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Sample records for acquired melanocytic nevi

  1. Genetics of Melanocytic Nevi

    PubMed Central

    Roh, Mi Ryung; Eliades, Philip; Gupta, Sameer; Tsao, Hensin

    2015-01-01

    Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial “driver” mutations are thought to trigger the establishment of benign nevi. After this initial phase of cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy. PMID:26300491

  2. Amelanotic Melanoma in the Vicinity of Acquired Melanocytic Nevi and not Arising from Agminated Melanocytic Nevi: Masquerading as Pyogenic Granuloma

    PubMed Central

    Rao, Angoori Gnaneshwar; Babu, V Ashok; Koppada, Divya; Haritha, M; Chandana, P; Swapna; Anoosha

    2016-01-01

    Amelanotic melanoma (AMM) presenting as pyogenic granuloma and occurring in the vicinity of acquired melanocytic nevi is rare. Herein, we report such a manifestation in a 68-year-old male who presented with the painful red nodule and multiple pigmented patches involving the left great toe. Histopathological examination of skin biopsy taken from the nodule with an immunohistochemical study using HMB45 and S-100 confirmed the diagnosis of AMM. Biopsy from the pigmented patch near the nodule showed features of melanocytic nevus. Investigative work up revealed metastatic deposits in the left inguinal lymph node with no evidence of systemic involvement, placing him in malignant melanoma Stage IIIC of American Joint Committee on Cancer (AJCC) tumor node metastasis system. The development of AMM in the vicinity of acquired melanocytic nevi and manifesting as granuloma pyogenicum is unique in this case. PMID:26955141

  3. Number and size of acquired melanocytic nevi and affecting risk factors in cases admitted to the dermatology clinic

    PubMed Central

    Gül, Ülker; Kılıç, Arzu

    2016-01-01

    Introduction The size and number of acquired melanocytic nevi (AMN) and presence of dysplastic nevi are the leading risk factors that should be recognized in the development of malignant melanoma. Aim To evaluate AMN and risk factors in the development of AMN in all age groups admitted to a dermatology outpatient clinic. Material and methods Four hundred and twelve patients who were admitted to the dermatology outpatient clinic for any dermatological symptom and who accepted to participate in the study were randomly included in the study. For each case, background-family history and dermatological findings were recorded. All AMN observed in the patients were dermatoscopically examined. Results The presence of more than 50 nevi was significantly higher in males, in individuals who had a history of sunburn and smokers. The number of nevi that were 5 mm and below was found to be higher in individuals who regularly sunbathed their face/body, in individuals using sunscreen, in individuals who had a history of sunburn, smokers and alcohol users. The number of nevi that were above 5 mm was higher in smokers. The total dermatoscopy score between 4.75 and 5.45 was found to be higher in individuals who had more than 50 nevi, in individuals exposed to more than one chemical substance and in alcohol users. Conclusions When determining the patient’s risk factors, factors such as the patient’s sunbathing habits and chemical substance exposure features should be taken into consideration besides the number and size of nevi. PMID:27881943

  4. The Relationship of Psoriasis and Melanocytic Nevi

    PubMed Central

    Cengiz, Fatma Pelin; Emiroglu, Nazan; Bahali, Anil Gulsel; Ozkaya, Dilek Biyik; Su, Ozlem; Onsun, Nahide

    2016-01-01

    Background: There is limited data about the relationship between psoriasis and melanocytic lesions and melanoma. Immunologic pathways which were implicated in psoriasis induce a reduction in the number of melanocytic nevi. Aims and Objectives: To investigate the number of melanocytic nevi in psoriatic patients compared with controls and its relationship with disease severity and type of treatment. Methods: We performed a prospective study in 100 psoriatic patients and 100 controls. Clinical data were recorded for all participants. Results: As compared with controls, patients had overall fewer nevi congenital nevi. Among psoriatic patients, biologic agents and disease severity did not correlate with the number of nevi. Conclusions: Psoriatic patients have fewer nevi than controls. Frequency of nevi in psoriatic patients is not related to treatment and disease severity. PMID:27904187

  5. Giant melanocytic nevi with neurocutaneous melanosis masquerading as neurofibromas

    PubMed Central

    Gowda, Vykuntaraju K.; Basude, Anita; Srinivas, Sahana M.; Bhat, Maya

    2016-01-01

    Neurocutaneous melanosis is congenital melanocytic nevus with neurological manifestations. We report a 4-year-old female child presenting with hyperpigmented and nodular skin lesion associated with developmental delay and convulsions. The child had multiple brownish-black nevi on the face and chest and giant melanocytic nevi on thoraco-abdomen, back, and gluteal region. Computed tomography scan of the brain showed calcification in the pons, right cerebellar hemisphere, and left medial temporal lobe. Skin biopsy done from nodular hyperpigmented site was suggestive of melanocytic nevi. Electroencephalogram showed multifocal epileptiform discharges. PMID:27857802

  6. Discrimination of Dysplastic Nevi from Common Melanocytic Nevi by Cellular and Molecular Criteria.

    PubMed

    Mitsui, Hiroshi; Kiecker, Felix; Shemer, Avner; Cannizzaro, Maria Vittoria; Wang, Claire Q F; Gulati, Nicholas; Ohmatsu, Hanako; Shah, Kejal R; Gilleaudeau, Patricia; Sullivan-Whalen, Mary; Cueto, Inna; McNutt, Neil Scott; Suárez-Fariñas, Mayte; Krueger, James G

    2016-10-01

    Dysplastic nevi (DNs), also known as Clark's nevi or atypical moles, are distinguished from common melanocytic nevi by variegation in pigmentation and clinical appearance, as well as differences in tissue patterning. However, cellular and molecular differences between DNs and common melanocytic nevi are not completely understood. Using cDNA microarray, quantitative RT-PCR, and immunohistochemistry, we molecularly characterized DNs and analyzed the difference between DNs and common melanocytic nevi. A total of 111 probesets (91 annotated genes, fold change > 2.0 and false discovery rate < 0.25) were differentially expressed between the two lesions. An unexpected finding in DNs was altered differentiation and activation of epidermal keratinocytes with increased expression of hair follicle-related molecules (keratin 25, trichohyalin, ribonuclease, RNase A family, 7) and inflammation-related molecules (S100A7, S100A8) at both genomic and protein levels. The immune microenvironment of DNs was characterized by an increase of T helper type 1 (IFNγ) and T helper type 2 (IL13) cytokines as well as an upregulation of oncostatin M and CXCL1. DUSP3, which regulates cellular senescence, was identified as one of the disease discriminative genes between DNs and common melanocytic nevi by three independent statistical approaches and its altered expression was confirmed by immunohistochemistry. The molecular and cellular changes in which the epidermal-melanin unit undergoes follicular differentiation as well as upregulation of defined cytokines could drive complex immune, epidermal, and pigmentary alterations.

  7. Management considerations for giant congenital melanocytic nevi in adults.

    PubMed

    Green, Margaret C; Mitchum, Marsha D; Marquart, Jason D; Bingham, Jonathan L

    2014-04-01

    Giant congenital melanocytic nevi (GCMN) are a rare type of melanocytic nevus that covers a large body surface, often with satellite nevi scattered on the rest of the skin. There are several complications associated with GCMN, including malignant melanoma and neurocutaneous melanosis. The management of GCMN is very complex because of the cosmetic appearance and the associated psychological distress, the risk of severe complications, and the need for long-term follow-up. We report a case of a 43-year-old active-duty female with a GCMN reporting new and symptomatic satellite lesions with atypical features on dermoscopy.

  8. Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas.

    PubMed

    Lazova, Rossitza; Pornputtapong, Natapol; Halaban, Ruth; Bosenberg, Marcus; Bai, Yalai; Chai, Hao; Krauthammer, Michael

    2017-02-10

    We performed exome sequencing of 77 melanocytic specimens composed of Spitz nevi (n=29), Spitzoid melanomas (n=27), and benign melanocytic nevi (n=21), and compared the results with published melanoma sequencing data. Our study highlights the prominent similarity between Spitzoid and conventional melanomas with similar copy number changes and high and equal numbers of ultraviolet-induced coding mutations affecting similar driver genes. Mutations in MEN1, PRKAR1A, and DNMT3A in Spitzoid melanomas may indicate involvement of the protein kinase A pathway, or a role of DNA methylation in the disease. Other than activating HRAS variants, there were few additional mutations in Spitz nevi, and few copy number changes other than 11p amplification and chromosome 9 deletions. Similarly, there were no large-scale copy number alterations and few somatic alterations other than activating BRAF or NRAS mutations in conventional nevi. A presumed melanoma driver mutation (IDH1(Arg132Cys)) was revealed in one of the benign nevi. In conclusion, our exome data show significantly lower somatic mutation burden in both Spitz and conventional nevi compared with their malignant counterparts, and high genetic similarity between Spitzoid and conventional melanoma.Modern Pathology advance online publication, 10 February 2017; doi:10.1038/modpathol.2016.237.

  9. A comparative study of mitochondrial ultrastructure in melanocytes from perilesional vitiligo skin and perilesional halo nevi skin.

    PubMed

    Ding, Gao-Zhong; Zhao, Wen-E; Li, Xue; Gong, Qing-Li; Lu, Yan

    2015-04-01

    Vitiligo and halo nevi are both pigmentary disorders of the skin characterized by the acquired loss of functional epidermal melanocytes manifesting as white macules and patches. The cellular mechanism(s) and biochemical changes that result in the appearance of these two types of achromic lesions are still uncertain; and the relationship between vitiligo and halo nevi has been in dispute. In this study, we investigated the ultrastructure of mitochondria in melanocytes and in keratinocytes from perilesional vitiligo skin and from perilesional halo nevi skin using Transmission Electron Microscopy. Furthermore, we performed a quantitative analysis of mitochondrial morphology through a stereological study. As previously reported, we found that melanocytes from perilesional active vitiligo skin were loosely connected with their surroundings by their retracted dendrites. The surface density and the volume density of mitochondria in melanocytes and in keratinocytes from perilesional vitiligo skin are increased significantly compared with the controls, especially in active vitiligo. In contrast, there are no significant differences in mitochondria in melanocytes and in keratinocytes from perilesional halo nevi skin compared with the controls. In summary, the tendency of different morphologic alterations in mitochondria from perilesional vitiligo skin and from perilesional halo nevi skin reflect heterogeneous backgrounds between the two diseases, revealing that vitiligo and halo nevi may have separate pathogenic mechanisms. These findings may help elucidate the relationship of these two diseases and their underlying mechanisms.

  10. A murine model for the development of melanocytic nevi and their progression to melanoma

    PubMed Central

    Nasti, Tahseen H.; Cochran, J. Barry; Tsuruta, Yuko; Yusuf, Nabiha; McKay, Kristopher M.; Athar, Mohammad; Elmets, Craig A.

    2015-01-01

    Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA). Dysplastic pigmented skin lesions appeared in 7–9 wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25 wk, but not in age matched controls. Immunohistochemistry, real‐time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage‐independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H‐Ras mutations and lost tumor suppressor p16Ink4a expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune‐prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion. © 2015 The Authors. Molecular Carcinogenesis, published by Wiley Periodicals, Inc. PMID:25788145

  11. Sunscreen use and melanocytic nevi in children: a systematic review.

    PubMed

    de Maleissye, Marie-Florence; Beauchet, Alain; Saiag, Phillippe; Corrêa, Marcelo; Godin-Beeckmann, Sophie; Haeffelin, Martial; Mahé, Emmanuel

    2013-01-01

    We conducted a systematic review of the association between melanocytic nevi (MN) in childhood and sunscreen use. A bibliographic search was conducted between November 2008 and January 2009 using the following key words on MEDLINE and EMBASE: child*, in combination with naevi, nevi, naevus, nevus and sunscreen, sun protection. We also used Medical Subject Headings [sunscreening agents], or [radiation protection] with [nevus, pigmented]. A first screening was done on title and abstract reading. Randomized trials and cohort and cross-sectional studies analyzing the relationship between the use of sunscreen and MN in children were selected. Three reviewers abstracted data from each article. The three sets of results were compared for concordance and rereviewed if necessary. Fifteen articles were included (20,743 children). The studies were not consistent in terms of the ages of the children, MN count methods, or sunscreen use assessment. Owing to this heterogeneity, we were unable to pool the studies and conduct a meta-analysis. Twelve studies did not report that the use of sunscreen had a protective effect against MN development. Three studies reported a lower MN count when sunscreen was applied. This systematic review underlines the methodologic differences between studies. Eight of 15 studies reported a positive association between sunscreen application and MN count. Differences in MN counts, overexposure to sun, and inadequate sunscreen application on fair-skinned children could explain the disparity in the results. There is still no evidence of a protective effect of sunscreen against MN development in children.

