Faculty Bibliography

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.Oncogene advance online publication, 20 June 2016; doi:10.1038/onc.2016.214.

Vitiligo, characterized by progressive skin depigmentation, results from autoimmune-mediated melanocyte loss. The mechanisms underlying disease onset are poorly delineated. Triggers, including exposure to phenols such as monobenzone (MB), are thought to disrupt melanocyte homeostasis and ultimately instigate an autoimmune reaction. We have shown that MB disrupts cellular homeostasis and induces endoplasmic reticulum (ER) stress that leads to activation of the unfolded protein response (UPR). Three proteins, including PERK, each activate UPR arms that orchestrate the restoration of homeostasis. When activated, PERK phosphorylates eIF2a, a translation initiation factor, thus reducing protein synthesis and ER stress. In this study, we investigated the impact of the PERKeIF2a cascade on melanocyte viability and sensitivity to MB. Basal levels of phospho-eIF2a are higher in melanocytes compared to cutaneous fibroblasts or keratinocytes. When PERK expression is downregulated by RNAi, there is a significant reduction in melanocyte viability (88% decrease, p < 0.05 shPERK versus non-target/ shNT; n = 3). Some melanocytes (shPERKLT) can however survive despite prolonged PERK downregulation. Survival correlated with a paradoxical increase in phospho-eIF2a levels and reduced sensitivity to MB (Cleaved/c-PARP levels lower in shPERKLT cells treated with 400 muM MB compared to shNT cells). Chemical inhibition of PERK kinase activity, using GSK2606414, prevented eIF2a phosphorylation and sensitized melanocytes to MB (c-PARP observed with 250 muM MB+ GSK2606414, compared to 400 muM MB + vehicle). PERK-eIF2a axis activity contributes to melanocyte viability and determines sensitivity to MB. Pathways, such the UPR, which has also been implicated in autoimmune diabetes, may link exposure to vitiligo-inducing triggers and onset of autoimmunity. These pathways represent novel therapeutic targets to prevent vitiligo progression or improve efficacy of repigmentation protocols

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: 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.

BACKGROUND: Stiff skin syndrome (SSS) is a noninflammatory, fibrosing condition of the skin, often affecting the limb girdles. OBJECTIVE: We present 4 new patients with SSS with largely unilateral, segmental distribution. To date, reported cases of SSS have been grouped based on generally accepted clinical and histopathologic findings. The purpose of this study was to analyze differences in clinical and histopathologic findings between previously reported SSS cases. METHODS: This is a retrospective review of 4 new cases and 48 previously published cases of SSS obtained from PubMed search. RESULTS: Of 52 total cases, 18 (35%) were segmentally distributed and 34 (65%) were widespread. The average age of onset was 4.1 years versus 1.6 years for segmental versus widespread SSS, respectively. Limitation in joint mobility affected 44% of patients with segmental SSS and 97% of patients with widespread SSS. Histopathologic findings were common between the 2 groups. LIMITATIONS: This was a retrospective study of previously published cases limited by the completeness and accuracy of the reviewed cases. CONCLUSIONS: We propose a distinct clinical entity, segmental SSS, characterized by a segmental distribution, later age of onset, and less severe functional limitation. Both segmental SSS and widespread SSS share common diagnostic histopathologic features.

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.

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.

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.

Atopic dermatitis (AD) is a chronic, inflammatory skin condition caused by a complex interaction of genetic and environment factors. Inherited defects within the stratum corneum are increasingly recognised as a key causative factor in the development of AD. Patients with AD also demonstrate a high rate of colonisation by microbes, notably Staphylococcus aureus. Controversy exists regarding the use of antimicrobial agents in the management of AD. We briefly review the role of stratum corneum dysfunction in AD, the influence of cutaneous colonisation and infections, and provide an update on the utility of anti-staphylococcal treatment in AD.

Vitiligo is a common, acquired disorder of skin pigmentation that can significantly impact quality of life. It often represents a therapeutic challenge, which has resulted in interest in alternative treatments such as herbal and vitamin supplements. In this review, we provide an overview of the most commonly studied complementary agents, describe proposed mechanisms of action, identify potential adverse effects, and discuss the primary evidence supporting their use. Our discussion focuses on L-phenylalanine, Polypodium leucotomos, khellin, Ginkgo biloba, and vitamins and minerals, including vitamins B12, C, and E, folic acid, and zinc used as monotherapy or in combination with other treatments for the management of vitiligo.