Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6.

Endogenous sphingolipids (ceramide) and related synthetic molecules (FTY720, SH-BC-893) reduce nutrient access by decreasing cell surface expression of a subset of nutrient transporter proteins. Here, we report that these sphingolipids disrupt endocytic recycling by inactivating the small GTPase ARF6. Consistent with reported roles for ARF6 in maintaining the tubular recycling endosome, MICAL-L1-positive tubules were lost from sphingolipid-treated cells. We propose that ARF6 inactivation may occur downstream of PP2A activation since: (1) sphingolipids that fail to activate PP2A did not reduce ARF6-GTP levels; (2) a structurally unrelated PP2A activator disrupted tubular recycling endosome morphology and transporter localization; and (3) overexpression of a phosphomimetic mutant of the ARF6 GEF GRP1 prevented nutrient transporter loss. ARF6 inhibition alone was not toxic; however, the ARF6 inhibitors SecinH3 and NAV2729 dramatically enhanced the killing of cancer cells by SH-BC-893 without increasing toxicity to peripheral blood mononuclear cells, suggesting that ARF6 inactivation contributes to the anti-neoplastic actions of sphingolipids. Taken together, these studies provide mechanistic insight into how ceramide and sphingolipid-like molecules limit nutrient access and suppress tumor cell growth and survival

Trichoscopic features of tinea capitis in a straight-haired Hispanic woman

Comma and corkscrew hairs are trichoscopic markers of tinea capitis. Although comma hairs have been reported in both black and white patients with tinea capitis, corkscrew hairs were previously hypothesized to manifest exclusively in patients with curly or African hair types. However, we report a significant number of comma and corkscrew hairs in a Hispanic female patient with naturally straight hair and Trichophyton tonsurans tinea capitis. Thus, dermoscopy is a rapid, noninvasive, and cost-effective tool for evaluating tinea capitis and should be used in combination with culture in all patients regardless of hair texture or race

Laser Treatment of Nongenital Verrucae: A Systematic Review.

ImportanceAlthough cutaneous warts are common lesions, full remission is not always achieved with conventional therapies. Laser modalities including carbon dioxide (CO2), erbium:yttrium-aluminum-garnet (Er:YAG), pulsed dye (PDL), and Nd:YAG have been investigated as alternative treatments for warts.ObjectiveTo review the use and efficacy of lasers for treating nongenital cutaneous warts.Evidence reviewPublished randomized clinical trials (RCTs), cohort studies, case series, and case reports involving laser treatment of nongenital warts were retrieved by searching PubMed with no date limits. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine scheme for rating individual studies. A higher emphasis was placed on RCTs and prospective cohort studies with large sample sizes and detailed methodology.FindingsThere were 35 studies published between 1989 and 2015 that comprised an aggregate of 2149 patients. Simple and recalcitrant nongenital warts treated with lasers show variable response rates (CO2 laser, 50%-100%; Er:YAG laser, 72%-100%; PDL, 47%-100%; and Nd:YAG laser, 46%-100%). Current RCTs suggest that PDL is equivalent to conventional therapies such as cryotherapy and cantharidin. Combination therapies with lasers and other agents including bleomycin, salicylic acid, and light-emitting diode have shown some success.Conclusions and relevanceLasers can be an effective treatment option for both simple and recalcitrant warts. The lasers most studied for this purpose are CO2, PDL, and Nd:YAG, and of these, PDL has the fewest adverse effects. Currently, use of lasers for wart treatment is limited by lack of established treatment guidelines. Future studies are needed to compare laser modalities with each other and with nonlaser treatment options, and to establish optimal treatment protocols

ATOH1, TFAP2B, and CEACAM6 as Immunohistochemical Markers to Distinguish Merkel Cell Carcinoma and Small Cell Lung Cancer

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To identify new diagnostic markers, we performed differential gene expression analysis on transcriptome data from MCC and SCLC tumors. Candidate markers included atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2β (TFAP2B) for MCC, as well as carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for SCLC. Immunostaining for CK20, TTF-1, and new candidate markers was performed on 43 MCC and 59 SCLC samples. All three MCC markers were sensitive and specific, with CK20 and ATOH1 staining 43/43 (100%) MCC and 0/59 (0%) SCLC cases and TFAP2B staining 40/43 (93%) MCC and 0/59 (0%) SCLC cases. TTF-1 stained 47/59 (80%) SCLC and 1/43 (2%) MCC cases. CEACAM6 stained 49/59 (83%) SCLC and 0/43 (0%) MCC cases. Combining CEACAM6 and TTF-1 increased SCLC detection sensitivity to 93% and specificity to 98%. These data suggest that ATOH1, TFAP2B, and CEACAM6 should be explored as markers to differentiate MCC and SCLC