  12. Melanocytic lesions of the genital area with attention given to atypical genital nevi.

    PubMed

    Ribé, Adriana

    2008-11-01

    Melanocytic lesions of the genital area are rare. They arise mainly in the vulva, although they can also occur less frequently in the perineum, mons pubis and male genitalia and represent 10-12% of pigmented lesions of White women. These pigmented lesions include melanocytic nevi, lentigines, melanocytic nevi with architectural disorder and atypia of melanocytes (dysplastic nevi) and melanomas with microscopic features similar to those seen elsewhere on the body. There is a small subset of benign nevi named atypical melanocytic nevi of the genital type (AMNGT) that occur in young women, with distinctive histologic features in some cases overlapping morphologically with those of melanoma. Thus, it is important to distinguish AMNGT from melanomas in terms of prognosis and treatment. We retrieved 58 cases of genital pigmented lesions diagnosed at our hospital from 1986 to 2008 to evaluate their clinicopathologic features with especial consideration to those cases with atypical features. Thirty-two cases (55%) were common nevi, 10 (17%) lentigines, 6 (10%) melanomas, 3 (5%) dysplastic nevi and 1 blue nevus. Six cases (10%) corresponded to AMNGT and were taken from women with a median age of 21 years. All cases showed symmetry, and the melanocytic proliferation was well demarcated at the lateral margins. The junctional component was very prominent and formed by round or fusiform nests with common retraction artifact and/or cellular dyshesion or as a single cell proliferation with mild (33%) to moderate (67%) cytologic atypia, focal pagetoid spread (17%) and a benign-appearing dermal component (83%) with maturation and dense eosinophilic fibrosis in the superficial dermis. Neither nuclear atypia of melanocytes in the superficial dermis nor dermal mitoses were observed. AMNGT were excised, and no recurrences were recorded in the follow up (median 10.5 years). Therefore, it seems that there is no evidence that AMNGT are precursors of dysplastic nevi or melanomas.

  13. Reelin and its receptors, VLDLR and ApoER2, in melanocytic nevi

    PubMed Central

    Mihail, A; Coman, G; Staniceanu, F; Coman, L; Zurac, S; Coman, OA

    2017-01-01

    Reelin is an extracellular signaling protein synthesized by Cajal-Retius cells in utero and early after birth, its presence being signaled in adult life too. Reelin acts on its receptors, VLDLR and ApoER2, acting on cytoskeleton, controlling migration and subsequently positioning and stabilizing the cortical neurons. We investigated the reelin presence and its receptors, VLDLR and ApoER2, in melanocytic nevi considering the neural crest origin of the nevus cells and their migration into skin during embrionary period. Melanocytic nevi present a strict cellular architecture and an increased malignant transforming capacity. We investigated reelin presence in 32 melanocytic nevi (5 junctional, 27 compound or 14 dysplastic nevi and 18 non dysplastic nevi). The assessment of reelin presence was performed by histological semiquantitative criteria. Results showed the presence of reelin in 29 cases (29/ 32). The presence of reelin was elevated in junctional areas as in dysplastic nevi. VLDLR presented positive values in 16 cases (16/ 32) and ApoER2 was weak positive in 7 cases. Reelin or its receptors was peritumorally absent. Our study showed the presence of reelin in nevus cells from cutaneous melanocytic nevi and, in these cells, only the VLDLR receptor was present in half of the cases. The significance of the reelin presence in cutaneous nevus cells may be hypothetically considered correlated with the position maintenance of the nevus cells or migration of these cells in malignant transforming situation. Abbreviations: ApoER2 = apolipoprotein receptor 2, VLDLR = very low density lipoprotein receptor, DAB-1 = DIABLO protein, HMB45 = gene HMB45 PMID:28255385

  14. Meyerson phenomenon in children: observation in five cases of congenital melanocytic nevi.

    PubMed

    Rolland, Sébastien; Kokta, Victor; Marcoux, Danielle

    2009-01-01

    To describe the characteristics of five pediatric patients with the Meyerson phenomenon associated with congenital melanocytic nevi, five cases were reviewed to retrieve information relating to clinical presentation, treatment and evolution of the eczematous phenomenon and of the nevi. Three of five patients were male. Mean age at presentation of the Meyerson phenomenon was 23 months (range: 4 mos-4 yrs). Three patients presented with only one halo eczematous lesion, while two patients presented with more then one halo eczematous lesions. The halo eczematous lesions were located on the leg, arm, and trunk in four, two, and two patients, respectively. All were associated with congenital melanocytic nevi with overlying hypertrichosis. Four were treated with topical corticosteroids, and five developed some degree of hypopigmentation within the nevic lesion. In children with Meyerson phenomenon associated with congenital hairy melanocytic nevi, neither trigger to the eczematous eruption nor preferential gender or anatomical site location was identified. The Meyerson phenomenon evolved towards hypopigmentation of the congenital melanocytic nevic lesions in all patients but no other cutaneous changes were observed on follow-up.

  15. Tissue expansion in the treatment of giant congenital melanocytic nevi of the upper extremity

    PubMed Central

    Ma, Tengxiao; Fan, Ke; Li, Lei; Xie, Feng; Li, Hao; Chou, Haiyan; Zhang, Zhengwen

    2017-01-01

    Abstract The aim of our study was to use tissue expansion for the treatment of giant congenital melanocytic nevi of the upper extremity and examine potential advantages over traditional techniques. There were 3 stages in the treatment of giant congenital melanocytic nevi of the upper extremities using tissue expansion: first, the expander was inserted into the subcutaneous pocket; second, the expander was removed, lesions were excised, and the wound of the upper extremity was placed into the pocket to delay healing; third, the residual lesion was excised and the pedicle was removed. The pedicle flap was then unfolded to resurface the wound. During the period between June 2007 and December 2015, there were 11 patients with giant congenital melanocytic nevi of the upper extremities who underwent reconstruction at our department with skin expansion. Few complications were noted in each stage of treatment. The functional and aesthetic results were observed and discussed in this study. Optimal aesthetic and functional results were obtained using tissue expansion to reconstruct the upper extremities due to the giant congenital melanocytic nevi. PMID:28353563

  16. Installation of a network for patients with congenital melanocytic nevi in German-speaking countries.

    PubMed

    Krengel, Sven; Breuninger, Helmut; Hauschild, Axel; Höger, Peter; Merl, Volker; Hamm, Henning

    2008-03-01

    In 2005, an Internet-based network for the support of patients with congenital melanocytic nevi in German-speaking countries was started (http://www.naevus-netzwerk.de). Along with detailed information for patients and parents, the home-page includes a nevus registry which is based on an electronic questionnaire and which aims at providing data on the long-term course of nevi estimated to reach > 10 cm in largest diameter. In the past, congenital melanocytic nevi have been subject to various mythological interpretations ("Tierfellnävus", lit."animal coat nevus";"Muttermal"). Today an increasing body of reliable scientific data allows a differentiated reflection of the risk of malignant transformation and has led to progress in the diagnostic and therapeutic management. Recent findings from the literature and considerations from scientific meetings are reviewed.

  17. Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi.

    PubMed

    Margaryan, Naira V; Gilgur, Alina; Seftor, Elisabeth A; Purnell, Chad; Arva, Nicoleta C; Gosain, Arun K; Hendrix, Mary J C; Strizzi, Luigi

    2016-03-22

    Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro

  18. Dermoscopic Features of Small, Medium, and Large-Sized Congenital Melanocytic Nevi

    PubMed Central

    Emiroglu, Nazan; Ozkaya, Dilek Biyik; Su, Ozlem; Onsun, Nahide

    2017-01-01

    Background Congenital melanocytic nevi (CMN) are present at birth. It is well known that the presence of large-sized congenital nevus in early life could predict a major risk of developing melanoma. Objective To investigate the clinical and dermoscopic features of the CMN, to search for and highlight any differences between small-sized, medium-sized, large-sized CMN. Methods A nonrandomized observational study was performed. A total of 108 melanocytic nevi were analysed by clinical and dermoscopic examination. Results Of the subjects, 57.4% were aged less than 16 years, 42.6% were aged 16 and more. Of the nevi, 26 had reticular pattern (24.1%), 35 had globular pattern (32.4%), 13 had reticular-globular pattern (12.0%), 16 had homogeneous pattern (14.8%), 6 had reticular-homogeneous pattern (5.6%), 2 had globular-homogeneous pattern (1.9%), 7 had cobblestone pattern (6.5%), 3 had reticular patchy pattern (2.8%). Atypical dots and globules, focal hypopigmentation and perifollicular hypopigmentation are the most common dermoscopic features of CMN. The rarest dermoscopic feature is the blue-whitish veil. Conclusion Most of the dermoscopic features related with dysplastic nevi up to the present, such as atypical dots and globules, focal hypopigmentation, perifollicular hypopigmentation were observed in CMN, in our study. Congenital nevus and dysplastic nevi may share the same dermoscopic features, therefore it is important to know it is found at birth or not. PMID:28223743

  19. Increased melanocytic nevi in patients with inherited ichthyoses: report of a previously undescribed association.

    PubMed

    Fernandes, Juliana Dumêt; Machado, Maria Cecilia Rivitti; Oliveira, Zilda Najjar P

    2010-01-01

    Ichthyosis is a heterogeneous cornification disorder. Melanocytic lesions have not been previously described in association with ichthyosis. Their clinical importance lies in the fact that they may simulate melanoma clinically and dermoscopically, as seen in epidermolysis bullosa. The objective of this study was to evaluate the clinical, dermoscopic, and histopathologic features of nevi and lentigines in 16 patients with autosomal recessive congenital ichthyosis-lamellar ichthyosis and nonbullous ichthyosiform congenital erythroderma. Patients underwent general clinical examination dermoscopy. The more suspicious lesions were excised and to histopathologic examination. Most patients (n = 13) reported no personal or familial history of melanoma or atypical nevi. All of the patients had at least five atypical melanocytic lesions. Ten of the 16 patients had at least one atypical nevus or lentigo. This study suggests that increased atypical melanocytic nevi may be a feature of long-standing congenital ichthyoses. Whether this finding is disease-related or a coincidental observation is difficult to ascertain. As an unequivocal discrimination from malignant melanoma in vivo is not always possible, regular clinical follow-up of patients with ichthyosis and increased or unusual nevi is recommended.

  20. [The congenital melanocytic nevi of the face in child: What's new?].

    PubMed

    Captier, G

    2015-09-01

    Congenital melanocytic nevi of the face are a frequent reason for consultation in paediatric plastic surgery. Usually of small size, they raise a complex problem of reconstruction when they are large and giant. The indication of excision is generally stated on aesthetic criteria whereas the risk of melanoma is especially important in the giant nevi. Simple suture, full thickness skin graft and expanded skin flaps are the techniques of choice. The treatment must be carried out precociously, follow a surgical planning, respect the aesthetic units of the face and the periorificial areas, adapt to the age of the child and bring psychological benefit to the child.

  1. The risk of cutaneous melanoma in melanocytic nevi*

    PubMed Central

    Fernandes, Nurimar Conceição

    2013-01-01

    The data on melanoma associaed with melanocytic nevus are controversial. A longitudinal prospective study of 107 cases of cutaneous melanoma revealed that 9 (8.4%) cases were presumed to be linked to a precursor lesion, but only in 1 (0.9%) out of these cases the histopathological examination showed an associated melanocytic nevus. The vague information of a preexisting lesion of cutaneous melanoma is not sufficient to consider it a tumour precursor and it requires histopathological evidence to confirm the diagnosis. PMID:23739702

  2. The incidence and position of melanocytic nevi for the purposes of forensic image comparison.

    PubMed

    Black, S; MacDonald-McMillan, B; Mallett, X; Rynn, C; Jackson, G

    2014-05-01

    Expert witness opinion based on the comparison of images has been accepted by UK courts as admissible evidence in relation to issues of identity. Within images of the hand are a multiplicity of anatomical features of different aetiology, incidence and distribution patterns and this includes melanocytic nevi, referred to more colloquially as moles and/or birthmarks. The hand is not a common place for these isolated features to develop and so their presence in this anatomical region has the potential to be useful for issues of identity. The results of this study show that approximately 9 % of individuals in a sample of 476 hands, displayed at least one nevus on the back of their hand and, contrary to the literature, the incidence was found to be greater in females (15 % of female cohort) than males (7 % of male cohort). Almost a third of all nevi identified on the dorsum of the hand were abnormal or dysplastic. The most frequent location for these aggregations of melanocytes was in the central region of the dorsum of the hand or at the base of the index finger. The relevance of nevi identified in the image of a perpetrator's hand and also on that of a suspect/accused is discussed in relation to the issue of whether the images have originated from the same individual.

