIPs). VIPs generate oxidative stress in melanocytes and activate the master antioxidant regulator NRF2. While NRF2-regulated antioxidants are reported to protect melanocytes from oxidative stress, the role of NRF2 in the melanocyte response to monobenzone, a clinically relevant VIP, has not been characterised. We hypothesised that activation of NRF2 may protect melanocytes from monobenzone-induced toxicity. We observed that knockdown of NRF2 or NRF2-regulated antioxidants NQO1 and PRDX6 reduced melanocyte viability, but not viability of keratinocytes and fibroblasts, suggesting that melanocytes were preferentially dependent upon NRF2 activity for growth compared to other cutaneous cells. Furthermore, melanocytes activated the NRF2 response following monobenzone exposure and constitutive NRF2 activation reduced monobenzone toxicity, supporting NRF2's role in the melanocyte stress response. In contrast, melanocytes from individuals with vitiligo (vitiligo melanocytes) did not activate the NRF2 response as efficiently. Dimethyl fumarate-mediated NRF2 activation protected normal and vitiligo melanocytes against monobenzone-induced toxicity. Given the contribution of oxidant-antioxidant imbalance in vitiligo, modulation of this pathway may be of therapeutic interest.
- Published
- 2017
35. Genital melanocytic nevi in children: Experience in a pediatric dermatology practice
- Author
-
Seth J. Orlow, Raegan Hunt, and Julie V. Schaffer
- Subjects
Male ,medicine.medical_specialty ,Skin Neoplasms ,Adolescent ,Dermoscopy ,Dermatology ,Risk Assessment ,Cohort Studies ,Age Distribution ,Epidemiology ,Prevalence ,medicine ,Humans ,Nevus ,Neoplasm Invasiveness ,Sex organ ,Sex Distribution ,Family history ,Child ,skin and connective tissue diseases ,neoplasms ,Monitoring, Physiologic ,Neoplasm Staging ,Retrospective Studies ,Nevus, Pigmented ,integumentary system ,business.industry ,Melanoma ,Biopsy, Needle ,Melanocytic nevus ,Prognosis ,medicine.disease ,Immunohistochemistry ,Natural history ,Treatment Outcome ,medicine.anatomical_structure ,Child, Preschool ,Scalp ,Female ,New York City ,Genital Diseases, Male ,business ,Genital Diseases, Female - Abstract
Background Little is known about the prevalence and clinical characteristics of genital melanocytic nevi in children. Objective We sought to describe the epidemiology, clinical and dermoscopic features, and natural history of genital nevi in pediatric patients. Methods We reviewed charts of 1159 children given the diagnosis of melanocytic nevi over 11 years. Those with genital nevus as a chief symptom were contacted for follow-up. Results Among children/adolescents evaluated for nevi, the prevalence of genital nevus was 3.5% (40/1159), with a male:female ratio of 1.3:1. There were no statistically significant differences in age, sex, total nevus number, presence of acral and scalp nevi, or family history of dysplastic nevi and melanoma between patients with and without genital nevi. Genital nevus onset was before age 2 years in 63.6% of patients. A globular dermoscopic pattern was observed in 93.3%. Most genital nevi underwent a gradual change in diameter, elevation (becoming soft papules), color, texture, or a combination of these. After median follow-up of 1.5 years, no melanoma or other adverse outcome was observed. Limitations This was a retrospective chart analysis and questionnaire-based study of a limited number of patients. Conclusions Increased awareness of the clinical characteristics, dermoscopic features, and evolution of genital nevi in children may help to avoid unnecessary surgery.
