Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is... more
Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.
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Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar... more
Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities. PC is diagnosed by clinical findings and by molecular genetic testing. Molecular genetic testing of the four keratin genes (KRT6A, KRT6B, KRT16, and KRT17) in which mutations are known to cause PC is clinically available. Treatment of manifestations: Pain from the palmoplantar keratoderma can be reduced by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight. Foot care includes paring down hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics). Care of thickened ...
Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far... more
Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far identified. Therefore, alternative approaches that exploit distinct melanoma phenotypes are necessary in order to develop new approaches for therapeutic intervention. Tissue microarrays containing human nevi and melanomas were used to evaluate levels of the antioxidant protein thioredoxin reductase 1 (TR1), which was found to increase dramatically as a function of disease progression. Melanoma cell lines revealed metabolic differences that correlated with TR1 levels. We used this new insight to design a model treatment strategy that creates a synthetic lethal interaction wherein targeting TR1sensitizes melanoma to inhibition of glycolytic metabolism, resulting in a dramatic decrease in metastases in vivo. This approach holds the promise of a new clini...
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The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be resolved to facilitate definitive molecular diagnosis and genetic... more
The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be resolved to facilitate definitive molecular diagnosis and genetic counseling. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features. In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature. Some families presenting with FPPK alone, or with minimal nail changes, carry mutations in KRT16; however, most FPPK families do not harbor mutations in any of these keratin genes. Here, we report three unrelated families who presented with familial FPPK with minor or absent nail changes. The four PC/FPPK-related keratin genes were excluded; however, mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous...
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To determine whether receiving melanoma genetic test results undermines perceived control over melanoma prevention, control-related beliefs were examined among 60 adults from melanoma-prone families receiving CDKN2A/p16 test results (27... more
To determine whether receiving melanoma genetic test results undermines perceived control over melanoma prevention, control-related beliefs were examined among 60 adults from melanoma-prone families receiving CDKN2A/p16 test results (27 unaffected noncarriers, 15 unaffected carriers, 18 affected carriers; response rate at 2 years = 64.9 % of eligible respondents). Multilevel modeling of perceived control ratings over a 2-year period revealed significant variation in individual trajectories: most participants showed increases (45 %) or no change (38.3 %), while 16.7 % showed decreases. At the group level, noncarriers reported sustained increases through the 2-year follow-up (ps < .05); unaffected carriers reported significant short-term increases (ps < .05); and affected carriers reported no change. Participants in all groups continued to rate photoprotection as highly effective in reducing melanoma risk and reported decreased beliefs that carrying the p16 mutation would inevit...
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Beginning in the last decade of the twentieth century, the fields of pigment cell research and melanoma have witnessed major breakthroughs in the understanding of the role of melanocortins in human pigmentation and the DNA damage response... more
Beginning in the last decade of the twentieth century, the fields of pigment cell research and melanoma have witnessed major breakthroughs in the understanding of the role of melanocortins in human pigmentation and the DNA damage response of human melanocytes to solar ultraviolet radiation (UV). This began with the cloning of the melanocortin 1 receptor (MC1R) gene from human melanocytes and the demonstration that the encoded receptor is functional. Subsequently, population studies found that the MC1R gene is highly polymorphic, and that some of its variants are associated with red hair phenotype, fair skin and poor tanning ability. Using human melanocytes cultured from donors with different MC1R genotypes revealed that the alleles associated with red hair color encode for a non-functional receptor. Epidemiological studies linked the MC1R red hair color variants to increased melanoma risk. Investigating the impact of different MC1R variants on the response of human melanocytes to UV led to the important discovery that the MC1R signaling activates antioxidant, DNA repair and survival pathways, in addition to stimulation of eumelanin synthesis. These effects of MC1R were absent in melanocytes expressing 2 MC1R red hair color variants that result in loss of function of the receptor. The importance of the MC1R in reducing UV-induced genotoxicity in melanocytes led us to design small peptide analogs of the physiological MC1R agonist α-melanocortin (α-melanocyte stimulating hormone; α-MSH) for the goal of utilizing them for melanoma chemoprevention.