  3. Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Song, J S; London, W B; Hawryluk, E B; Guo, D; Sridharan, M; Fisher, D E; Lehmann, L E; Duncan, C N; Huang, J T

    2017-04-03

    There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.57.

  4. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

    PubMed Central

    Flake, Darl D.; Busam, Klaus; Cockerell, Clay; Helm, Klaus; McNiff, Jennifer; Reed, Jon; Tschen, Jaime; Kim, Jinah; Barnhill, Raymond; Elenitsas, Rosalie; Prieto, Victor G.; Nelson, Jonathan; Kimbrell, Hillary; Kolquist, Kathryn A.; Brown, Krystal L.; Warf, M. Bryan; Roa, Benjamin B.; Wenstrup, Richard J.

    2016-01-01

    BACKGROUND Recently, a 23‐gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617–628. © 2016 American Cancer Society. PMID:27768230

  5. Mechanical properties of growing melanocytic nevi and the progression to melanoma

    NASA Astrophysics Data System (ADS)

    Taloni, Alessandro; Alemi, Alexander; Ciusani, Emilio; Sethna, James P.; Zapperi, Stefano; La Porta, Caterina A. M.; National Research Council Of Italy Team; Lassp, Department Of Physics, Cornell University Team; Istituto Neurologico Carlo Besta Collaboration; Department Of Biosciences, University Of Milano Team

    2015-03-01

    Melanocytic nevi are benign proliferations that sometimes turn into malignant melanoma in a way that is still unclear from the biochemical and genetic point of view. Diagnostic and prognostic tools are then mostly based on dermoscopic examination and morphological analysis of histological tissues. To investigate the role of mechanics and geometry in the morpholgical dynamics of melanocytic nevi, we present a computational model for cell proliferation in a layered non-linear elastic tissue. Our simulations show that the morphology of the nevus is correlated to the initial location of the proliferating cell starting the growth process and to the mechanical properties of the tissue. We also demonstrate that melanocytes are subject to compressive stresses that fluctuate widely in the nevus and depend on the growth stage. Numerical simulations of cells in the epidermis releasing matrix metalloproteinases display an accelerated invasion of the dermis by destroying the basal membrane. Moreover, we show experimentally that osmotic stress and collagen inhibit growth in primary melanoma cells while the effect is much weaker in metastatic cells.

  6. Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort

    PubMed Central

    Kvaskoff, Marina; Bijon, Anne; Mesrine, Sylvie; Vilier, Alice; Baglietto, Laura; Fournier, Agnès; Clavel-Chapelon, Françoise; Dossus, Laure; Boutron-Ruault, Marie-Christine

    2014-01-01

    Background While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk. Methods and Findings We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7

  7. Melanocytic nevi with an atypical epithelioid cell component: clinical, histopathologic, and fluorescence in situ hybridization findings.

    PubMed

    Pouryazdanparast, Pedram; Haghighat, Zahra; Beilfuss, Beth Ann; Guitart, Joan; Gerami, Pedram

    2011-09-01

    Combined melanocytic nevi can contain a phenotypically distinct population of large atypical epithelioid cells in a background of smaller banal-appearing melanocytes. On the basis of the pattern of proliferation and degree of pigmentation, nevi with this pattern have been referred to as nevi with an atypical epithelioid cell component (N-AECC). When N-AECC display sheet-like or an expansile nodular growth pattern, notable cytologic atypia, and any level of mitotic activity, they can be difficult to distinguish from melanoma. The clinical history and appearance of these lesions may similarly raise concern for melanoma. In view of this diagnostic problem, we present 28 cases of N-AECC from our dermatopathology consultation and in-house practice. All 28 cases were found to be negative on the basis of fluorescence in situ hybridization (FISH) for imbalanced chromosomal aberrations commonly found in melanoma. The clinical outcomes showed a benign clinical course for all cases for which the outcome information was available. FISH analysis also revealed that, in 4 of 28 cases (14%), the AECC of the lesion demonstrated polyploidy localized to the large epithelioid cell component. This is likely more common among cases of N-AECC that have an atypical spitzoid epithelioid cell component, particularly those with obvious senescent nuclear changes. Care must be taken to avoid the pitfall of misinterpreting these FISH findings as changes consistent with melanoma. The use of ancillary testing methods including FISH may be beneficial in improving the diagnostic accuracy involved in making the distinction of N-AECC from melanoma. Further, we report a novel finding of polyploidy seen in certain cases of benign N-AECC.

  8. Expression of Phosphatase and Tensin Homologue, phospho-Akt, and p53 in Acral Benign and Malignant Melanocytic Neoplasms (Benign Nevi, Dysplastic Nevi, and Acral Melanomas)

    PubMed Central

    Lyu, So Min; Wu, Ju Yeon; Byun, Ji Yeon; Choi, Hae Young; Park, Sang Hee

    2016-01-01

    Background The role of the phosphatidylinositol-3 kinase signaling pathway in the development of acral melanoma has recently gained evidence. Phosphatase and tensin homologue (PTEN), one of the key molecules in the pathway, acts as a tumor suppressor through either an Akt-dependent or Akt-independent pathway. Akt accelerates degradation of p53. Objective We assessed the expression of PTEN, phospho-Akt (p-Akt), and p53 by immunohistochemistry in benign acral nevi, acral dysplastic nevi, and acral melanomas in the radial growth phase and with a vertical growth component. Methods Ten specimens in each group were included. Paraffin-embedded specimens were immunostained with antibodies for PTEN, p-Akt, and p53. We scored both the staining intensity and the proportion of positive cells. The final score was calculated by multiplying the intensity score by the proportion score. Results All specimens of benign acral nevi except one showed some degree of PTEN-negative cells. The numbers of p-Akt and p53-positive cells were higher in acral dysplastic nevi and melanoma than in benign nevi. P-Akt scores were 1.7, 1.8, 2.6, and 4.4, and p53 scores were 2.0, 2.1, 3.8, and 4.1 in each group. PTEN and p-Akt scores in advanced acral melanoma were higher than in the other neoplasms. Conclusion The expression of PTEN was decreased and the expression of p-Akt was increased in acral melanoma, especially in advanced cases. The PTEN-induced pathway appears to affect the late stage of melanomagenesis. Altered expression of p-Akt is thought to be due to secondary changes following the loss of PTEN. PMID:27746632

  9. Giant congenital melanocytic nevus*

    PubMed Central

    Viana, Ana Carolina Leite; Gontijo, Bernardo; Bittencourt, Flávia Vasques

    2013-01-01

    Giant congenital melanocytic nevus is usually defined as a melanocytic lesion present at birth that will reach a diameter ≥ 20 cm in adulthood. Its incidence is estimated in <1:20,000 newborns. Despite its rarity, this lesion is important because it may associate with severe complications such as malignant melanoma, affect the central nervous system (neurocutaneous melanosis), and have major psychosocial impact on the patient and his family due to its unsightly appearance. Giant congenital melanocytic nevus generally presents as a brown lesion, with flat or mammilated surface, well-demarcated borders and hypertrichosis. Congenital melanocytic nevus is primarily a clinical diagnosis. However, congenital nevi are histologically distinguished from acquired nevi mainly by their larger size, the spread of the nevus cells to the deep layers of the skin and by their more varied architecture and morphology. Although giant congenital melanocytic nevus is recognized as a risk factor for the development of melanoma, the precise magnitude of this risk is still controversial. The estimated lifetime risk of developing melanoma varies from 5 to 10%. On account of these uncertainties and the size of the lesions, the management of giant congenital melanocytic nevus needs individualization. Treatment may include surgical and non-surgical procedures, psychological intervention and/or clinical follow-up, with special attention to changes in color, texture or on the surface of the lesion. The only absolute indication for surgery in giant congenital melanocytic nevus is the development of a malignant neoplasm on the lesion. PMID:24474093

  10. Giant congenital melanocytic nevus.

    PubMed

    Viana, Ana Carolina Leite; Gontijo, Bernardo; Bittencourt, Flávia Vasques

    2013-01-01

    Giant congenital melanocytic nevus is usually defined as a melanocytic lesion present at birth that will reach a diameter ≥ 20 cm in adulthood. Its incidence is estimated in <1:20,000 newborns. Despite its rarity, this lesion is important because it may associate with severe complications such as malignant melanoma, affect the central nervous system (neurocutaneous melanosis), and have major psychosocial impact on the patient and his family due to its unsightly appearance. Giant congenital melanocytic nevus generally presents as a brown lesion, with flat or mammilated surface, well-demarcated borders and hypertrichosis. Congenital melanocytic nevus is primarily a clinical diagnosis. However, congenital nevi are histologically distinguished from acquired nevi mainly by their larger size, the spread of the nevus cells to the deep layers of the skin and by their more varied architecture and morphology. Although giant congenital melanocytic nevus is recognized as a risk factor for the development of melanoma, the precise magnitude of this risk is still controversial. The estimated lifetime risk of developing melanoma varies from 5 to 10%. On account of these uncertainties and the size of the lesions, the management of giant congenital melanocytic nevus needs individualization. Treatment may include surgical and non-surgical procedures, psychological intervention and/or clinical follow-up, with special attention to changes in color, texture or on the surface of the lesion. The only absolute indication for surgery in giant congenital melanocytic nevus is the development of a malignant neoplasm on the lesion.

  11. Assessment of the effect of phenytoin on cutaneous healing from excision of melanocytic nevi on the face and on the back

    PubMed Central

    2010-01-01

    Background Topical phenytoin is a powerful skin wounds healing and it may be useful in clinical practice. The purpose of this study was to evaluate the effect of topical phenytoin 0.5%, by comparing it with cream (control) in wounds resulting from excision of two melanocytic nevi in the same patient. Our purpose was also to assess if phenytoin had better therapeutic and cosmetic outcomes when compared with cream (control). Methods This study evaluated 100 patients with skin wounds from excision of melanocytic nevi. 50 patients with lesions on the face and 50 patients with lesions on the back, totalizing 200 lesions excised with modified punch. The resulting superficial skin wounds had the same diameter and depth, and second intention healing followed. Patients were followed for 60 days. Student's t-test, Mann Whitney nonparametric test, analysis of variance, LSD test, Shapiro-Wilks test and Fisher test were used to analyze the results, depending on the nature of the variables being studied. Results Phenytoin showed better therapeutic and cosmetic results, by healing faster, with more intense epithelization in wounds in comparison with cream (control). Phenytoin showed a statistically significant difference regarding the following parameters (p < 0.05): wounded area and healing time. Phenytoin application resulted in a smaller area and a shorter healing time. Also the intensity of exudates, bleeding, and the epithelization were more intense in phenytoin-treated wounds. Regarding the shape and thickness of the scar, injuries treated with phenytoin had round and flat shaped scars in most of the cases. Considering patient's gender and phototype, female patients presented smaller wounds and scar areas; and phototype I had the largest scar areas. Contact eczema was an adverse reaction in 7 injuries located on the back caused by cream (control) and hypoallergenic tape. Conclusions Phenytoin showed better therapeutic and cosmetic results compared with cream (control

  12. Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development.

    PubMed

    Kinsler, Veronica A; Abu-Amero, Sayeda; Budd, Peter; Jackson, Ian J; Ring, Susan M; Northstone, Kate; Atherton, David J; Bulstrode, Neil W; Stanier, Philip; Hennekam, Raoul C; Sebire, Neil J; Moore, Gudrun E; Healy, Eugene

    2012-08-01

    Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.

  13. "Halo nevi" and UV radiation.

