Faculty Bibliography

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

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

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

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.

The substantial clinical and histologic overlap between neurotized congenital melanocytic nevi and the subset of plexiform neurofibromas with hyperpigmentation and hypertrichosis of the overlying skin (pigmented neurofibroma) has led to considerable confusion in the literature. A dark-brown, hypertrichotic plaque covered much of the right lower aspect of the trunk of a 1-year-old girl with a diffuse and plexiform neurofibroma in the same area, numerous cafe-au-lait macules, and intertriginous freckling. The latter findings were diagnostic of neurofibromatosis-1, which was further supported by the presence of unidentified bright objects on magnetic resonance imaging of the brain. Histologic examination of the hyperpigmented plaque revealed melanocytic hyperplasia at the dermoepidermal junction and a proliferation of rounded, pigmented melanocytes dispersed individually and in occasional small nests in the papillary dermis and scattered within underlying neurofibromatous tissue. Immunohistochemical staining with A103 (Melan-A/MART-1) and PNL2 confirmed the melanocytic differentiation of the pigmented cells, whereas glial fibrillary acidic protein and Leu-7 were detected only within plexiform areas and slender neuroid spindle cells. This case draws attention to the pigmented neurofibroma as a distinct clinicopathologic entity resulting from proliferation of melanocytes and neurosustentacular cells in the setting of neurofibromatosis-1