Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.

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.

A toxicological and dermatological assessment of alkyl cyclic ketones when used as fragrance ingredients. RIFM Expert Panel.

The alkyl cyclic ketone (ACK) fragrance ingredients are a diverse group of structures with similar metabolic and toxicity profiles. ACK fragrance materials demonstrate low acute toxicity. Upon repeat dose testing, some adverse effects in biochemical and hematological parameters, and slightly increased liver and kidney weights were reported, primarily at high doses, resulting from adaptive effects. Developmental effects occurred only in the presence of maternal toxicity. Assays in bacteria and mammalian cell systems and the mouse micronucleus assay did not demonstrate genotoxicity. ACK fragrance ingredients are considered non-irritating to the skin of humans; results showed few reactions, most of which were equivocal or involved doses greater than those in consumer products. Mild to moderate eye irritation in animal tests was observed with most compounds; however, full recovery was usually observed. Human sensitization studies indicate that ACK fragrance ingredients have a low sensitization potential. Diagnostic patch-tests indicated low sensitizing potential in humans; except for fragrance materials which caused reactions at 1% or 5%. Phototoxicity and photosensitization were not demonstrated in humans, and, with the possible exception of acetyl cedrene, would not be expected. It is concluded that ACK materials do not present a safety concern at current levels of use as fragrance ingredients.

A toxicologic and dermatologic assessment of cyclopentanones and cyclopentenones when used as fragrance ingredients.

The cyclopentanone and cyclopentenone group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.002% to 15.16% in hydroalcoholic products; systemic exposures vary from 0.0003 to 0.7122 mg/kg/day. The cyclopentanones and cyclopentenones had a low order of acute toxicity and no significant toxicity in repeat dose studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Developmental toxicity was not observed. Minimal evidence of skin irritation in humans is associated with current levels of use. Eleven materials were tested undiluted for eye irritation; three were considered irritants. No phototoxic and photosensitization reactions were seen with nine materials tested. At concentrations higher than current reported use, 14 materials were non-sensitizing in HRIPT or maximization tests. 2-Hexylidene cyclopentanone, 2-heptylidenecyclopentan-1-one and 3-methyl-2-(pentyloxy)-2-cyclopenten-1-one are weak sensitizers and have IFRA Standards. Risk of sensitization to the cyclopentanones and cyclopentenones is generally small under current levels of use. The Panel is of the opinion that there are no safety concerns for the cyclopentanones and cyclopentenones at reported levels of use and exposure as fragrance ingredients.

A toxicological and dermatological assessment of aryl alkyl alcohol simple acid ester derivatives when used as fragrance ingredients.

The aryl alkyl alcohol simple acid ester derivatives (AAASAE) group of fragrance ingredients was critically evaluated for safety following a complete literature search of the pertinent data. For high end users, calculated maximum skin exposures vary widely from 0.01% to 4.17%. AAASAE exhibit a common route of primary metabolism by carboxylesterases resulting in the formation of the simple acid and an aryl alkyl alcohol. They have low acute toxicity. No significant toxicity was observed in repeat-dose toxicity tests. There was no evidence of carcinogenicity of benzyl alcohol when it was administered in the feed; gavage studies resulted in pancreatic carcinogenesis due to the corn oil vehicle. The AAASAE are not mutagenic in bacterial systems or in vitro in mammalian cells, and have little to no in vivo genotoxicity. Reproductive and developmental toxicity data show no indication of adverse effects on reproductive function and NOELs for maternal and developmental toxicity are far in excess of current exposure levels. The AAASAE are generally not irritating or sensitizing at the current levels of exposure. The Panel is of the opinion that there are no safety concerns regarding the AAASAE at the current levels of use and exposure.

A toxicological and dermatological assessment of aryl alkyl alcohols when used as fragrance ingredients.

