JZ, et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat Genet 2015;47:1194e9.

No abstract

This issue provides a clinical overview of Common Cutaneous Parasites focusing on prevention, diagnosis, treatment, practice improvement, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic.

Endothelin-1 (ET-1) is a pain mediator, elevated in skin after injury, which potentiates noxious thermal and mechanical stimuli (hyperalgesia) through the activation of ETA (and, perhaps, ETB) receptors on pain fibers. Part of the mechanism underlying this effect has recently been shown to involve potentiation of neuronal TRPV1 by PKCε. However, the early steps of this pathway, which is recapitulated in HEK 293 cells co-expressing TRPV1 and ETA receptors, remain unexplored. To clarify these steps we investigated the pharmacological profile and signaling properties of native endothelin receptors in immortalized cell lines including HEK 293 and ND-7 model sensory neurons. Previously we showed that in ND7/104, a dorsal root ganglia-derived cell line, ET-1 elicits a rise in intracellular calcium ([Ca2+]in) which is blocked by BQ-123, an ETA receptor antagonist, but not by BQ-788, an ETB receptor antagonist, suggesting that ETA receptors mediate this effect. Here we extend these findings to HEK 293T cells. Examination of the expression of ETA and ETB receptors by RT-PCR and [125I]-ET-1 binding experiments confirms the slight predominance of ETA receptor binding sites and messenger RNA in both ND7/104 and HEK 293T cells. In addition, selective agonists of the ETB receptor (sarafotoxin 6c, BQ-3020 or IRL-1620) do not induce a transient increase in [Ca2+]in. Furthermore, reduction of ETB mRNA levels by siRNA do not abrogate calcium mobilization by ET-1 in HEK 293T cells, corroborating the lack of an ETB receptor role in this response. However, in cells with low endogenous ETA mRNA levels, ET-1 does not induce a transient increase in [Ca2+]in. Observation of the [Ca2+]in elevation in ND7/104 and HEK 293T cells in the absence of extracellular calcium suggests that ET-1 elicits a release of calcium from intracellular stores, and pretreatment of the cells with pertussis toxin or a selective inhibitor of phospholipase C (PLC) point to a mechanism involving Gαq/11 coupling. These results are consistent with the hypothesis that a certain threshold of ETA receptor expression is necessary to drive a transient [Ca2+]in increase in these cells and that this process involves release of calcium from intracellular stores following Gαq/11 activation.

Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by overgrowth of flat warts, pityriasis versicolor-like lesions and an increased propensity for developing cutaneous squamous cell carcinomas due to abnormal susceptibility to infection with beta-human papilloma viruses. Adnexal tumors are not typically associated with EV. Here we report a spectrum of hybrid adnexal tumors with divergent eccrine and folliculosebaceous differentiation, and cytologic features ranging from benign to frankly atypical, in a patient with inherited EV.