- Published
- 2014
36. Bathing and Associated Treatments in Atopic Dermatitis
- Author
-
Seth J. Orlow, Jason F. Wang, and Julia K. Gittler
- Subjects
Balneotherapy ,medicine.medical_specialty ,Time Factors ,Bathing ,medicine.medical_treatment ,Pharmacology toxicology ,Dermatology ,law.invention ,Dermatitis, Atopic ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Dermatologic agents ,Medicine ,Humans ,030212 general & internal medicine ,Randomized Controlled Trials as Topic ,Skin care ,Emollients ,business.industry ,Baths ,General Medicine ,Atopic dermatitis ,medicine.disease ,Skin Care ,body regions ,Practice Guidelines as Topic ,Allergists ,Dermatologic Agents ,business - Abstract
Atopic dermatitis is one of the most common complaints presenting to dermatologists, and patients typically inquire as to appropriate bathing recommendations. Although many dermatologists, allergists, and primary-care practitioners provide explicit bathing instructions, recommendations regarding frequency of bathing, duration of bathing, and timing related to emollient and medication application relative to bathing vary widely. Conflicting and vague guidelines stem from knowledge related to the disparate effects of water on skin, as well as a dearth of studies, especially randomized controlled trials, evaluating the effects of water and bathing on the skin of patients with atopic dermatitis. We critically review the literature related to bathing and associated atopic dermatitis treatments, such as wet wraps, bleach baths, bath additives, and balneotherapy. We aim to provide readers with a comprehensive understanding of the impact of water and related therapies on atopic dermatitis as well as recommendations based upon the published data.
- Published
- 2016
37. XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts
- Author
-
Nicole A. Doudican, Pamela M. Pollock, Seth J. Orlow, and Sara A. Byron
- Subjects
Cancer Research ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Inhibitor of apoptosis ,Mice ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Line, Tumor ,Temozolomide ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Phosphorylation ,Melanoma ,Pharmacology ,medicine.disease ,Xenograft Model Antitumor Assays ,XIAP ,Dacarbazine ,Transplantation ,Mebendazole ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Cell culture ,Cancer research ,Female ,Growth inhibition - Abstract
Mebendazole (MBZ) was identified as a promising therapeutic on the basis of its ability to induce apoptosis in melanoma cell lines through a B-cell lymphoma 2 (BCL2)-dependent mechanism. We now show that in a human xenograft melanoma model, oral MBZ is as effective as the current standard of care temozolomide in reducing tumor growth. Inhibition of melanoma growth in vivo is accompanied by phosphorylation of BCL2 and decreased levels of X-linked inhibitor of apoptosis (XIAP). Reduced expression of XIAP on treatment with MBZ is partially mediated by its proteasomal degradation. Furthermore, exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating XIAP's inhibition on apoptosis. XIAP expression on exposure to MBZ is indicative of sensitivity to MBZ as MBZ-resistant cells do not show reduced levels of XIAP after treatment. Resistance to MBZ can be reversed partially by siRNA knockdown of cellular levels of XIAP. Our data indicate that MBZ is a promising antimelanoma agent on the basis of its effects on key antiapoptotic proteins.
- Published
- 2013
38. Vitiligo-Inducing Phenols Activate the Unfolded Protein Response in Melanocytes Resulting in Upregulation of IL6 and IL8
- Author
-
Siavash Toosi, Prashiela Manga, and Seth J. Orlow
- Subjects
X-Box Binding Protein 1 ,XBP1 ,Vitiligo ,Gene Expression ,Autoimmunity ,Regulatory Factor X Transcription Factors ,Dermatology ,Biology ,Melanocyte ,medicine.disease_cause ,Biochemistry ,Cell Line ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Phenols ,Downregulation and upregulation ,medicine ,Humans ,skin and connective tissue diseases ,Transcription factor ,Molecular Biology ,Skin ,030304 developmental biology ,0303 health sciences ,integumentary system ,Interleukin-6 ,Endoplasmic reticulum ,Interleukin-8 ,Infant, Newborn ,Cell Biology ,medicine.disease ,Hydroquinones ,Up-Regulation ,Cell biology ,DNA-Binding Proteins ,Oxidative Stress ,medicine.anatomical_structure ,Immunology ,Unfolded Protein Response ,Unfolded protein response ,Melanocytes ,Oxidative stress ,Transcription Factors - Abstract
Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.