The aryl alkyl alcohol (AAA) fragrance ingredients are a diverse group of chemical structures with similar metabolic and toxicity profiles. The AAA fragrances demonstrate low acute and subchronic dermal and oral toxicity. No carcinogenicity in rats or mice was observed in 2-year chronic testing of benzyl alcohol or α-methylbenzyl alcohol; the latter did induce species and gender-specific renal adenomas in male rats at the high dose. There was no to little genotoxicity, mutagenicity, or clastogenicity in the mutagenic in vitro bacterial assays, and in vitro mammalian cell assays. All in vivo micronucleus assays were negative. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels. At concentrations likely to be encountered by consumers, AAA fragrance ingredients are non-irritating to the skin. The potential for eye irritation is minimal. With the exception of benzyl alcohol and to a lesser extent phenethyl and 2-phenoxyethyl AAA alcohols, human sensitization studies, diagnostic patch tests and human induction studies, indicate that AAA fragrance ingredients generally have no or low sensitization potential. Available data indicate that the potential for photosensitization is low. It is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.

A toxicological and dermatological assessment of macrocyclic ketones when used as fragrance ingredients: the RIFM Expert Panel.

The macrocyclic ketone (MK) group of fragrance ingredients was evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.13% to 1.10%; systemic exposures vary from 0.0005 to 0.0441 mg/kg/day. The MKs had low acute toxicity and no significant repeat dose toxicity. Liver weight and blood biochemistry effects were reversible after 2 weeks. No genotoxicity in bacteria and mammalian cell lines was observed. Reproductive toxicity was not observed for 3-methylcyclopentadecenone in an OECD compliant study. In humans, MKs are generally not irritating after one application. Animal studies showed irritation for some materials at concentrations higher than current consumer exposure. At rates consistent with current human exposure, phototoxicity and photosensitization were not observed. In animals, some MKs are sensitizers only at concentrations of 20%, 30%, or 100%, which are higher than current consumer exposure. No evidence of sensitization was observed in human tests. In patients with fragrance allergy, reactions were seen with cyclopentadecanone (3/178). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MKs at reported levels of use and exposure as fragrance ingredients.

A toxicologic and dermatologic assessment of cinnamyl phenylpropyl materials when used as fragrance ingredients.

The cinnamyl phenylpropyl fragrance ingredients are a diverse group of chemical structures that have similar metabolic and toxicity profiles. A toxicological and dermatological review of these fragrance ingredients is presented. The common characteristic structural element of cinnamyl phenylpropyl materials is an aryl substituted primary alcohol/aldehyde/ester. For high end users, calculated maximum dermal exposures vary from 0.14% to 0.72%; systemic exposures vary from 0.0002 to 0.0280 mg/kg/day. Human dermatological studies show that these materials are not generally irritants or sensitizers at lower exposures from consumer products. Reactions (0.9%) in fragrance sensitive patients were observed with 3-phenyl-1-propanol at 5% in petrolatum. The cinnamyl phenylpropyl materials had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. The cinnamyl phenylpropyl alcohol materials participate in the same beta oxidation pathways as their parent cinnamic acid derivatives, including common routes of absorption, distribution, and metabolic detoxification, and exhibit similar toxicological endpoints. Based on the review of available data, it is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.

A toxicological and dermatological assessment of macrocyclic lactone and lactide derivatives when used as fragrance ingredients.

The Macrocyclic Lactone and Lactide derivative (ML) group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.47% to 11.15%; systemic exposures vary from 0.0008 to 0.25mg/kg/day. The MLs had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. Effects on blood biochemistry were reversible after 2 weeks of no treatment. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Reproductive and developmental toxicity was not observed. Human dermatological studies show MLs are generally not irritating after one application. Minor irritation was observed in a few individuals following multiple applications. At rates consistent with reported levels for current human exposure, no phototoxicity or photosensitization was observed. In animal studies, the MLs are not sensitizers at lower exposures from consumer products. Eleven ML materials were evaluated for human sensitization. Of these, only ethylene brassylate showed evidence of sensitization in 2/27 studies (sensitization frequency 4/2059 total). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MLs at reported levels of use and exposure as fragrance ingredients.

Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells.

BACKGROUND: Interleukin (IL)-31 is a novel Th2 T-cell cytokine that induces pruritus and dermatitis in transgenic mice. While enhanced mRNA expression of this cytokine is detected in skin samples of inflammatory skin diseases, the regulation of IL-31 expression is poorly understood. OBJECTIVES: To assess the effects of ultraviolet (UV) B radiation and H2O2 on IL-31 mRNA and protein expression in skin and different peripheral blood mononuclear cells (PBMCs). METHODS: The effects of UVB radiation and H2O2, as a prototypic reactive oxygen species, on IL-31 mRNA and protein expression were analysed in various inflammation-related cells and murine skin tissue. RESULTSTreatment of cells with UVB radiation and H2 O2 strongly induced IL-31 mRNA and protein expression in human PBMCs and in the skin of SKH-1 mice. Following exposure to UVB or H2O2, we observed increased expression of IL-31 mRNA in T cells, monocytes, macrophages, and immature and especially mature dendritic cells. H2O2 treatment but not UVB radiation led to a moderate upregulation of IL-31 mRNA expression in epidermal keratinocytes and dermal fibroblasts. Pretreatment of T lymphocytes with the MAPK p38 inhibitor SB203580 or the MEK1 inhibitor U0126 reduced the stimulatory effect of H2O2. These experiments suggest that p38 is involved in the regulation of IL-31 expression in human skin. CONCLUSIONS: Our studies reveal that UVB and reactive oxygen species stimulate the expression of IL-31 in PBMCs and skin, especially in T cells, monocytes and monocyte-derived dendritic cells.

A safety assessment of branched chain saturated alcohols when used as fragrance ingredients.

The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In humans, no evidence of skin irritation was found at concentrations of 2-10%. Undiluted, 11 materials evaluated caused moderate to severe eye irritation. As current end product use levels are between 0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to elicit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that 2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no safety concerns regarding BCSA under the present levels of use and exposure.

A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Expression and function of cytochrome p450-dependent enzymes in human skin cells.

Scientific interest in defining the human body's ability to limit the effects of administered drugs and xenobiotics dates from the mid-19th century when developing knowledge and techniques in the field of organic chemistry first made such studies possible. The first experimental evidence documenting the existence of cytochrome p450 (CYP) dates to the year 1955, when an enzyme system capable of oxidizing xenobiotic compounds was identified in the endoplasmic reticulum of liver homogenates. From these days on several studies analyzed the expression and function of metabolizing phase I enzymes in liver cells. Due to the unique structural features of human skin, little was known about the expression and function of CYP enzymes in this tissue and their role in uptake, metabolism and elimination of xenobiotics as well as endogenous substrates. Lasting recent years it has become clear that human skin cells express various CYP enzymes, including CYP26AI which is responsible for the metabolism of retinoic acid in skin cells. It has been also shown that CYP enzyme expression patterns are cell type and tissue specific and that in skin cells this differs significantly from its expression in other environmental interfaces such as the liver, lung and gastrointestinal tract. Therefore knowledge of skin-specific CYP expression and function is a prerequisite for pharmacological studies of the skin.

A toxicologic and dermatologic assessment of related esters and alcohols of cinnamic acid and cinnamyl alcohol when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix.

Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair resulting from periodic thinning of the shaft (MIM 158000). The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. Mutations of the helix-encoded region in two hair-specific keratins (hHb1 and hHb6) have been identified as responsible for this disorder. We investigated two unrelated families from Russia and Colombia with monilethrix and found two missense mutations in hHb6. In the Russian family, we found a G to A transition at the first base of codon 402, resulting in a lysine substitution (GAG to AAG), designated E402K. In the Colombian family, affected patients carried a missense mutation of codon 413, involving a transition from G to A causing a lysine substitution (GAG to AAG), designated E413K. These two mutations have been identified in other monilethrix families from Europe. Our findings extend the body of evidence implicating recurrent hHb6 and hHb1 mutations in monilethrix families from around the world.