    PubMed

    Pustisek, Nives; Sikanić-Dugić, Nives; Hirsl-Hećej, Vlasta; Domljan, Mislav Luka

    2010-04-01

    Halo nevi, also termed Sutton nevi, are defined as benign melanocytic nevi that are surrounded by an area of depigmentation resembling a halo. Halo nevi are common in children and young adults, with a mean age at onset of 15 years. The incidence in the population is estimated to be approximately 1%. Affected individuals frequently have multiple lesions which are usually localized on the back. A familial tendency for halo nevi has been reported. The etiology of halo nevi is unknown. It is an autoimmune response and T lymphocytes are considered to play a key role in the progressive destruction of nevus cells. Halo nevi may be associated with autoimmune disorders such as vitiligo, Hashimoto thyroiditis, alopecia areata, celiac disease, atopic dermatitis and others. It has been proved that halo nevi are detected after an intense sun exposure especially after sunburns. The etiology of halo nevi, association with malignant melanoma and the role of sun exposure in the development of halo nevi are discussed.

  14. Clinical and dermoscopic stability and volatility of melanocytic nevi in a population-based cohort of children in Framingham school system

    PubMed Central

    Scope, Alon; Dusza, Stephen W.; Marghoob, Ashfaq A.; Satagopan, Jaya M.; Braga, Casagrande Tavoloni Juliana; Psaty, Estee L.; Weinstock, Martin A.; Oliveria, Susan A.; Bishop, Marilyn; Geller, Alan C.; Halpern, Allan C.

    2011-01-01

    Nevi are important risk markers of melanoma. The study aim was to describe changes in nevi of children using longitudinal data from a population-based cohort. Overview back photography and dermoscopic imaging of up to 4 index back nevi was performed at age 11 (baseline) and repeated at age 14 (follow-up). Of 443 children (39% females) imaged at baseline, 366 children (39% females) had repeated imaging three year later. At age 14, median back nevus counts increased by 2; 75% of students (n=274) had at least one new back nevus and 28% (n=103) had at least one nevus that disappeared. Of 936 index nevi imaged dermoscopically at baseline and follow-up, 69% (645 nevi) had retained the same dermoscopic classification from baseline evaluation. Only 4% (n=13) of nevi assessed as globular at baseline were classified as reticular at follow-up, and just 3% (n=3) of baseline reticular nevi were classified as globular at follow-up. Of 9 (1%) index nevi that disappeared at follow-up, none showed halo or regression at baseline. In conclusion, the relative stability of dermoscopic pattern of individual nevi in the face of the overall volatility of nevi during adolescence suggests that specific dermoscopic patterns may represent distinct biologic nevus subsets. PMID:21562569

  15. Oral Congenital Melanocytic Nevus: A Rare Case Report and Review of the Literature.

    PubMed

    Marangon Júnior, Helvécio; Souza, Paulo Eduardo Alencar; Soares, Rodrigo Villamarim; de Andrade, Bruno Augusto Benevenuto; de Almeida, Oslei Paes; Horta, Martinho Campolina Rebello

    2015-12-01

    Melanocytic nevi are congenital or acquired benign proliferations of cells of melanocytic origin. Oral congenital melanocytic nevi are rare, and only a few cases have been reported in the literature. The purpose of this study is to present the clinical, histological and immunohistochemical features of an oral congenital melanocytic nevus in a 16-year-old female with an 11-year follow-up and to review the pertinent literature. The reported case is the fifth well-documented case report of oral congenital melanocytic nevus in the English literature and the first with a long period of follow-up, thereby making it an important contribution to the knowledge regarding this uncommon oral mucosa lesion.

  16. Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi.

    PubMed

    Sand, Michael; Skrygan, Marina; Sand, Daniel; Georgas, Dimitrios; Gambichler, Thilo; Hahn, Stephan A; Altmeyer, Peter; Bechara, Falk G

    2013-01-01

    Perturbations in microRNA (miRNA) expression profiles have been reported for cutaneous malignant melanoma (CMM) predominantly when examined in cell lines. Despite the rapidly growing number of newly discovered human miRNA sequences, the availability of up-to-date miRNA expression profiles for clinical samples of primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM), and benign melanocytic nevi (BMN) is limited. Specimens excised from the center of tumors (lesional) from patients with PCMM (n=9), CMMM (n=4), or BMN (n=8) were obtained during surgery. An exploratory microarray analysis was performed by miRNA expression profiling based on Agilent platform screening for 1205 human miRNAs. The results from the microarray analysis were validated by TaqMan quantitative real-time polymerase chain reaction. In addition to several miRNAs previously known to be associated with CMM, 19 unidentified miRNA candidates were found to be dysregulated in CMM patient samples. Among the 19 novel miRNA candidates, the genes hsa-miR-22, hsa-miR-130b, hsa-miR-146b-5p, hsa-miR-223, hsa-miR-301a, hsa-miR-484, hsa-miR-663, hsa-miR-720, hsa-miR-1260, hsa-miR-1274a, hsa-miR-1274b, hsa-miR-3663-3p, hsa-miR-4281, and hsa-miR-4286 were upregulated, and the genes hsa-miR-24-1*, hsa-miR-26a, hsa-miR-4291, hsa-miR-4317, and hsa-miR-4324 were downregulated. The results of this study partially confirm previous CMM miRNA profiling studies identifying miRNAs that are dysregulated in CMM. However, we report several novel miRNA candidates in CMM tumors; these miRNA sequences require further validation and functional analysis to evaluate whether they play a role in the pathogenesis of CMM.

  17. Inactivation of Human Nevus Tissue Using High Hydrostatic Pressure for Autologous Skin Reconstruction: A Novel Treatment for Giant Congenital Melanocytic Nevi.

    PubMed

    Jinno, Chizuru; Morimoto, Naoki; Mahara, Atsushi; Liem, Pham Hieu; Sakamoto, Michiharu; Ogino, Shuichi; Kakudo, Natsuko; Inoie, Masukazu; Fujisato, Toshia; Kusumoto, Kenji; Suzuki, Shigehiko; Yamaoka, Tetsuji

    2015-11-01

    Giant congenital melanocytic nevi are intractable lesions associated with a risk of melanoma. High hydrostatic pressure (HHP) technology is a safe physical method for producing decellularized tissues without chemicals. We have reported that HHP can inactivate cells present in various tissues without damaging the native extracellular matrix (ECM). The objectives of this study were to inactivate human nevus tissue using HHP and to explore the possibility of reconstructing skin using inactivated nevus in combination with cultured epidermis (CE). Human nevus specimens 8 mm in diameter were pressurized by HHP at 100, 200, 500, and 1000 MPa for 10 min. The viability of specimens just after HHP, outgrowth of cells, and viability after cultivation were evaluated to confirm the inactivation by HHP. Histological evaluation using hematoxylin-eosin staining and immunohistochemical staining for type IV collagen was performed to detect damage to the ECM of the nevus. The pressurized nevus was implanted into the subcutis of nude mice for 6 months to evaluate the retention of human cells. Then, human CE was applied on the pressurized nevus and implanted into the subcutis of nude mice. The viability of pressurized nevus was not detected just after HHP and after cultivation, and outgrowth of fibroblasts was not observed in the 200, 500, and 1000 MPa groups. Human cells were not observed after 6 months of implantation in these groups. No apparent damage to the ECM was detected in all groups; however, CE took on nevus in the 200 and 500 MPa groups, but not in the 1000 MPa group. These results indicate that human nevus tissue was inactivated by HHP at more than 200 MPa; however, HHP at 1000 MPa might cause damage that prevents the take of CE. In conclusion, all cells in nevus specimens were inactivated after HHP at more than 200 MPa and this inactivated nevus could be used as autologous dermis for covering full-thickness skin defects after nevus removal. HHP between 200 and 500 MPa

  18. Senescence-like Phenotypes in Human Nevi

    PubMed Central

    Joselow, Andrew; Lynn, Darren; Terzian, Tamara; Box, Neil F.

    2016-01-01

    Summary Cellular senescence is an irreversible arrest of cell proliferation at the G1 stage of the cell cycle in which cells become refractory to growth stimuli. Senescence is a critical and potent defense mechanism that mammalian cells have to suppress tumors. While there are many ways to induce a senescence response, oncogene-induced senescence (OIS) remains key to inhibiting progression of cells that have acquired oncogenic mutations. In primary cells in culture, OIS induces a set of measurable phenotypic and behavioral changes, in addition to cell cycle exit. Senescence-associated β-Galactosidase (SA-β-Gal) activity is a main hallmark of senescent cells, along with morphological changes that may depend on the oncogene that is activated, or on the primary cell type. Characteristic cellular changes of senescence include increased size, flattening, multi-nucleation, and extensive vacuolation. At the molecular level, tumor suppressor genes such as p53 and p16INK4a may play a role in initiation or maintenance of OIS. Activation of a DNA damage response and a senescence-associated secretory phenotype could delineate the onset of senescence. Despite advances in our understanding of how OIS suppresses some tumor types, the in vivo role of OIS in melanocytic nevi and melanoma remains poorly understood and not validated. In an effort to stimulate research in this field, we review in this chapter the known markers of senescence and provide experimental protocols for their identification by immunofluorescent staining in melanocytic nevi and malignant melanoma. PMID:27812879

  19. The correlation of TRPM1 (Melastatin) mRNA expression with microphthalmia-associated transcription factor (MITF) and other melanogenesis-related proteins in normal and pathological skin, hair follicles and melanocytic nevi

    PubMed Central

    Lu, Song; Slominski, Andrzej; Yang, Sung-Eun; Sheehan, Christine; Ross, Jeffrey; Carlson, J. Andrew

    2010-01-01

    Background Melastatin (TRPM1), a.k.a. transient receptor potential cation channel, subfamily M, member 1 (TRPM-1) regulates melanocyte differentiation and proliferation. TRPM1 is transcriptionally regulated by the essential melanocyte transcription factor MITF (microphthalmia-associated transcription factor). For the most part, MITF expression is preserved during melanoma progression, while TRPM1 mRNA expression decreases or is completely lost. The loss of TRPM1 is associated with melanomas that are more aggressive. Objective To assess the relationship between TRPM1 mRNA expression and the expression of MITF and nine other markers of melanocytes and melanin-related proteins by immunohistochemistry in normal skin, scars, hair follicles and ordinary melanocytic nevi. Methods Samples of normal skin (n = 102; from tumor excisions and plastic procedures), scars (n = 5; from re-excision specimens) and compound melanocytic nevi (n = 4) were evaluated for the presence of TRPM1 mRNA transcripts as detected by chromogenic in situ hybridization (CISH). Immunohistochemical techniques were used to detect melanin-related proteins including: MITF, S100 protein, Mart-1, tyrosinase, Mel5, HMB45, tyrosinase-related protein-1 (TRP1), TRP2 and α-melanocyte stimulating hormone (αMSH). The labeling index (LI) was defined as the number of intraepidermal cells expressing mRNA or protein per one hundred basal keratinocytes. Results A wide range of LI was found for all markers (0–33 positive cells/100 keratinocytes). When these LI were compared, no significant differences in the expression of MITF, S100, Mart1, tyrosinase proteins and TRPM1 mRNA were identified. The LI for TRPM1 mRNA expression ranged from 74% of that for MITF to 86% for tyrosinase. The LI for TRP-1, TRP-2 and Mel5 was similar to that of TRPM1, while HMB-45 had a significantly lower LI than all other markers. TRPM1 mRNA correlated most tightly with MITF and tyrosinase expression (r = 0.81 and 0.68, respectively, both p

  20. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals.

    PubMed

    Shapiro, R L; Duquette, J G; Roses, D F; Nunes, I; Harris, M N; Kamino, H; Wilson, E L; Rifkin, D B

    1996-08-01

    Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.

