Faculty Bibliography

A screen of a library of 2,000 drugs and natural products in murine melanocytes identified 10 tricyclic antidepressants (TCAs) as compounds that potently decreased intracellular melanin content. The rank order of potency of these compounds for decreasing melanin content was different than their relative potencies as antidepressants. These compounds had no effect on either the level or the enzymatic activity of cellular tyrosinase (Tyr). Increased presence of both Tyr and melanin in the culture media was observed in treated melanocytes. Immunofluorescence localization revealed that these compounds decreased intracellular melanin content by disrupting the intracellular trafficking of Tyr gene family proteins. In treated melanocytes, Tyr, Tyr-related protein 1, and dopachrome tautomerase accumulated in enlarged granules distributed throughout the cytoplasm. Colocalization of Tyr with lysosome-associated membrane protein 1 was observed within many of these granules. Partial colocalization of Tyr with the Hermansky-Pudlak syndrome 1 gene product observed in control melanocytes was abolished by TCA treatment. Our results show that these compounds decreased intracellular melanin content by altering the trafficking of Tyr gene family proteins and inducing abnormal secretion of Tyr. Results from our screening have implications for the design of products for skin lightening and treatment of hyperpigmentation

Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a 'Stealth' (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules

Skin cancer is one of the most preventable groups of malignancies; however, skin cancer incidence continues to rise in the United States. The relationship between skin cancer and ultraviolet (UV) radiation is well known. Many interventions to prevent skin cancer by reducing exposure to UV radiation have been employed throughout the United States. Studies show an increase in knowledge and awareness regarding sun exposure and skin cancer. Unfortunately, sun protection interventions are slow at effecting behavioral change. In this review, we examine current barriers facing youth today in regards to sun protection practices, appropriate age groups to target for intervention, proposed methods of sun protection, the influence of role models in changing sun protective behavior, the stages of behavioral change, and characteristics and techniques of sun protection programs that can not only increase knowledge but actually elicit changes in sun protection behavior

BACKGROUND: Reports of successful treatment of atopic dermatitis (AD) with mycophenolate mofetil (MMF) have thus far been limited to adults. Considering that the condition typically develops during childhood and is most active during this period, MMF would represent a valuable addition to the therapeutic armamentarium for paediatric AD. OBJECTIVES: To evaluate the safety and efficacy of MMF in the treatment of severe childhood AD. METHODS: A retrospective analysis was performed of all children treated with MMF as systemic monotherapy for severe, recalcitrant AD between August 2003 and August 2006 at New York University Medical Center. Fourteen patients meeting these criteria were identified. RESULTS: Four patients (29%) achieved complete clearance, four (29%) had > 90% improvement (almost complete), five (35%) had 60-90% improvement and one (7%) failed to respond. Initial responses occurred within 8 weeks (mean 4 weeks), and maximal effects were attained after 8-12 weeks (mean 9 weeks) at MMF doses of 40-50 mg kg(-1) daily in younger children and 30-40 mg kg(-1) daily in adolescents. The medication was well tolerated in all patients, with no infectious complications or development of leucopenia, anaemia, thrombocytopenia or elevated aminotransferases. CONCLUSIONS: This retrospective case series demonstrates that MMF can be a safe and effective treatment for severe, refractory AD in children. MMF represents a promising therapeutic alternative to traditional systemic immunosuppressive agents with less favourable side-effect profiles, and prospective controlled studies are warranted, further to assess its benefits in paediatric AD