- Published
- 2012
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39. Comparison of Childhood Vitiligo Presenting with or without Associated Halo Nevi
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Seth J. Orlow, Euphemia W. Mu, and Brandon E. Cohen
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Male ,medicine.medical_specialty ,Adolescent ,Vitiligo ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Nevus ,Humans ,030212 general & internal medicine ,Pediatric dermatology ,Family history ,skin and connective tissue diseases ,Child ,Halo nevus ,Retrospective Studies ,integumentary system ,business.industry ,Disease progression ,Infant ,Retrospective cohort study ,medicine.disease ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,Halo ,business ,Nevus, Halo - Abstract
Background Previous studies have characterized differences in vitiligo associated with halo nevi, but the features of vitiligo presenting with halo nevus in children have yet to be fully described. Aims We sought to provide an epidemiologic and clinical comparison of cases of childhood vitiligo presenting with or without associated halo nevi. Materials and Methods This was a retrospective chart review of children diagnosed with vitiligo in an academic pediatric dermatology practice from January 1990 to November 2014. The characteristics of children with vitiligo with or without associated halo nevi were compared. Results Halo nevi were identified in 55 (26%) of 208 children with vitiligo. Patients with halo nevi were significantly more likely to be male and develop vitiligo at a later age. Children with vitiligo associated with halo nevi were more likely to present with generalized vitiligo, defined according to the presence of bilateral macules. Discussion There was no significant association between groups in the percentage of body surface area with vitiligo or family history of vitiligo or autoimmune diseases. Patients with halo nevi were no more likely to develop new areas of vitiligo during the follow-up period, but there was a nonsignificant trend toward a higher rate of repigmentation in vitiligo associated with halo nevus. Conclusion Halo nevi are a common finding in children with vitiligo. The presence of a halo nevus in a child with vitiligo is associated with generalized vitiligo. The presence of a halo nevus does not significantly alter the risk of disease progression and rate of treatment.
- Published
- 2015
40. Cutaneous microbiome effects of fluticasone propionate cream and adjunctive bleach baths in childhood atopic dermatitis
- Author
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Mercedes E. Gonzalez, Zhan Gao, Huilin Li, Alexander V. Alekseyenko, Julie V. Schaffer, Martin J. Blaser, and Seth J. Orlow
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Staphylococcus aureus ,Sodium Hypochlorite ,Dermatology ,Skin infection ,medicine.disease_cause ,Administration, Cutaneous ,Eczema Area and Severity Index ,Fluticasone propionate ,Article ,Dermatitis, Atopic ,Pathogenesis ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Single-Blind Method ,Microbiome ,Skin ,business.industry ,Microbiota ,Infant ,Baths ,Atopic dermatitis ,medicine.disease ,030104 developmental biology ,Child, Preschool ,Fluticasone ,Female ,Dermatologic Agents ,business ,Staphylococcus ,medicine.drug - Abstract
Patients with atopic dermatitis (AD) are prone to skin infections, with microbes such as Staphylococcus aureus suspected of contributing to pathogenesis. Bleach baths might improve AD by reducing skin microbial burden.We sought to characterize the microbiota of lesional and nonlesional skin in young children with AD and control subjects and compare changes after treatment with a topical corticosteroid (TCS) alone or TCS + dilute bleach bath.In a randomized, placebo-controlled, single-blinded clinical trial in 21 children with AD and 14 healthy children, lesional and nonlesional AD skin was examined at baseline and after 4-week treatment with TCS alone or TCS plus bleach bath. Microbial DNA was extracted for quantitative polymerase chain reaction of predominant genera and 16S rRNA sequencing.At baseline, densities of total bacteria and Staphylococcus, including Staphylococcus aureus, were significantly higher at the worst AD lesional site than nonlesional (P = .001) or control (P .001) skin; bacterial communities on lesional and nonlesional AD skin significantly differed from each other (P = .04) and from control (P .001). After TCS + bleach bath or TCS alone, bacterial compositions on lesional skin normalized (P .0001), resembling nonlesional skin, with microbial diversity restored to control skin levels.The 4-week time period and/or the twice-weekly baths may not have been sufficient for additional impact on the cutaneous microbiome. More detailed sequencing may allow better characterization of the distinguishing taxa with bleach bath treatment.Treatment with a TCS cream suffices to normalize the cutaneous microbiota on lesional AD; after treatment, bacterial communities on lesional skin resemble nonlesional skin but remain distinct from control.