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Humans, Mutation, Female, Male, Phenotype, and 5 moreGenotype, Darier Disease, INVESTIGATIVE, Ectodermal Dysplasia, and Keratins
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Genetics, DNA, Humans, Mutation, Female, and 7 moreMale, Pedigree, Phenotype, Darier Disease, Base Sequence, Ectodermal Dysplasia, and Keratins
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ABSTRACT The ongoing search for specialty substances with unique physical and chemical properties has motivated the development of numerous types of metal oxide nanomaterials, but concerns remain regarding biological effects of particles... more
ABSTRACT The ongoing search for specialty substances with unique physical and chemical properties has motivated the development of numerous types of metal oxide nanomaterials, but concerns remain regarding biological effects of particles that are comparable in size to ultrafine air pollution (d &lt; 100 nm). Much of the nanoparticle toxicological research has been on inhalation and intact-skin dermal exposures. Lung epithelial cells exposed to oxide nanoparticles show diverse responses, most notably upregulation of pro-inflammatory signaling pathways. This chapter addresses potential etiologies, mechanisms, and methodologies for investigating potential unforeseen toxicities of nanoparticles that are likely to occur in skin as nanoproducts become more and more available.
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Isotretinoin (Accutane, Roche Laboratories Inc, Nutley, NJ) is an important drug, not only for the treatment of severe acne, but also for other diagnoses and in chemoprevention settings. Because the use of isotretinoin is increasing, it... more
Isotretinoin (Accutane, Roche Laboratories Inc, Nutley, NJ) is an important drug, not only for the treatment of severe acne, but also for other diagnoses and in chemoprevention settings. Because the use of isotretinoin is increasing, it is important for physicians to be aware of the adverse events, toxicities, and management issues related to its use. The most important issue is that of congenital defects, which has resulted in new pregnancy prevention policies and programs implemented by the manufacturer. A relatively new concern is that of depression associated with isotretinoin use, also resulting in new policies placed by the manufacturer and the FDA. The most common adverse effects observed during treatment are mucocutaneous and ocular in nature, but laboratory abnormalities and effects in the nervous, musculoskeletal, gastrointestinal, pulmonary, hematologic, and other systems are also described. Additionally, potential drug interactions, follow-up, and toxicity prevention measures are discussed.
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The purpose of this study was to test the hypothesis that regardless of human skin phototype, areas of depigmented skin, as seen in vitiligo, are optically indistinguishable among skin phototypes. The average of the depigmented skin... more
The purpose of this study was to test the hypothesis that regardless of human skin phototype, areas of depigmented skin, as seen in vitiligo, are optically indistinguishable among skin phototypes. The average of the depigmented skin measurements can be used to develop the base color of realistic prostheses. Data was analyzed from 20 of 32 recruited vitiligo study participants. Diffuse reflectance spectroscopy measurements were made from depigmented skin and adjacent pigmented skin, then compared with 66 pigmented polydimethylsiloxane phantoms to determine pigment concentrations in turbid media for making realistic facial prostheses. The Area Under spectral intensity Curve (AUC) was calculated for average spectroscopy measurements of pigmented sites in relation to skin phototype (P = 0.0505) and depigmented skin in relation to skin phototype (P = 0.59). No significant relationship exists between skin phototypes and depigmented skin spectroscopy measurements. The average of the depigmented skin measurements (AUC 19,129) was the closest match to phantom 6.4 (AUC 19,162). Areas of depigmented skin are visibly indistinguishable per skin phototype, yet spectrometry shows that depigmented skin measurements varied and were unrelated to skin phototype. Possible sources of optical variation of depigmented skin include age, body site, blood flow, quantity/quality of collagen, and other chromophores. The average of all depigmented skin measurements can be used to derive the pigment composition and concentration for realistic facial prostheses.
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In the present study, we examined the response of confluent, primary human fibroblasts and cells of a melanoma (YUSAC2) cell line to ionizing radiation mediated through post-translational protein phosphorylation. Since the purpose of our... more
In the present study, we examined the response of confluent, primary human fibroblasts and cells of a melanoma (YUSAC2) cell line to ionizing radiation mediated through post-translational protein phosphorylation. Since the purpose of our study was to identify novel radiation-induced phosphoproteins in the DNA damage stress response of melanoma cells, we were primarily interested in changes in protein phosphoserine expression at early times after irradiation. Our rationale was that by examining the overall protein phosphorylation profile (the phosphoproteome) in irradiated cells, we might discover novel radiation-induced phosphoproteins that distinguish fibroblasts from melanoma cells. Cell proteins were separated by gel electrophoresis and phosphoproteins were identified by Western blot analysis using nonspecific anti-phosphoamino acid antibodies. This approach was not pursued previously since adequate antibodies for examining global protein phosphoserine expression were unavailable. While some radiation-induced phosphoprotein changes in high-abundance proteins were identified, in general the sensitivity of this approach was not sufficient to detect changes in low-abundance, regulatory proteins. Characterization of these phosphoproteins will require greater enrichment of low-abundance proteins.