OA1 (GPR143) is a pigment cell-specific intracellular glycoprotein consisting of 404 amino acid residues that is mutated in patients with ocular albinism type 1, the most common form of ocular albinism. While its cellular localization is suggested to be endolysosomal and melanosomal, the physiological function of OA1 is currently unclear. Recent reports predicted that OA1 functions as a G protein coupled receptor (GPCR) based on its weak amino acid sequence similarity to known GPCRs, and on demonstration of GPCR activity in OA1 mislocalized to the plasma membrane. Because mislocalization of proteins is often caused by or induces defects in their proper folding/assembly, the significance of these studies remains unclear. A characteristic feature of GPCRs is a seven transmembrane domain structure. We analyzed the membrane topology of OA1 properly localized to intracellular lysosomal organelles in COS-1 cells. To accomplish this analysis, we established experimental conditions that allowed selective permeabilization of the plasma membrane while leaving endolysosomal membranes intact. Domains were mapped by the insertion of a hemagglutinin (HA) tag into the predicted cytosolic/luminal regions of OA1 molecule and the accessibility of tag to HA antibody was determined by immunofluorescence. HA-tagged lysosome associated membrane protein 1 (LAMP1), a type I membrane protein, was employed as a reporter for selective permeabilization of the plasma membrane. Our results show experimentally that the C-terminus of OA1 is directed to the cytoplasm and that the protein spans the intracellular membrane 7 times. Thus, OA1, properly localized intracellularly, is a 7 transmembrane domain integral membrane protein consistent with its putative role as an intracellular GPCR

We describe two young children who developed relapsing, pruritic, papulovesicular eruptions in multiple bands along Blaschko lines on the neck, trunk, and extremities. Skin specimens in both revealed spongiotic dermatitis. This represents the first report of 'blaschkitis' in children, providing further evidence that lichen striatus and blaschkitis are related acquired Blaschko-linear dermatoses that exist on a spectrum rather than as the childhood and adult form of a single disease entity. We highlight the features that differentiate blaschkitis from lichen striatus, review the potential roles of cutaneous mosaicism, environmental triggers, and background immunologic state in their pathogenesis, and discuss the spectrum of inflammatory dermatoses that can follow Blaschko lines

Atopic dermatitis (AD) is a common disease in children. Despite good skin care and trigger avoidance, many children with AD require pharmacologic treatment to manage their disease. In recent years, topical calcineurin inhibitors (TCIs) have been used as an alternative to topical corticosteroids to treat some children with AD. However, revisions to the US labeling for TCIs (i.e. a boxed warning and a medication guide) have generated concern among pediatricians regarding TCI safety and raised questions about the appropriate use of TCIs in the pediatric population. Data from several well designed studies support the efficacy of TCIs in the treatment of AD. Safety concerns arise from a small number of reported malignancies, animal toxicology studies, and the potential adverse effects (including immunosuppression and risk of lymphoma) observed in patients who received systemically administered calcineurin inhibitors for suppression of solid-organ transplant rejection. Several factors indicate that these effects do not occur with topical administration: (i) systemic levels following topical administration are at least 10-fold lower than with oral administration; (ii) the small number of lymphomas reported to date in persons exposed to TCI use are not consistent with the types seen in transplant patients or other immunosuppressed patients; and (iii) no adverse effects on the immune system (as assessed by measures including vaccination response and skin delayed-type hypersensitivity reaction) have been observed in clinical trials of TCIs in children with AD. Overall, TCIs have an established safety and efficacy profile as long-term maintenance therapy in children with AD

There is a continual need for compounds that effectively modulate melanin synthesis. To identify novel pigmentation modulators and their cellular targets, chemical genetic screenings were performed with triazine-based combinatorial libraries that include various linkers as intrinsic components of the small molecules in the library. The linker provides a ready means of attachment to beads, eliminating several common time-consuming downstream steps in the isolation of cellular targets for the small molecules of interest. Twelve compounds were identified as novel pigmentation modulators from various screenings performed in normal and albino murine melanocytes and zebrafish. Target identification by affinity chromatography revealed unexpected roles for prohibitin and mitochondrial F1F0-adenotriphosphatase in the regulation of mammalian pigmentation. The identification of prohibitin, a "scaffold protein", as a propigmentation effector represents a novel mechanism by which propigmentary signals are transduced. Results from our screenings provide potential active agents and targets for the medical and aesthetic treatment of disorders of pigmentation.