- Published
- 2015
41. Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism
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Prashiela Manga and Seth J. Orlow
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medicine.medical_specialty ,Nitisinone ,Skin Pigmentation ,Melanin ,Pregnancy ,medicine ,Eye color ,Animals ,Humans ,Reduced visual acuity ,Hypopigmentation ,Eye Color ,integumentary system ,Cyclohexanones ,business.industry ,General Medicine ,medicine.disease ,Dermatology ,Oculocutaneous albinism ,eye diseases ,Hereditary tyrosinemia ,Albinism, Oculocutaneous ,Nitrobenzoates ,Female ,sense organs ,medicine.symptom ,Skin cancer ,business ,Research Article ,medicine.drug - Abstract
Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.
- Published
- 2011
42. ILDS Newsletter No. 21
- Author
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Seth J. Orlow, Nobukazu Hayashi, H.H. van der Zee, B. Pakkenberg, A.K. Langenbruch, Seok-Jong Lee, Simon M. Mueller, Mi Ri Kim, Ines Fortmeier, T.N. Dam, Matthias Augustin, Tina P. Andersen, K. Kemp, C. Rosada, S. Mahner, G.M. Strutton, S. Kamp, Mae Ja Park, Yoshiki Miyachi, D. Lombard, Peter Itin, Helen J. Lachmann, Soo Chan Kim, Satz Mengensatzproduktion, Druck Reinhardt Druck Basel, Kayoko Matsunaga, Ghil Suk Yoon, Harald Voth, K. Stenderup, Karsten Fogh, C. Eulenburg, Tobias Hoeller, Jun Young Kim, M. Ihnen, Ayşe Tülin Mansur, Torsten Hinz, Weon Ju Lee, J. Schwarz, Errol P. Prens, A.C. Green, M.C. Hughes, Hyeon Chang Kim, İkbal Esen Aydıngöz, F. Salas, Lin-Kristin Ehler, L. Woelber, Fukumi Furukawa, Do Won Kim, C. Bredoux, Peter Haeusermann, Hirohiko Akamatsu, Han Jin Jung, J. Schwegler, Dan Lipsker, Julie V. Schaffer, F. Jaenicke, E. Beket, L.S. Balkert, Shinichi Watanabe, Christine Blome, Dong-Sun Kim, Gregor B.E. Jemec, Makoto Kawashima, A. Fourtanier, Thorsten Hornung, and Monika-Hildegard Schmid-Wendtner
- Subjects
medicine.medical_specialty ,business.industry ,Medicine ,Dermatology ,business - Published
- 2011
43. LB1508 A survey of medical students’ knowledge of isotretinoin’s adverse effects
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A. Bienenfeld and Seth J. Orlow
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,medicine ,Cell Biology ,Dermatology ,business ,Adverse effect ,Molecular Biology ,Biochemistry ,Isotretinoin ,medicine.drug - Published
- 2018
44. Androgenetic alopecia in the paediatric population: a retrospective review of 57 patients
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Seth J. Orlow, Mercedes E. Gonzalez, and Julie L. Cantatore-Francis
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Pediatrics ,medicine.medical_specialty ,education.field_of_study ,integumentary system ,business.industry ,Population ,Retrospective cohort study ,Dermatology ,medicine.disease ,Surgery ,Hair loss ,Minoxidil ,medicine ,Congenital adrenal hyperplasia ,Young adult ,Family history ,Age of onset ,education ,business ,medicine.drug - Abstract
Summary Background Hair loss is an unwelcome event at any age, but it can be particularly distressing for adolescents and their families. While androgenetic alopecia (AGA) is the most common form of hair loss in adults, little is known about its prevalence, clinical features and response to treatments in the paediatric population. Objectives To better characterize the causes of alopecia in a paediatric population. Methods We performed a retrospective chart review to identify all patients with hair loss seen in an academic paediatric dermatology practice at New York University over a 12-year period to better characterize the causes of alopecia in this population. We review the clinical and histological features, natural progression and associated laboratory abnormalities of AGA in 57 paediatric patients. Results AGA was identified as the most frequent cause of hair loss in adolescents and the second most common diagnosis overall. The male to female ratio was 2 : 1 and the average age at initial presentation with AGA was 14·8 years. Adolescent girls had diffuse thinning or thinning at the crown, and boys frequently presented with female pattern hair loss. When biopsies were performed, perifollicular inflammation was a common finding. A family history of AGA was reported in 83% of patients. Laboratory evaluation for androgens revealed polycystic ovarian syndrome in three girls and late-onset congenital adrenal hyperplasia in one boy. Conclusions AGA is the most common form of hair loss in adolescents, and can be the presenting sign of an underlying endocrine disorder. An accurate and timely diagnosis is essential for appropriate medical and psychosocial intervention when warranted.
