Multiple primary melanomas in a CDKN2A mutation carrier exposed to ionizing radiation

Background: Recent research has shown a possible causal relationship between ionizing radiation exposure and melanoma. Individuals with mutations in CDKN2A (cyclin-dependent kinase inhibitor 2A), the major melanoma predisposition gene, have an increased susceptibility to melanoma-promoting exposures, such as UV light. We describe a patient from a familial melanoma pedigree with 7 primary melanomas on the right side of her body, the first occurring 5 years after exposure to atmospheric nuclear bomb testing in the 1950s. Observations: Physical examination revealed phototype I skin, red hair, and 26 nevi (14 on the right and 12 on the left side of her body). One nevus was larger than 5 mm, and 2 were clinically atypical. Sequence analysis demonstrated a known deleterious mutation in CDKN2A (G-34T) and homozygosity for a red hair color variant in MC1R (melanocortin 1 receptor) (R151C). Fluorescence in situ hybridization analysis of blood, fibroblasts, and melanocytes from both upper extremities ruled out mosaicism. Conclusions: Individuals such as this patient, who has CDKN2A and MC1R mutations, are likely to be more susceptible to environmental insults. A careful review of environmental exposures in these vulnerable cases may reveal cancer-promoting agents, such as ionizing radiation, that go unnoticed in less susceptible populations

Cellular and ultrastructural characterization of the grey-morph phenotype in southern right whales (Eubalaena australis)

Southern right whales (SRWs, Eubalena australis) are polymorphic for an X-linked pigmentation pattern known as grey morphism. Most SRWs have completely black skin with white patches on their bellies and occasionally on their backs; these patches remain white as the whale ages. Grey morphs (previously referred to as partial albinos) appear mostly white at birth, with a splattering of rounded black marks; but as the whales age, the white skin gradually changes to a brownish grey color. The cellular and developmental bases of grey morphism are not understood. Here we describe cellular and ultrastructural features of grey-morph skin in relation to that of normal, wild-type skin. Melanocytes were identified histologically and counted, and melanosomes were measured using transmission electron microscopy. Grey-morph skin had fewer melanocytes when compared to wild-type skin, suggesting reduced melanocyte survival, migration, or proliferation in these whales. Grey-morph melanocytes had smaller melanosomes relative to wild-type skin, normal transport of melanosomes to surrounding keratinocytes, and normal localization of melanin granules above the keratinocyte nuclei. These findings indicate that SRW grey-morph pigmentation patterns are caused by reduced numbers of melanocytes in the skin, as well as by reduced amounts of melanin production and/or reduced sizes of mature melanosomes. Grey morphism is distinct from piebaldism and albinism found in other species, which are genetic pigmentation conditions resulting from the local absence of melanocytes, or the inability to synthesize melanin, respectively

Circadian Rhythm and Cartilage Extracellular Matrix Genes in Osseointegration: A Genome-Wide Screening of Implant Failure by Vitamin D Deficiency

Successful dental and orthopedic implants require the establishment of an intimate association with bone tissue; however, the mechanistic explanation of how biological systems accomplish osseointegration is still incomplete. We sought to identify critical gene networks involved in osseointegration by exploring the implant failure model under vitamin D deficiency.Adult male Sprague-Dawley rats were exposed to control or vitamin D-deficient diet prior to the osteotomy surgery in the femur bone and the placement of T-shaped Ti4Al6V implant. Two weeks after the osteotomy and implant placement, tissue formed at the osteotomy site or in the hollow chamber of T-shaped implant was harvested and total RNA was evaluated by whole genome microarray analyses.Two-way ANOVA of microarray data identified 103 genes that were significantly (>2 fold) modulated by the implant placement and vitamin D deficiency. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assigned the highest z-score to the circadian rhythm pathway including neuronal PAS domain 2 (NPAS2), and period homolog 2 (Per2). NPAS2 and Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/Bmal 1) were upregulated around implant and diminished by vitamin D deficiency, whereas the expression pattern of Per2 was complementary. Hierarchical cluster analysis further revealed that NPAS2 was in a group predominantly composed of cartilage extracellular matrix (ECM) genes. Whereas the expression of bone ECM genes around implant was not significantly affected by vitamin D deficiency, cartilage ECM genes were modulated by the presence of the implant and vitamin D status. In a proof-of-concept in vitro study, the expression of cartilage type II and X collagens was found upregulated when mouse mesenchymal stem cells were cultured on implant disk with 1,25D supplementation.This study suggests that the circadian rhythm system and cartilage extracellular matrix may be involved in the establishment of osseointegration under vitamin D regulation

Wildtype, grey-morph and partial grey-morph phenotypes of southern right whales.

<p><i>Wild-type</i> adults (panel a) have black skin and often have white skin patches on their bellies. <i>Grey morphs</i> (calf in panel b) are primarily white at birth with splatterings of rounded black spots that extend dorso-laterally around their bodies (calf in panel b). Their white skin becomes light grey or brown with age (panel c). <i>Partial grey morphs</i> are primarily black with splatterings of white skin at birth (calf in panel d) which also darkens with age (adults in panels b and d).. (Photos: J. Atkinson, Ocean Alliance).</p

Light microscopy reveals reduced pigmentation and a decreased number of melanocytes in the affected skin of grey-morph SRWs.

<p>A comparison of Fontana Masson melanin staining is shown in wild type (Panels A, C, and E) versus grey-morph SRWs (Panels B, D, and F) at low-power (20X, Panels A and B), high-power (400X, Panels C and D), and extra high-power (600X, Panels E and F) magnification. Low-power magnification shows less melanin staining, particularly in the melanocytes distributed along the basal layer of the epidermal rete ridges (arrowheads, Panels A and B). Rete ridges and dermal papillae appear similar in grey-morph and wild-type whales. Dermal papillae are marked with “= >” in panels A, B and C. High-power magnification shows reduced melanin content and fewer positively-stained cells in the grey-morph skin (Panels C and D). Extra high-power magnification shows typical melanocyte dendrite morphology (arrowhead, Panels E and F) and normal melanosome transfer and capping of keratinocyte nuclei (asterisks, Panels E and F).</p

Melanocyte counts are reduced in grey-morph relative to wild-type SRW skin.

<p>Bars represent the absolute number of melanocytes counted in grey-morph and wild-type whales. Darkly shaded bars represent the number of melanocytes in each of 5 high-powered fields and lightly shaded blue bars represent the number of melanocytes along each 0.25 mm of the basement membrane measured. Data were compared for both measurement methods using T-tests. Both tests yielded p-values smaller than 1x10^-5.</p

Identities and characteristics of sampled whales.

<p>Identities and characteristics of sampled whales.</p