  1. An Exploratory Clinical Trial of a Novel Treatment for Giant Congenital Melanocytic Nevi Combining Inactivated Autologous Nevus Tissue by High Hydrostatic Pressure and a Cultured Epidermal Autograft: Study Protocol

    PubMed Central

    Jinno, Chizuru; Sakamoto, Michiharu; Kakudo, Natsuko; Yamaoka, Tetsuji; Kusumoto, Kenji

    2016-01-01

    Background Giant congenital melanocytic nevi (GCMNs) are large brown to black skin lesions that appear at birth and are associated with a risk of malignant transformation. It is often difficult to reconstruct large full-thickness skin defects after the removal of GCMNs. Objective To overcome this difficulty we developed a novel treatment to inactivate nevus tissue and reconstruct the skin defect using the nevus tissue itself. For this research, we designed an exploratory clinical study to investigate the safety and efficacy of a novel treatment combining the engraftment of autologous nevus tissue inactivated by high hydrostatic pressurization with a cultured epidermal autograft (CEA). Methods Patients with congenital melanocytic nevi that were not expected to be closed by primary closure will be recruited for the present study. The target number of nevi is 10. The full-thickness nevus of the target is removed and pressurized at 200 MPa for 10 minutes. The pressurized and inactivated nevus is sutured to the original site. A small section of the patient’s normal skin is taken from around the nevus region and a CEA is prepared after a 3-week culturing process. The CEA is then grafted onto the engrafted inactivated nevus at four weeks after its retransplantation. The primary endpoint is the engraftment of the CEA at 8 weeks after its transplantation and is defined as being engrafted when the engraftment area of the inactivated nevus is 60% or more of the pretransplantation nevus area and when 80% or more of the transplanted inactivated nevus is epithelialized. Results The study protocol was approved by the Institutional Review Board of Kansai Medical University (No. 1520-2, January 5, 2016: version 1.3). The study opened for recruitment in February 2016. Conclusions This protocol is designed to show feasibility in delivering a novel treatment combining the engraftment of inactivated autologous nevus tissue and CEA. This is the first-in-man clinical trial of this

  2. Congenital agminated melanocytic nevus - case report*

    PubMed Central

    da Rocha, Camila Roos Mariano; Grazziotin, Thaís Corsetti; Rey, Maria Carolina Widholzer; Luzzatto, Laura; Bonamigo, Renan Rangel

    2013-01-01

    Agminated nevus is a cluster group of melanocytic nevi confined to a localized area of the body. There are many pigmented lesions described in the literature as agminated, such as blue nevi, multiple lentigines and Spitz nevi, but only a few cases of congenital agminated melanocytic nevi have been described. We report a case of a male child who presented with congenital agminated nevi, emphasizing the importance of physical examination, dermoscopy, histopathological evaluation, differential diagnosis and follow up to rule out the possibility of dysplastic or malignant changes. PMID:24346910

  3. Suprabasal spread of melanocytes in dysplastic nevi and melanoma in situ: Ki-67-labeling rate of junctional melanocytes and suprabasal cells may be a helpful clue to the diagnosis.

    PubMed

    Hall, Brian J; LeBoit, Philip E

    2014-08-01

    Multiple criteria on routinely stained sections allow one to make a diagnosis of a dysplastic or "Clark" nevus (CN) versus melanoma in situ (MIS), and one of these is suprabasal spread of melanocytes. The extent of suprabasal spread of melanocytes in otherwise conventional CN and the combination of a sensitive marker of melanocytes combined with Ki-67 to assess the differences between the proliferation of melanocytes at the junction and those above it have not yet been studied. Fifty classic examples of CN and 27 cases of MIS were culled from the files of a university-based dermatopathology practice. All cases were stained with a 2-color method (MART-1/tyrosinase red, Ki-67 brown) to evaluate morphologic and immunohistochemical differences in these lesions. Fifteen of 50 cases of benign CN demonstrated suprabasal spread compared with 27 of 27 cases of MIS. The majority of CNs with suprabasal spread (13 of 15) showed a 0% Ki-67-labeling rate among the suprabasal melanocytes, and the majority of MISs (23 of 27) showed a 20% or greater Ki-67-labeling rate in suprabasal cells. Suprabasal melanocytes can be seen by immunostaining in otherwise unremarkable CN, wherein they are not notable in routinely stained sections, but their proliferation rate is much less than in MIS.

  4. Intense Pulsed Light Alone and in Combination with Erbium Yttrium-Aluminum-Garnet Laser on Small-to-Medium Sized Congenital Melanocytic Nevi: Single Center Experience Based on Retrospective Chart Review

    PubMed Central

    Lee, Mi So; Jun, Hee Jin; Cho, Sang Hyun; Lee, Jeong Deuk

    2017-01-01

    Background Treatment of congenital melanocytic nevi (CMN) with intense pulsed light (IPL) has recently produced promising results. Objective To evaluate the clinical and histological outcomes of small-to-medium sized CMN treated with IPL alone and in combination with erbium: yttrium-aluminum-garnet (Er: YAG) laser. Methods We performed a retrospective chart review of 26 small-to-medium sized CMN treated as described above. The reduction in visible pigmentation, signs of recurrence and any adverse skin changes were evaluated by two independent clinicians. Results Seventeen patients completed treatment and were followed-up. Nine were not able to complete treatment due to work, change in residence, and treatment related stress. Ten patients received IPL alone (mean: 10.5 sessions) and 7 underwent treatment with IPL (mean: 7.7 sessions) and Er: YAG/IPL combination therapy (mean: 4.7 sessions). The initial treatment outcome was cleared in 5 patients and excellent in 12. Fourteen patients (82.4%) showed CMN recurrence one year after treatment completion. The histological results from a patient with an excellent clinical outcome showed remnant nevus cells nests in the deep dermis. Conclusion IPL treatment alone and in combination with Er: YAG laser are not definitive treatments for CMN and should not be considered as first-line treatment. PMID:28223745

  5. Melasma and its association with different types of nevi in women: A case-control study

    PubMed Central

    Adalatkhah, Hassan; Sadeghi-bazargani, Homayoun; Amini-sani, Nayereh; Zeynizadeh, Somayeh

    2008-01-01

    Background Very little is known about possible association of nevi and melasma. The study objective was to determine if there is an association between melasma and existence of different kinds of nevi. Methods In a case-control study, 120 female melasma patients referred to dermatology clinic of Ardabil and 120 patients referred to other specialty clinics who lacked melasma were enrolled after matching for age. Number of different types of nevi including lentigines and melanocytic nevi were compared between case and control group patients. Data were entered into the computer and analyzed by SPSS 13 statistical software. Results Mean number of lentigines was 25.5 in melasma group compared to 8 in control group(P < 0.01). Mean number of melanocytic nevi was 13.2 in cases compared to 2.8 in control group(P < 0.001). Multivariate analysis showed that existence of freckles, lentigines and more than three melanocytic nevi were positively related to developing melasma. The chance of melasma increased up to 23 times for patients having more than three melanocytic nevi. Congenital nevi were observed among 10% both in case and control groups. Campbell de morgan angiomas were seen among 26 patients(21.8%) in case group compared to 6 patients(5%) in control group. Conclusion Existence of lentigines and melanocytic nevi increases chance of having melasma PMID:18680608

  6. FTIR microspectroscopic characterization of Spitz nevi

    NASA Astrophysics Data System (ADS)

    Giorgini, Elisabetta; Tosi, Giorgio; Conti, Carla; Staibano, Stefania; Ilardi, Gennaro; Sabbatini, Simona

    2015-04-01

    In the last 10 years, few efforts have been carried out to apply vibrational spectroscopy in the study of dermal pathologies in order to characterize the most relevant spectral markers for distinguishing benign from cancerous lesions. Spitz nevi are a special group of benign melanocytic lesions, characterized by spindled and/or epithelioid nevomelanocytes, with peculiar clinical, dermoscopic and histopathological features. The "atypical forms" of Spitz nevi are among the commonest problems of differential diagnosis with the so-called "spitzoid melanomas". The clinical and histological criteria for discriminating these two entities are very subtle and often still quite subjective, and, in a significant percentage of cases, can lead to diagnostic pitfalls and inadequate therapies. Therefore, it is noteworthy to outline that the diagnosis of melanocytic lesions still represents a challenging problem and a continue matter of discussion. We exploited FTIR microspectroscopy to study the different kinds of spitzoid melanocytes, in order to define the most relevant spectral markers of each specimen and to achieve objective information on "borderline" histologically atypical lesions. In particular, the spectroscopic investigation was carried out on melanocytes deriving from normal skin (as a normal control), malignant melanoma and Spitz nevi. The presence of the characteristic bands of melanin was investigated, too.

  7. Differentiation of pigmented Spitz nevi and Reed nevi by integration of dermatopathologic and dermatoscopic findings

    PubMed Central

    Bär, Michael; Tschandl, Philipp; Kittler, Harald

    2012-01-01

    Background: It is unclear whether pigmented Spitz and Reed nevi are distinct morphologic entities or part of the spectrum of Spitz nevi. Methods: In a retrospective observational study we analyzed dermatopathologic slides of 22 cases with clinical and dermatoscopic features indicative of pigmented Spitz or Reed nevus in a blinded fashion according to predefined criteria and subsequently correlated dermatopathologic with clinical and dermatoscopic findings. Results: We differentiated pigmented Spitz and Reed nevus dermatopathologically by their capacity of melanin production and a vertical versus horizontal growth pattern. Based on histopathology 20 nevi (91%) could be reliably diagnosed as Reed nevus (68%, n=15) or as pigmented Spitz nevus (23%, n=5). In two cases (9%, n=2) it was not possible to make a clear distinction from a dermatopathologic point of view. Dermatopathologic-dermatoscopic correlation showed that Reed nevi were characterized by a dermatoscopic pattern of peripheral radial lines or pseudopods (fascicular growth pattern), whereas pigmented Spitz nevi were typified by a pattern consisting of clods (nested growth pattern). “Spitz cells” (large epithelioid melanocytes) were more commonly found in Spitz nevi (100%, n = 5) but were also present in Reed nevi (n=6, 40%). Spindle cells were found in both types of nevi. Conclusions: Pigmented Spitz and Reed nevi can be reliably distinguished based on their dermatopathologic and dermatoscopic patterns. The specific dermatopathologic patterns of pigmented Spitz and Reed nevi correspond well to their dermatoscopic patterns. The presence of “Spitz cells” or spindle cells should not be regarded as the decisive criterion to differentiate between these two entities. PMID:24765545

  8. The ultrastructure of conjunctival melanocytic tumors.

    PubMed Central

    Jakobiec, F A

    1984-01-01

    The ultrastructure of conjunctival melanocytic lesions in 49 patients was evaluated to find significant differences between benign and malignant cells. The patients studied included 9 with benign epithelial (racial) melanosis, 2 with pigmented squamous cell papillomas, 16 with conjunctival nevi, 18 with primary acquired melanosis, and 11 with invasive nodules of malignant melanoma. In benign epithelial melanosis, dendritic melanocytes were situated along the basement membrane region of the conjunctival epithelium, with one basilar dendritic melanocyte lodged among every five or six basilar keratinocytes. The dendritic melanocytes extended arborizing cellular processes between the basilar and among the suprabasilar keratinocytes, which manifested considerable uptake of melanin granules into their cytoplasm. The benign dendritic melanocytes possessed nuclei with clumped heterochromatin at the nuclear membrane, small, tightly wound nucleoli, and large, elongated, fully melaninized melanin granules. In two patients with benign hyperplasia of the dendritic melanocytes, occasional dendritic melanocytes were located in a suprabasilar position, but were always separated from each other by keratinocytes or their processes. In the two black patients with benign pigmented squamous papillomas, the benign dendritic melanocytes were located hapharzardly at all levels of the acanthotic epithelium and not just along the basement membrane region. Melanin uptake by the proliferating keratinocytes was minimal. In benign melanocytic nevi of the conjunctiva, nevus cells within the intraepithelial junctional nests displayed a more rounded cellular configuration; short villi and broader cellular processes suggestive of abortive dendrites were found. The nuclear chromatin pattern was clumped at the nuclear membrane, but the nucleoli were somewhat larger than those of benign dendritic melanocytes in epithelial melanosis. The melanosomes were smaller and rounder than those in dendritic

  9. Association of giant congenital melanocytic nevus, halo nevus and vitiligo in a 75-year-old patient.

    PubMed

    Silveira, Marina Leite da; Ferreira, Flávia Regina; Alvarenga, Marcia Lanzoni; Mandelbaum, Samuel Henrique

    2012-01-01

    A giant congenital melanocytic nevus represents a rare condition. The halo phenomenon may be seen in congenital or acquired melanocytic nevi. In the literature, association of halo nevus and giant congenital melanocytic nevus is rare and the association of both with vitiligo even more rare. A 75-yearold woman at first consultation complained of a hyperchromic bluish-brown hairy macula on the lower back, buttocks and thighs present since birth and an achromic halo of onset three years ago. The histological features were consistent with congenital melanocytic nevus and halo nevus, respectively. After two years the patient developed achromic areas in normal skin, histologically consistent with vitiligo. The authors emphasize the rarity of this triple combination, the patient's age and the absence of malignant degeneration to date.

  10. [Dysplastic melanocytic nevus].

