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Background: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development. Objective: To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS. Results: We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763‐6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss‐of‐function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. Conclusions: Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS. [ABSTRACT FROM AUTHOR]

Epizoonoses such as scabies, lice and cimicosis are common, vexing disorders that occur worldwide. Historically, many treatment modalities have been employed in the management of these disorders, and most of the drugs described in this review are of historical interest and no longer recommended or in widespread use because of their wide spectrum of adverse effects. More recently, reports documenting resistance against various antiectoparasite drugs, complicated and severe courses of the diseases, and adverse effects of drug therapy have prompted the development of new treatment strategies and drugs for optimal disease management. Because the strategies currently recommended for the treatment of ectoparasites differ worldwide, this review proposes a rational approach to selecting the best therapeutic agent by comparing the pharmacokinetics, pharmacodynamics, drug efficacy and adverse effects. A literature search of the currently Internet accessible libraries PubMed, Medline and Ideal library, of citations of articles found there, and from communications with the Federal Institute for Drugs and Medical Devices, Germany, was conducted based on this approach. One major observation of this literature search is that permethrin is the treatment of choice for lice and scabies in the US and in Great Britain, whereas lindane is still recommended for scabies in most other European countries because of its longer-standing record of effectiveness. Although permethrin has not yet been proven to be more effective than lindane in treating infections with these ectoparasites, it currently appears to have the best efficacy versus safety profile of topical treatments for scabies and lice. Ivermectin is a newer oral drug for the treatment of ectoparasites, which has been used with great success in the treatment of onchocercosis and other endoparasites. Although ivermectin appears to be a promising drug, its role in the treatment of ectoparasitic infections will be clarified as more study data become available. Finally, it is important to emphasise the clinical aspects of ectoparasite therapy and that providing the patient with optimal instructions on the use of topical therapeutics is of great importance in avoiding adverse effects and assuring complete removal of the ectoparasite, thereby avoiding the development of drug-resistance. [ABSTRACT FROM AUTHOR]

The skin is a major interface between the body and the environment and possesses membrane-bound cytochrome P-450-dependent enzyme activity that is capable of both detoxifying endogenous and exogenous substrates and enhancing the toxic effects of selected substances. The use of chemical inhibitors of enzyme activation of P-450-dependent enzymes represents one possible approach to controlling toxic responses in target tissue such as the skin. Our data indicate that certain polyphenols and imidazoles are potent inhibitors of epidermal carcinogen metabolism, and of the DNA binding and the carcinogenicity of PAHs such as BP. The use of such agents may offer a novel approach to the prevention of environmentally induced cancer. [ABSTRACT FROM AUTHOR]