- Published
- 2010
45. Morphea, Diabetes Mellitus Type I, and Celiac Disease: Case Report and Review of the Literature
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Thomas J.A. Lehman, Elnaz F. Firoz, Hideko Kamino, and Seth J. Orlow
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medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,nutritional and metabolic diseases ,Dermatology ,Disease ,Right lower extremity ,medicine.disease ,Diabetes mellitus type i ,Surgery ,Celiac Disease ,Scleroderma, Localized ,Diabetes Mellitus, Type 1 ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Female ,Girl ,Presentation (obstetrics) ,Child ,business ,Morphea ,Skin ,media_common - Abstract
An 11-year-old girl with a history of diabetes mellitus type I and celiac disease presented with multiple, depressed patches of purple-brown skin on the right lower extremity and central back, with histopathologic features of early morphea. Though morphea may coexist with other autoimmune diseases, its presentation with both diabetes mellitus type I and celiac disease has not yet been described.
- Published
- 2010
46. Celastrol Synergistically Enhances Temozolomide Cytotoxicity in Melanoma Cells
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Nicole A. Doudican, Ming Chen, Iman Osman, Seth J. Orlow, and Amy E. Rose
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Proteasome Endopeptidase Complex ,Cancer Research ,Dacarbazine ,Biology ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,NF-KappaB Inhibitor alpha ,Cell Line, Tumor ,Temozolomide ,medicine ,Humans ,Cytotoxic T cell ,Phosphorylation ,RNA, Small Interfering ,Cytotoxicity ,Protein kinase A ,Melanoma ,Molecular Biology ,Cell Proliferation ,Cell Nucleus ,Cell Death ,Tumor Necrosis Factor-alpha ,Cell growth ,Kinase ,NF-kappa B ,Drug Synergism ,medicine.disease ,Ubiquitinated Proteins ,Triterpenes ,Protein Transport ,Oncology ,chemistry ,Celastrol ,Gene Knockdown Techniques ,Cancer research ,I-kappa B Proteins ,Drug Screening Assays, Antitumor ,Mitogen-Activated Protein Kinases ,Pentacyclic Triterpenes ,medicine.drug - Abstract
Efforts to improve melanoma response rates to temozolomide (TMZ) have thus far been unsuccessful. We screened a library of 2,000 marketed drugs and natural products to identify agents with the potential to sensitize melanoma cells to the effects of TMZ. Celastrol (CEL), a natural compound found in the Thunder of God vine, was identified based on its ability to enhance cell death in TMZ-resistant melanoma cells. A cell proliferation assay was used to compare the growth-inhibitory effects of TMZ alone versus TMZ/CEL combination treatment. Cytotoxic synergy was assessed using combination-index methods. The expression of nuclear factor-κB (NF-κB), IκB, mitogen-activated protein kinase, and ubiquitinated proteins were examined using Western blotting, and the localization of NF-κB in CEL-treated melanoma cells was evaluated using immunofluorescence microscopy. The CEL/TMZ combination synergistically inhibited cell proliferation in melanoma cells. CEL treatment increased the levels of ubiquitinated proteins, reduced the levels of tumor necrosis factor-α–induced IκB phosphorylation, and blocked NF-κB translocation to the nucleus. Inhibition of NF-κB with small interfering RNA mimicked the ability of CEL to sensitize melanoma cells to TMZ, suggesting that inhibition of NF-κB may play a role in TMZ/CEL-induced cytotoxicity. The TMZ/CEL combination induced the phosphorylation of c-Jun NH2-terminal kinase, implicating the mitogen-activated protein kinase pathway in the treatment effects. Our data suggest that CEL may be effective in sensitizing resistant melanoma cells to the effects of TMZ. (Mol Cancer Res 2009;7(12):1946–53)
- Published
- 2009
47. From the Rarest to the Most Common: Insights from Progeroid Syndromes into Skin Cancer and Aging
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Brook E. Tlougan, Brian C. Capell, and Seth J. Orlow