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In this study, we examined effects of low-dose ionizing radiation on organ cultured human foreskin and, in particular, on the epidermis. Diagnostic, therapeutic, natural environmental and incidental exposures to moderate to low doses of... more
In this study, we examined effects of low-dose ionizing radiation on organ cultured human foreskin and, in particular, on the epidermis. Diagnostic, therapeutic, natural environmental and incidental exposures to moderate to low doses of radiation are inevitable and, although information on cultured cells continues to accumulate, little is known about the effects of low-dose radiation on human tissues. Our hypothesis is that ex vivo organ cultured foreskin is a simple and reliable model to study the biochemical effects of low-dose radiation exposure on skin. A model such as this will aid in the identification and quantification of low-dose radiation-induced changes in proteins in human skin and may be useful in the development of a precise, non-invasive, and reliable assay of exposure. In this work, several aspects of skin responses to culture conditions and radiation were examined. The responses of epidermal TP53 from organ cultured skin irradiated in medium with and without serum were found to be similar. TP53 levels in organ cultured neonatal foreskin epidermis were then examined for baseline TP53 expression. After an initial increase at 4 h, the TP53 D01 signal returned to low steady-state levels for at least 72 h. Irradiated skin samples from different individuals revealed variations in the TP53 D01 signal. The dose and temporal response of dermis and epidermis to radiation were examined by Western blotting from 0 to 24 h after exposure. After irradiation and incubation, the epidermis was removed and assayed by Western blotting and was found to have increases in the TP53 D01 epitope and the TP53 phosphoserine 15 (TP53-S15p) epitope that reached a maximum at about 3 h. In the epidermis, doses of 1-5 cGy of radiation were detectable with the TP53 D01, and CDKN1A antibodies and doses greater than 10 cGy were detectable with the TP53-S15p antibody. When the dermis was compared to epidermis, it was found that dermis had a smaller response to radiation and more phosphorylated TP53.
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The gene transcript profile responses to metal oxide nanoparticles was studied using human cell lines derived from the colon and skin tumors. Much of the research on nanoparticle toxicology has focused on models of inhalation and intact... more
The gene transcript profile responses to metal oxide nanoparticles was studied using human cell lines derived from the colon and skin tumors. Much of the research on nanoparticle toxicology has focused on models of inhalation and intact skin exposure, and effects of ingestion exposure and application to diseased skin are relatively unknown. Powders of nominally nanosized SiO2, TiO2, ZnO and Fe2O3 were chosen because these substances are widely used in consumer products. The four oxides were evaluated using colon-derived cell lines, RKO and CaCo-2, and ZnO and TiO2 were evaluated further using skin-derived cell lines HaCaT and SK Mel-28. ZnO induced the most notable gene transcription changes, even though this material was applied at the lowest concentration. Nano-sized and conventional ZnO induced similar responses suggesting common mechanisms of action. The results showed neither a non-specific response pattern common to all substances nor synergy of the particles with TNF-α cotreatment. The response to ZnO was not consistent with a pronounced proinflammatory signature, but involved changes in metal metabolism, chaperonin proteins, and protein folding genes. This response was observed in all cell lines when ZnO was in contact with the human cells. When the cells were exposed to soluble Zn, the genes involved in metal metabolism were induced but the genes involved in protein refoldling were unaffected. This provides some of the first data on the effects of commercial metal oxide nanoparticles on human colon-derived and skin-derived cells.