    PubMed

    Bierhoff, E

    2015-02-01

    Dysplastic nevus is still a controversial entity both clinically and histologically. The occurrence of dysplastic nevus especially in the context of dysplastic nevus cell syndrome is associated with an increased risk for melanoma. The following minimal histological criteria should be fulfilled: nests of melanocytes varying in size and shape, bridging and confluent, proliferation of single melanocytes basal and suprabasal, cytoplasmic and nuclear atypia of melanocytes and subepidermal fibroplasia. The biological behavior (common nevus variant or precursor of melanoma?) is difficult to evaluate by presently available methods. The further development of new molecular biology techniques may allow a better prognosis of dysplastic nevi in an objective and reproducible manner. Against this background complete excision followed by clinical surveillance has to be recommended for the routine practice.

  11. Epidemiology of Melanocytic Naevi in Children from Lleida, Catalonia, Spain: Protective Role of Sunscreen in the Development of Acquired Moles.

    PubMed

    Moreno, Sara; Soria, Xavier; Martínez, Montserrat; Martí, Rosa M; Casanova, Josep M

    2016-05-01

    The worldwide incidence of malignant melanoma is increasing. The number of pigmented naevi and amount of solar exposure are important risk factors. The aim of this study was to characterize a paediatric population (from Lleida, Catalonia, Spain) in terms of phenotype, sun behaviour and naevi prevalence. Data on the numbers and distributions of acquired naevi in 369 children, aged 4, 8 and 14 years, were collected and correlated with age, sex, skin phototype and environmental factors (annual/lifetime intermittent and chronic sun exposure, sunburns and sunscreen use). The density of naevi increased with age. Boys had more naevi on the trunk and girls had more naevi on the legs. Children with light skin phototype had more naevi. A higher level of accumulated sun exposure correlated with a higher number of naevi in children with non-adequate sunscreen use. In conclusion, several risk factors associated with naevi density and distribution were found, as previously reported by others. Multivariate analysis confirmed a protective role of sunscreen in the development of acquired melanocytic naevi.

  12. Clear-cell melanocytic lesions with balloon-cell and sebocyte-like melanocytes: a unifying concept.

    PubMed

    Kazlouskaya, Viktoryia; Guo, Ying; Maia-Cohen, Sandra; Mones, Joan

    2014-05-01

    Melanocytes may assume unique shapes and sizes but rarely have clear cytoplasm. We studied 28 melanocytic lesions that contained clear-cell melanocytes of the balloon-cell and sebocyte-like types. Clear-cell melanocytes were found more commonly in females (64%) than in males (36%), with predominance in females younger than 50 years (79%) and predominance in males older than 50 years (67%). They were distributed evenly throughout the body but were not found on acral sites. Clear-cell melanocytes were most prevalent in congenital nevi (18 or 72%) but were also found in 5 Clark nevi, 2 Meischer nevi, 1 Unna nevus, 1 atypical intra-epidermal proliferation, and 1 melanoma. The clear cells were distributed diffusely in 86% of the lesions and focally in 14%. The overall percentage of clear-cell melanocytes was 56%. The percentage of balloon cells was 57% and sebocyte-like melanocytes 32%. Clear cells with morphologic features of both balloon cells and sebocyte-like melanocytes, that is, intermediate cells, were present in all lesions with an overall percentage of 12%. The presence of melanocytes of both the balloon-cell and sebocyte-like types and the finding of clear-cell melanocytes with intermediate features in all lesions lends support to the theory that balloon-cell and sebocyte-like melanocytes may represent morphologic expressions of the same alteration in melanogenesis.

  13. Immunohistochemical expression of Skp2 protein in oral nevi and melanoma

    PubMed Central

    León, Jorge E.; Carlos, Román; Delgado-Azañero, Wilson; Mosqueda-Taylor, Adalberto; Paes-de-Almeida, Oslei

    2013-01-01

    Objective: The aim of this study was to analyze the immunohistochemical expression of Skp2 protein in 38 oral nevi and 11 primary oral melanomas. Study Design: Expression of this ubiquitin protein was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 38 intramucosal nevi and 11 primary oral melanomas. The labeling index (LI) was assessed considering the percentage of cells expressing nuclear positivity out of the total number of cells, counting 1000 cells per slide. Results: Skp2 protein was rarely expressed in intramucosal nevi, in contrast to oral melanomas, which showed high levels of this protein. Conclusion: These results indicate that Skp2 protein may play a role in the development and progression of oral melanomas, and it also could be useful as an immunohistochemical marker for differential diagnosis of oral benign and malignant melanocytic lesions. Key words:Oral melanoma, oral nevi, Skp2, cell cycle, immunohistochemistry. PMID:23385514

  14. Towards robust identification and tracking of nevi in sparse photographic time series

    NASA Astrophysics Data System (ADS)

    Vogel, Jakob; Duliu, Alexandru; Oyamada, Yuji; Gardiazabal, Jose; Lasser, Tobias; Ziai, Mahzad; Hein, Rüdiger; Navab, Nassir

    2014-03-01

    In dermatology, photographic imagery is acquired in large volumes in order to monitor the progress of diseases, especially melanocytic skin cancers. For this purpose, overview (macro) images are taken of the region of interest and used as a reference map to re-localize highly magni ed images of individual lesions. The latter are then used for diagnosis. These pictures are acquired at irregular intervals under only partially constrained circumstances, where patient positions as well as camera positions are not reliable. In the presence of a large number of nevi, correct identi cation of the same nevus in a series of such images is thus a time consuming task with ample chances for error. This paper introduces a method for largely automatic and simultaneous identi cation of nevi in di erent images, thus allowing the tracking of a single nevus over time, as well as pattern evaluation. The method uses a rotation-invariant feature descriptor that uses the local neighborhood of a nevus to describe it. The texture, size and shape of the nevus are not used to describe it, as these can change over time, especially in the case of a malignancy. We then use the Random Walks framework to compute the correspondences based on the probabilities derived from comparing the feature vectors. Evaluation is performed on synthetic and patient data at the university clinic.

  15. Dermoscopy for the pediatric dermatologist part III: dermoscopy of melanocytic lesions.

    PubMed

    Haliasos, Elena C; Kerner, Miryam; Jaimes, Natalia; Zalaudek, Iris; Malvehy, Josep; Hofmann-Wellenhof, Rainer; Braun, Ralph P; Marghoob, Ashfaq A

    2013-01-01

    Melanocytic nevi encompass a variety of lesions, including blue, Spitz, congenital, and acquired nevi. These nevi can occasionally manifest clinical morphologies resembling melanoma, and the presence of such nevi in children can elicit anxiety in patients, parents, and clinicians. Dermoscopy has been shown to increase the diagnostic accuracy for melanoma and to help differentiate melanoma from nevi, ultimately aiding in the decision-making process as to whether to perform a biopsy. Dermoscopy is the perfect instrument to use during the evaluation of pigmented skin lesions in children because it is painless and provides important information for the clinician that can assist in formulating appropriate management decisions. This review highlights the most common benign dermoscopic patterns encountered in nevi and discuss the 10 most common dermoscopic structures seen in melanomas. Lesions manifesting a benign dermoscopic pattern and lacking any melanoma-specific structures do not need to be excised and can safely be monitored. In contrast, melanomas will invariably deviate from the benign nevus patterns and will usually manifest at least 1 of the 10 melanoma-specific structures: atypical network, negative network, streaks, crystalline structures, atypical dots and globules, irregular blotch, blue-white veil, regression structures, peripheral brown structureless areas, and atypical vessels. It is important to be cognizant of the fact that melanomas in childhood usually do not manifest the clinical ABCD features. Instead, they are often symmetric, amelanotic, nodular lesions. Although the clinical appearance may not be alarming, with dermoscopy they will invariably manifest at least one melanoma-specific structure, the most common being atypical vascular structures and crystalline structures.

  16. Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results.

    PubMed

    Nedelcu, Roxana Ioana; Zurac, Sabina Andrada; Brînzea, Alice; Cioplea, Mirela Daniela; Turcu, Gabriela; Popescu, Raluca; Popescu, Cătălin Mihai; Ion, Daniela Adriana

    2015-01-01

    Halo (Sutton's) phenomenon has been described as a depigmented halo that is associated most commonly with acquired melanocytic nevi; but it may be associated with various types of melanocytic skin tumors, melanoma being the most concerning. Different authors have been preoccupied with elucidating morphological features of melanocytic tumors associated with a depigmented halo. We reviewed the literature and discussed the main features of melanocytic halo tumors regarding histopathological, immune microenvironment profile and dermatoscopic appearance. We highlighted similarities and differences between Sutton's nevus and halo melanoma, also presenting relevant aspects of our results. Depigmented halo must be regarded as a phenomenon that may be associated with different types of melanocytic tumors and with a broad spectrum of histopathological atypia degree. Certain correlations between the shape, diameter, symmetry observed in clinical examination, histopathological appearance, dermatoscopic aspect of peritumoral halo and central tumor type could not be established due to insufficient data and contrasting results. Further studies are expected to add valuable information regarding the depigmented halo tumors features.

  17. Melanomas and Dysplastic Nevi Differ in Epidermal CD1c+ Dendritic Cell Count

    PubMed Central

    Dyduch, Grzegorz; Tyrak, Katarzyna Ewa; Glajcar, Anna; Szpor, Joanna

    2017-01-01

    Background. Dendritic cells could be involved in immune surveillance of highly immunogenic tumors such as melanoma. Their role in the progression melanocytic nevi to melanoma is however a matter of controversy. Methods. The number of dendritic cells within epidermis, in peritumoral zone, and within the lesion was counted on slides immunohistochemically stained for CD1a, CD1c, DC-LAMP, and DC-SIGN in 21 of dysplastic nevi, 27 in situ melanomas, and 21 invasive melanomas. Results. We found a significant difference in the density of intraepidermal CD1c+ cells between the examined lesions; the mean CD1c cell count was 7.00/mm2 for invasive melanomas, 2.94 for in situ melanomas, and 13.35 for dysplastic nevi. The differences between dysplastic nevi and melanoma in situ as well as between dysplastic nevi and invasive melanoma were significant. There was no correlation in number of positively stained cells between epidermis and dermis. We did not observe any intraepidermal DC-LAMP+ cells neither in melanoma in situ nor in invasive melanoma as well as any intraepidermal DC-SIGN+ cells in dysplastic nevi. Conclusion. It was shown that the number of dendritic cells differs between dysplastic nevi, in situ melanomas, and invasive melanomas. This could eventually suggest their participation in the development of melanoma. PMID:28331853

  18. St. Kitts and Nevis.

    PubMed

    1989-11-01

    St. Kitts and Nevis have areas of 68 and 36 square miles respectively and the terrain is mountainous. The population is 45,800 total and the annual growth rate is .2%. The ethnic make up is almost all black African with some British, Portuguese, and Lebanese. The religions are primarily Anglican, with evangelical Protestant and Catholic minorities. Infant mortality stands at 41/1000. The government is a constitutional monarchy with a Westminster type parliament. There is a governor, a prime minister, a cabinet, an 11 -member appointed upper house and a 11- member elected house of representatives. The gross national product is $83 million and the annual growth rate is 4.6%. There are no natural resources, and agricultural products include sugarcane, cotton, peanuts, and vegetables. Industry is made up of manufacturing 12.9%, transport and communications 13%, construction 9.1% and hotels and restaurants 4.5%. The Federation of St. Kitts and Nevis became independent in 1983. The government diversified the agriculture by planting other crops than sugar, producing gelled ethanol, and developing a cane spirits liquor. Tourism has grown the most and in 1987 passed sugar as the main source of income. International aid will assist in finishing a road that will open the southeast area of St. Kitts for construction of hotels, where some of the best beaches are located.

  19. The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions

    PubMed Central

    Pilloni, L.; Bianco, P.; Difelice, E.; Cabras, S.; Castellanos, M.E.; Atzori, L.; Ferreli, C.; Mulas, P.; Nemolato, S.; Faa, G.