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Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Xeroderma pigmentosum ,Skin Neoplasms ,Trichothiodystrophy ,Dermatology ,Biology ,Biochemistry ,Cockayne syndrome ,Progeroid syndromes ,Genomic Instability ,Progeria ,medicine ,Humans ,Bloom syndrome ,Molecular Biology ,Cellular Senescence ,Werner syndrome ,Genetics ,integumentary system ,nutritional and metabolic diseases ,Aging, Premature ,Syndrome ,Cell Biology ,medicine.disease ,Mutation ,DNA Damage - Abstract
Despite their rarity, diseases of premature aging, or “progeroid” syndromes, have provided important insights into basic mechanisms that may underlie cancer and normal aging. In this review, we highlight these recent developments in Hutchinson—Gilford progeria syndrome (HGPS), Werner syndrome, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, ataxia-telangiectasia, Rothmund–Thomson syndrome, and xeroderma pigmentosum. Though they are caused by different mutations in various genes and often result in quite disparate phenotypes, deciphering the molecular bases of these conditions has served to highlight their underlying basic similarities. Studies of progeroid syndromes, particularly HGPS, the most dramatic form of premature aging, have contributed to our knowledge of fundamental processes of importance to skin biology, including DNA transcription, replication, and repair, genome instability, cellular senescence, and stem-cell differentiation.
- Published
- 2009
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48. Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
- Author
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Seth J. Orlow, Iman Osman, and Ming Chen
- Subjects
Cancer Research ,Cell cycle checkpoint ,Cell Survival ,Blotting, Western ,Apoptosis ,Biology ,Pharmacology ,chemistry.chemical_compound ,Cell Line, Tumor ,Temozolomide ,medicine ,Humans ,Cytotoxicity ,Antineoplastic Agents, Alkylating ,Melanoma ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Caspase 3 ,Cell growth ,Drug Synergism ,Glioma ,Cell cycle ,medicine.disease ,Dacarbazine ,Pyrimethamine ,Oncology ,chemistry ,Antifolate ,Cancer research ,Folic Acid Antagonists ,Drug Screening Assays, Antitumor ,Poly(ADP-ribose) Polymerases ,DNA Damage ,medicine.drug - Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O6-methylguanine-DNA-methyltransferase, apoptosis [measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703–12)
- Published
- 2009
49. Membrane Glycoproteins Common to Vesicles and Melanosomes in Mouse Melanoma Cells
- Author
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John M. Pawelek, Ashok K. Chakraborty, and Seth J. Orlow
- Subjects
Male ,Clinical Biochemistry ,Melanoma, Experimental ,Plant Science ,Membrane Fusion ,Mice ,1-Methyl-3-isobutylxanthine ,Acetamides ,Tumor Cells, Cultured ,Animals ,Melanocyte-Stimulating Hormones ,Immunosorbent Techniques ,Melanosome ,Melanins ,Membrane Glycoproteins ,biology ,Monophenol Monooxygenase ,Chemistry ,Vesicle ,Intracellular Membranes ,Cell Biology ,Mouse Melanoma ,Neoplasm Proteins ,Cell biology ,Gene Expression Regulation, Neoplastic ,Membrane glycoproteins ,Mice, Inbred DBA ,biology.protein ,Melanocytes ,Female ,Rabbits ,Agronomy and Crop Science ,Neoplasm Transplantation ,Developmental Biology - Published
- 2008
50. Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells
- Author
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Adrianna Rodriguez, Iman Osman, Nicole A. Doudican, and Seth J. Orlow
- Subjects
Cancer Research ,Mebendazole ,Apoptosis ,Biology ,Melanocyte ,Pharmacology ,Microtubules ,Inhibitory Concentration 50 ,Mice ,chemistry.chemical_compound ,Tubulin ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Phosphorylation ,Cytotoxicity ,Melanoma ,Molecular Biology ,Cell Proliferation ,bcl-2-Associated X Protein ,Cancer ,medicine.disease ,Mitochondria ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Cell culture ,Cancer research ,Melanocytes ,Benzimidazoles ,Drug Screening Assays, Antitumor ,Growth inhibition ,Protein Binding ,medicine.drug - Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 μmol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC50 of 0.32 μmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308–15)
- Published
- 2008
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