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Clinical genetic testing for mutations in CDKN2A (cyclin-dependent kinase inhibitor 2A), a melanoma susceptibility gene, is now available. The International Melanoma Genetics Consortium advocates that genetic testing for CDKN2A should be... more
Clinical genetic testing for mutations in CDKN2A (cyclin-dependent kinase inhibitor 2A), a melanoma susceptibility gene, is now available. The International Melanoma Genetics Consortium advocates that genetic testing for CDKN2A should be done only as part of a research protocol. Experience with genetic testing for other cancer-susceptibility genes indicates that CDKN2A testing has enormous potential for the prevention and detection of a deadly disease. However, clinicians need to understand the benefits and shortcomings of clinical CDKN2A testing so that it can be used advantageously. Here, we examine whether CDKN2A meets the recommendations of the American Society of Clinical Oncology (ASCO) for cancer-susceptibility genetic testing. Although genetic testing for hereditary melanoma should, whenever possible, occur within research protocols, it might be successfully done outside of research protocols if attention is paid to selection, education, and counselling needs of patients; valid test interpretation; and the changing of medical management in appropriate individuals.
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Molecular Biology, Clinical Trial, Research, Translational Medicine, Signal Transduction, and 16 moreItaly, Pharmaceutical industry, Clinical Practice, Humans, Medical Oncology, Clinical research, Biomedical Research, Mutation, Mice, United States, Melanoma, Animals, Immunotherapy, Prognosis, Antineoplastic Agents, and Skin Neoplasms
Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in... more
Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in these reports were not genetically tested for PC. We sought to clarify the prevalence of clinical features associated with PC. We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis. Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2. Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred. We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development.
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Adolescent, Humans, Child, Female, Male, and 14 moreYoung Adult, Infant, Keratin, Registries, Phenotype, Clinical Sciences, Aged, Prevalence, Middle Aged, Adult, Prognosis, Logistic Models, Nails, and The American
Skin cancer screenings have the potential to reduce melanoma morbidity and mortality, especially if participants are from high-risk subgroups. Little is known about targeting these subgroups. This study investigates the attendance... more
Skin cancer screenings have the potential to reduce melanoma morbidity and mortality, especially if participants are from high-risk subgroups. Little is known about targeting these subgroups. This study investigates the attendance motivations of screening participants, including men 50 years of age and older, who are at heightened risk.
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The Italian Society of Human... more
The Italian Society of Human Genetics&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; (SIGU) recommendations on genetic counseling and testing for hereditary melanoma state that clinical genetic testing can be offered to Italian melanoma families with at least two affected members. In the framework of a cooperative study, we sought to establish the frequency of cyclin-dependent kinase inhibitor 2A mutations in melanoma families that underwent clinical genetic counseling and testing in accordance with the SIGU recommendations at 9 centers in different Italian regions. Cyclin-dependent kinase inhibitor 2A testing was conducted by direct sequencing and multiplex ligation-dependent probe amplification analysis in melanoma families with at least two affected members. A total of 33% (68/204) of the families harbored cyclin-dependent kinase inhibitor 2A mutations. In the 145 families with two affected members the mutation frequency was 25%. Three novel mutations, L94P, A86T, and c.407dupG, were identified among the cases and not in 200 controls. We were unable to perform separate analyses for individual centers, as in some cases the number of families was too small. The availability of clinical genetic testing for melanoma to families with just two affected members in the same branch is justified in Italy in terms of the likelihood of identifying a mutation.
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The impact of melanoma genetic testing and counseling on photoprotective behaviors is unknown. To determine if genetic testing and counseling alter compliance with photoprotection recommendations. Reported use of sunscreen, protective... more
The impact of melanoma genetic testing and counseling on photoprotective behaviors is unknown. To determine if genetic testing and counseling alter compliance with photoprotection recommendations. Reported use of sunscreen, protective clothing, and sun avoidance by 59 members of CDKN2A/p16-mutation positive pedigrees was assessed as a function of mutation status and melanoma history, before, immediately after, and 1 month following test reporting. Intentions to practice all photoprotective behaviors increased in all participant groups (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). At 1 month, 33% of participants reported the adoption of a new photoprotective behavior. Subpopulation analyses identified different patterns of change in photoprotection relative to baseline (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .005), with no net decline in any group. This initial study of CDKN2A/p16 families is small and awaits replication in a larger sample. Melanoma genetic testing and counseling enhanced intentions to implement photoprotective strategies and did not result in reduced compliance in the CDKN2A/p16-subpopulation.