    2011-01-01

    C-Kit (CD117), the receptor for the stem cell factor, a growth factor for melanocyte migration and proliferation, has shown differential immunostaining in various benign and malignant melanocytic lesions. The purpose of this study is to compare c-Kit immunostaining in benign nevi and in primary and metastatic malignant melanomas, to determine whether c-Kit can aid in the differential diagnosis of these lesions. c-Kit immunostaining was performed in 60 cases of pigmented lesions, including 39 benign nevi (5 blue nevi, 5 intra-dermal nevi, 3 junctional nevi, 15 cases of primary compound nevus, 11 cases of Spitz nevus), 18 cases of primary malignant melanoma and 3 cases of metastatic melanoma. The vast majority of nevi and melanomas examined in this study were positive for c-Kit, with minimal differences between benign and malignant lesions. C-Kit cytoplasmatic immunoreactivity in the intraepidermal proliferating nevus cells, was detected in benign pigmented lesions as well as in malignant melanoma, increasing with the age of patients (P=0.007) in both groups. The patient’s age at presentation appeared to be the variable able to cluster benign and malignant pigmented lesions. The percentage of c-Kit positive intraepidermal nevus cells was better associated with age despite other variables (P=0.014). The intensity and percentage of c-Kit positivity in the proliferating nevus cells in the dermis was significantly increased in malignant melanocytic lesions (P=0.015 and P=0.008) compared to benign lesions (compound melanocytic nevi, Spitz nevi, intradermal nevi, blue nevi). Immunostaning for c-Kit in metastatic melanomas was negative. Interestingly in two cases of melanoma occurring on a pre-existent nevus, the melanoma tumor cells showed strong cytoplasmatic and membranous positivity for c-kit, in contrast with the absence of any immunoreactivity in pre-existent intradermal nevus cells. C-Kit does not appear to be a strong immunohistochemical marker for distinguishing

  20. [Molecular diagnosis of melanocytic tumors].

    PubMed

    Bauer, J

    2016-01-01

    Melanoma therapy has undergone a paradigm shift. Classic chemotherapies with poor treatment responses have been replaced by modern immune checkpoint blockades and targeted therapies with excellent responses. The latter require precise diagnosis of mutations in the melanoma genome as molecular targets for the small molecules. The diagnosis of melanomas has also been supplemented by molecular techniques. Differential diagnosis of melanoma and melanoma simulators such as atypical Spitz nevi can be supported by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Here we review the indications and methods for molecular diagnosis of melanocytic tumors.

  1. Congenital melanocytic nevus with features of hybrid schwannoma/perineurioma.

    PubMed

    Wang, Lei; Wang, Gang; Gao, Tianwen

    2013-05-01

    Neural differentiation by melanocytic nevi represents a well-recognized phenomenon, and melanocytic nevi with perineurial differentiation have been reported recently. We reported a case of a congenital melanocytic nevus with histopathologic features of hybrid schwannoma/perineurioma. The patient was a 36-year-old male who presented with a black tumor on his arm since birth. Histopathology showed a congenital melanocytic nevus in the superficial dermis, but more strikingly, in continuity with the melanocytic nevus, there was a well-circumscribed but unencapsulated nodule in the deep dermis. The nodule was composed of cellular and myxoid areas with storiform, laminated or whorled growth patterns. The cellular area was mainly composed of proliferation of plump spindle, oval or epithelioid cells. The myxoid area was mainly composed of proliferation of slender spindle cells with mucin deposition. Immunohistochemical stains showed that the cellular area was positive for S100 and CD34, weakly positive for EMA, negative for Glut-1 and collagen IV, the myxoid area was positive for S100, negative for CD34, strongly positive for EMA and focally positive for Glut-1 and collagen IV. Our results show that congenital melanocytic nevi may show neural differentiation with histopathologic features of hybrid schwannoma/perineurioma.

  2. Pirin Inhibits Cellular Senescence in Melanocytic Cells

    PubMed Central

    Licciulli, Silvia; Luise, Chiara; Scafetta, Gaia; Capra, Maria; Giardina, Giuseppina; Nuciforo, Paolo; Bosari, Silvano; Viale, Giuseppe; Mazzarol, Giovanni; Tonelli, Chiara; Lanfrancone, Luisa; Alcalay, Myriam

    2011-01-01

    Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression. PMID:21514450

  3. The inflammatory infiltrate of melanocytic nevus.

    PubMed

    Fernandez-Flores, Angel; Saeb-Lima, Marcela

    2014-01-01

    Melanocytic nevi are frequently accompanied by inflammatory cells of different types, in varied amounts and distributed in different patterns. In the current report, we review the knowledge on inflammation seen in different types of melanocytic nevi. As an additional contribution, we studied the lymphocytic inflammatory component of Duperrat nevus, as well as the cytotoxic component of Sutton nevus, two contributions that we have not found in the literature. We conclude that: (a) Duperrat nevus has a mixed inflammatory reaction that includes histiocytes, foreign-body multinucleated giant cells, polymorphonuclears, lymphocytes (predominantly CD4+) and plasma cells (commonly abundant); (b) common melanocytic nevi with reactive inflammatory infiltrate usually show a CD4+ predominant population; (c) Meyerson nevus commonly shows an inflammatory infiltrate mainly made up of CD4+ T-cells; (d) Sutton nevus with halo phenomenon is accompanied by a dense inflammatory infiltrate with lymphocytes in a CD4:CD8 ratio varying from 1:1 to 1:3 and in which most of the CD8+ T-cells do not express cytotoxic markers; (e) Wiesner nevus commonly shows a spare lymphocytic infiltrate but the nature of the infiltrate has not yet been investigated.

  4. High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

    PubMed

    Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H

    2014-05-01

    We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population.

  5. Impression Cytology in a Series of Clinically Diagnosed Ocular Surface Melanocytic Lesions

    PubMed Central

    Kanavi, Mozhgan Rezaei; Hosseini, Seyed Bagher; Aliakbar-Navahi, Roshanak; Aghaei, Hossein

    2017-01-01

    Purpose: To report impression cytology (IC) results of clinically diagnosed ocular surface melanocytic lesions. Methods: Ten patients with a clinical diagnosis of an ocular surface melanocytic lesion underwent IC using cellulose acetate strips and Periodic acid Schiff-Papanicolaou staining. Excisional biopsy of lesions was performed in case of observing atypical cells on IC or at the patient's request, and excised specimens were subjected to histopathological analysis. Agreement between clinical diagnoses and IC results and between IC results and histopathology were evaluated. Results: Clinical diagnoses were nevi in 6, primary acquired melanosis (PAM) with atypia/melanoma in 2, and atypical nevus versus pigmented conjunctival intraepithelial neoplasia (CIN) in 2 cases. IC results were suggestive of a benign nevus in 7, PAM with atypia/melanoma in 2 and CIN versus an atypical epithelioid type melanocytic lesion in 1 case. IC results were consistent with the clinical diagnoses in 9 cases (Cohen's kappa index of 0.83) and excluded CIN in 1. Histopathology in 6 cases disclosed benign melanonevus in 3, malignant melanoma in the context of PAM with atypia in 2, and CIN in 1 case. Histologic results were well correlated with the IC features (Cohen's kappa index of 0.74). Conclusion: By demonstrating typical cytomorphological features of ocular superficial layers IC diagnosed the true nature of melanocytic ocular surface lesions in the majority of cases. Although IC does not substitute histopathology, given the high correlation between IC results and histopathology, it can be of great assistance in diagnosis and management of ocular surface melanocytic lesions. PMID:28299002

  6. [Gregor Mendel and dysplastic nevi].

    PubMed

    Happle, R

    1989-02-01

    In contrast to what has so far generally been believed, dysplastic nevi do not appear to be mendelizing, but rather due to polygenic inheritance. In order to explain this contrasting idea, the following six theses are presented: (1) All dysplastic nevi are inherited in the same manner. (2) Dysplastic nevi constitute a continuous trait. (3) A "dysplastic nevus syndrome" in the form of a monogenic autosomal dominant trait probably does not exist. (4) A nonhereditary dysplastic nevus syndrome does not exist. (5) The number of the underlying genes that, considered separately, do of course follow the rules of mendelian inheritance is so far unknown. (6) A search for a single underlying gene defect is probably hopeless.

  7. State of the art, nomenclature, and points of consensus and controversy concerning benign melanocytic lesions: outcome of an international workshop.

    PubMed

    Barnhill, Raymond L; Cerroni, Lorenzo; Cook, Martin; Elder, David E; Kerl, Helmut; LeBoit, Philip E; McCarthy, Stanley W; Mihm, Martin C; Mooi, Wolter J; Piepkorn, Michael W; Prieto, Victor G; Scolyer, Richard A

    2010-03-01

    The following communication summarizes the proceedings of a one-day International Workshop focusing on the histology of benign melanocytic nevi. Areas of controversy identified in 6 focus sessions were the nomenclature and relationships among common nevi including nevi with halo reactions, traumatized nevi, "dysplastic" nevi, and nevi from particular anatomic sites; developmental biology and frequency of malignant transformation associated with congenital nevi; the characterization and biologic nature of atypical spitzoid neoplasms; the basic definition of particular melanocytic cellular phenotypes, and the nomenclature and biologic nature of many candidate blue nevi, combined nevi, and other controversial lesions such as deep penetrating nevus and pigmented epithelioid melanocytoma. Concentrated data collection and follow-up, molecular characterization, and future consensus Workshops may facilitate the resolution of some of these problems. The Group recommended the description of ambiguous or "borderline" lesions as tumors with indeterminate or uncertain biologic/malignant potential. The participants also advised that such lesions at a minimum should be managed by complete excision with clear surgical margins.

  8. Spitz/Reed nevi: a review of clinical-dermatoscopic and histological correlation

    PubMed Central

    Pedrosa, Ana F.; Lopes, Jose M.; Azevedo, Filomena; Mota, Alberto

    2016-01-01

    Background: Spitz/Reed nevi are melanocytic lesions that may mimic melanoma at clinical, dermatoscopic and histopathological levels. Management strategies of these lesions remain controversial. Objectives: We aim a correlation among clinical-dermatoscopic and histological features of a series of Spitz/Reed nevi diagnosed during 7 years at the Department of Dermatology. Methods: Clinical, dermatoscopic and histological features of Spitz/Reed nevi diagnosed at our tertiary hospital from 2008 to 2014 were reviewed in order to seek correlation. Results: All described dermatoscopic patterns for Spitz/Reed nevi were found among the 47 enrolled patients; starburst and atypical/multicomponent patterns prevailed (57.4%). Reticular pattern predominated among children younger than 12 years, whereas homogeneous pattern was more frequent in patients older than 12 years, although these differences were not statistically significant (P=0.785). Among histological atypical lesions, all dermatoscopic patterns were represented, but the atypical/multicomponent predominated (56.3%). Two out of 11 dermatoscopically atypical lesions did not show histopathological counterpart. Conclusions: The excision of Spitz/Reed nevi in adults is supported, given the inability to accurately predict those with histopathological atypia, based on clinical and dermatoscopic features, which may raise concern about malignancy. PMID:27222770

  9. Spitz nevi in the classic histopathological pattern - lamb in wolf`s clothing*

    PubMed Central

    Verardino, Gustavo Costa; Rochael, Mayra Carrijo

    2015-01-01

    Spitz nevus is a benign melanocytic lesion and also one of the main differential diagnosis of melanoma. A descriptive and retrospective study of surgical specimens from patients with a diagnosis of Spitz nevus was conducted at two institutions in Niterói - RJ. 32 cases were analyzed. The most frequent histological subtype was compound (60 %), with a predominance of epithelioid cells (17 cases - 53%). Pagetoid spread was observed in 21 cases (68%). Maturation of melanocytes was present in 13 cases (81%). Kamino bodies were found in eight cases (25%). Atypical melanocytes were present in 18 cases (56%). Mitoses were present in 11 cases (34%). Detailed knowledge of the classical form of Spitz nevi is essential for the differential diagnosis with melanoma. However, no single criterium is definitive in the differential diagnosis between Spitz nevus and melanoma. PMID:25672303

  10. Melanocytes and Their Diseases

    PubMed Central

    Yamaguchi, Yuji; Hearing, Vincent J.

    2014-01-01

    Human melanocytes are distributed not only in the epidermis and in hair follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melanocytes, which are derived from the neural crest, are unique in that they produce eu-/pheo-melanin pigments in unique membrane-bound organelles termed melanosomes, which can be divided into four stages depending on their degree of maturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmentation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder. PMID:24789876

  11. Diagnostic utility of 5-hydroxymethylcytosine immunohistochemistry in melanocytic proliferations

    PubMed Central

    Rodić, Nemanja; Zampella, John; Sharma, Reema; Burns, Kathleen H.; Taube, Janis M.

    2015-01-01

    Decreased hydroxymethylated cytosine (5-hydroxymethycytosine, 5-hmC) is reported to correlate with melanocyte dysplasia. The purpose of this study was to assess the diagnostic utility of this observation. 5-hmC immunohistochemistry was performed on tissue microarrays containing 171-melanocytic lesions from two different institutions. An immunohistochemical staining score representing the percentage and intensity of nuclear staining was assigned. The performance characteristics of 5-hmC immunohistochemistry for discriminating between a nevus and melanoma were determined. Additional cases of melanoma arising in a nevus (n = 8), nodal nevi (n = 5) and melanoma micrometastases to a lymph node (n = 6) were also assessed. Pronounced 5-hmC loss was observed in melanomas when compared with nevi (mean ± standard deviation = 6.71 ± 11.78 and 55.19 ± 23.66, respectively, p < 0.0001). While the mean immunohistochemical staining score values for melanocytic nevi and melanoma were distinct, there was considerable variability in immunohistochemical staining score within a single diagnostic category. The sensitivity and specificity of this assay for nevus vs. melanoma is 92.74 and 97.78%, respectively. Distinct biphasic staining patterns were observed in cases of melanoma arising in association with a nevus. Relative changes of 5-hmC expression within a single lesion may be more informative than absolute values when using 5-hmC as a diagnostic adjunct. PMID:26239102

  12. Separating melanin from hemodynamics in nevi using multimode hyperspectral dermoscopy and spatial frequency domain spectroscopy

    NASA Astrophysics Data System (ADS)

    Vasefi, Fartash; MacKinnon, Nicholas; Saager, Rolf; Kelly, Kristen M.; Maly, Tyler; Booth, Nicholas; Durkin, Anthony J.; Farkas, Daniel L.

    2016-11-01

    Changes in the pattern and distribution of both melanocytes (pigment producing) and vasculature (hemoglobin containing) are important in distinguishing melanocytic proliferations. The ability to accurately measure melanin distribution at different depths and to distinguish it from hemoglobin is clearly important when assessing pigmented lesions (benign versus malignant). We have developed a multimode hyperspectral dermoscope (SkinSpect™) able to more accurately image both melanin and hemoglobin distribution in skin. SkinSpect uses both hyperspectral and polarization-sensitive measurements. SkinSpect's higher accuracy has been obtained by correcting for the effect of melanin absorption on hemoglobin absorption in measurements of melanocytic nevi. In vivo human skin pigmented nevi (N=20) were evaluated with the SkinSpect, and measured melanin and hemoglobin concentrations were compared with spatial frequency domain spectroscopy (SFDS) measurements. We confirm that both systems show low correlation of hemoglobin concentrations with regions containing different melanin concentrations (R=0.13 for SFDS, R=0.07 for SkinSpect).

  13. Vulvar nevi, melanosis, and melanoma: an epidemiologic, clinical, and histopathologic review.

    PubMed

    Murzaku, Era Caterina; Penn, Lauren A; Hale, Christopher S; Pomeranz, Miriam Keltz; Polsky, David

    2014-12-01

    Pigmented vulvar lesions are present in approximately 1 in 10 women and include melanocytic and nonmelanocytic proliferations. Vulvar nevi, melanosis, and melanoma are particularly challenging because of the similarity of their clinical and/or histopathological presentation. As a result, they are often difficult to diagnose, may result in patient and physician anxiety, and can lead to unneeded, potentially disfiguring surgical procedures. Because it is often detected late, vulvar melanoma carries a poor prognosis with associated significant morbidity and mortality, underscoring the importance of prompt recognition and treatment. In this review, we analyze the distinct epidemiologic, clinical, and histopathologic characteristics of vulvar nevi, melanosis, and melanoma, discuss treatment options, and propose a practical, systematic approach to facilitate formulation of a differential diagnosis and initiation of appropriate management.

  14. Differential expression of basic fibroblast growth factor (bFGF) in melanocytic lesions demonstrated by in situ hybridization. Implications for tumor progression.

    PubMed Central

    Reed, J. A.; McNutt, N. S.; Albino, A. P.

    1994-01-01

    Basic fibroblast growth factor (bFGF) is an angiogenic and mitogenic polypeptide produced by diverse cell types including cell lines derived from malignant melanomas but not from normal melanocytes. However, there is no consensus concerning in vivo expression of bFGF in melanocytic lesions due in part to the small numbers of cases studied to date. To evaluate further the possible differential expression of bFGF in melanocytic lesions, we examined 110 formalin-fixed, paraffin-embedded metastatic and primary invasive melanomas, melanomas in situ, nevi with architectural disorder and cytological atypia, and ordinary benign melanocyte nevi by nucleic acid in situ hybridization. All metastatic and primary invasive melanomas studied expressed bFGF mRNA, whereas melanomas in situ and benign melanocyte nevi were negative. Melanomas in situ with features of tumor regression and a majority of nevi with architectural disorder and cytological atypia also contained bFGF mrNA. The results suggest that in vivo bFGF expression is not requisite for malignant transformation per se, but appears to correlate more with invasion or fibroblastic reactions adjacent to the melanocyte lesions. Images Figure 1 Figure 2 PMID:8311116

  15. Localized Eruptive Blue Nevi after Herpes Zoster

    PubMed Central

    Colson, Fany; Arrese, Jorge E.; Nikkels, Arjen F.

    2016-01-01

    A 52-year-old White man presented with a dozen small, well-restricted, punctiform, asymptomatic, blue-gray macules on the left shoulder. A few months earlier, he had been treated with oral acyclovir for herpes zoster (HZ) affecting the left C7–C8 dermatomes. All the blue macules appeared over a short period of time and then remained stable. The patient had not experienced any previous trauma or had tattooing in this anatomical region. The clinical diagnosis suggested blue nevi. Dermatoscopy revealed small, well-limited, dark-blue, compact, homogeneous areas evoking dermal blue nevi. An excisional biopsy was performed and the histological examination confirmed a blue nevus. As far as we are aware of, this is the first report of eruptive blue nevi following HZ, and it should be included in the differential diagnosis of zosteriform dermatoses responding to an isotopic pathway. In addition, a brief review concerning eruptive nevi is presented. PMID:27462219

  16. The important role of interdisciplinary collaboration in the management of a melanocytic skin lesion

    PubMed Central

    Balato, Anna; Raimondo, Annunziata; Cantelli, Mariateresa; Siano, Maria; Lembo, Serena; Scalvenzi, Massimiliano; Balato, Nicola

    2011-01-01

    One of the most confounding characteristics, commonly seen in malignant, but even in benign melanocytic nevi, is represented by the regression phenomenon. The identification of regression, through dermoscopical observation, can be predictive of a tricky histopathological examination. Therefore, this feature should be an alert to a meticulous clinical, dermoscopical and histopathological correlation for correct analysis of melanocytic skin lesions. A 26-year-old man was referred to our department for a pigmented skin lesion localized on his trunk. It was clinically and dermoscopically diagnosed as atypical melanocytic nevus with central regression. After 1 year the lesion underwent considerable changes, leading to a nearly complete regression. The lesion was excised and, on the basis of clinical, dermoscopical and histopathological correlation, was interpreted as a junctional melanocytic nevus with regression. In our case the association of clinical, dermoscopical and histopathological experience, resulted an important and useful method, in order to proper interpret and correctly diagnose an atypical melanocytic skin lesion. PMID:25386254

  17. Signet ring cell melanocytic nevus: report of a case over trichilemmal cyst and review of the literature.

    PubMed

    Sabater Marco, Vicente; Escutia Muñoz, Begoña; Morera Faet, Arturo; Botella Estrada, Rafael

    2012-02-01

    Different melanocytic nevi have been reported as being associated with dermal cysts. Signet ring cell melanocytic nevus is a rare variant of melanocytic nevus characterized by cells with signet ring morphology within a common melanocytic nevus. This article describes an exceptional case of melanocytic nevus composed exclusively of signet ring cells over a trichilemmal cyst. Histologically, above the cyst, there was a small, symmetrical and sharply demarcated lesion showing a compound proliferation of small, round, monomorphous cells with signet ring morphology. Immunohistochemically, signet ring cells were negative for cytokeratin AE1/3, leukocyte common antigen, HMB-45, and CD34. Occasionally, isolated signet ring cells were positive for S-100 and melan A. Melanocytic nevus composed of signet ring cells should raise the differential diagnosis with other cutaneous tumors exhibiting signet ring cells. Previous cases of this entity reported in the literature are also reviewed.

  18. Automated detection of malignant features in confocal microscopy on superficial spreading melanoma versus nevi

    NASA Astrophysics Data System (ADS)

    Gareau, Dan; Hennessy, Ricky; Wan, Eric; Pellacani, Giovanni; Jacques, Steven L.

    2010-11-01

    In-vivo reflectance confocal microscopy (RCM) shows promise for the early detection of superficial spreading melanoma (SSM). RCM of SSM shows pagetoid melanocytes (PMs) in the epidermis and disarray at the dermal-epidermal junction (DEJ), which are automatically quantified with a computer algorithm that locates depth of the most superficial pigmented surface [DSPS(x,y)] containing PMs in the epidermis and pigmented basal cells near the DEJ. The algorithm uses 200 noninvasive confocal optical sections that image the superficial 200 μm of ten skin sites: five unequivocal SSMs and five nevi. The pattern recognition algorithm automatically identifies PMs in all five SSMs and finds none in the nevi. A large mean gradient ψ (roughness) between laterally adjacent points on DSPS(x,y) identifies DEJ disruption in SSM ψ = 11.7 +/- 3.7 [-] for n = 5 SSMs versus a small ψ = 5.5 +/- 1.0 [-] for n = 5 nevi (significance, p = 0.0035). Quantitative endpoint metrics for malignant characteristics make digital RCM data an attractive diagnostic asset for pathologists, augmenting studies thus far, which have relied largely on visual assessment.

  19. Low-risk and high-risk histologic features in conjunctival primary acquired melanosis with atypia: Clinicopathologic analysis of 29 cases.

    PubMed

    Sugiura, Mitsuhiro; Colby, Kathryn A; Mihm, Martin C; Zembowicz, Artur

    2007-02-01

    The current World Health Organization classification of conjunctival melanocytic proliferations divides them into conjunctival nevi and invasive melanoma but, in contrast to other anatomic sites, does not recognize melanoma in situ. All atypical intraepithelial conjunctival proliferations are included in a heterogeneous category designated as primary acquired melanosis (PAM) with atypia. We performed clinicopathologic analysis of 29 cases of PAM with atypia. On the basis of histologic features and frequency of association with invasive melanoma and metastases, we were able to divide our cases into 2 histologic groups. The low-risk group (13 cases) included lesions composed of small to medium size melanocytes with high nuclear to cytoplasmic ratio and small to medium size hyperchromatic nuclei devoid of nucleoli showing predominantly single cell lentiginous growth pattern. Invasive melanoma occurred in only 2 cases from this group. None of these lesions metastasized. The second, high-risk group (16 cases), showed increased frequency of association with invasive melanoma (15/16 cases, 94%) and metastases (4/16 cases, 25%). These lesions were more heterogeneous architecturally but were all composed of melanocytes showing various degrees of epithelioid features such as abundant cytoplasm, vesicular nuclei, or prominent nucleoli. In 4 cases discrete areas showing high-risk and low-risk features were identified. All 4 lesions were associated with invasion. Our findings offer a practical approach for prognostically useful subclassification of PAM with atypia, which emphasizes cytologic features of intraepithelial conjunctival melanocytic proliferation.

  20. Study of the immunophenotype of the inflammatory cells in melanomas with regression and halo nevi.

    PubMed

    Botella-Estrada, Rafael; Kutzner, Heinz

    2015-05-01

    The pathogenesis and prognostic implications of regression in melanoma are not well understood. It has traditionally been considered an immunologically mediated phenomenon. Improvement in the knowledge of the mechanisms that lead to regression may prove to be of great value in an era in which treatments oriented to the augmentation of the host's immunity against melanoma have demonstrated excellent clinical results. This study was designed to improve the understanding of the mechanisms underlying melanoma regression and the differences between similar situations in benign melanocytic nevus. The study sample consisted of 77 lesions: 62 melanomas and 15 halo nevi. The following markers were included in the study: CD4, CD8, FoxP3, PD1, CD123, granzyme, and TIA-1. Staining was evaluated in 5 categories, according to the percentage of labeled cells. Granzyme, PD1, and TIA-1 stained significantly more cells in halo nevi than in melanomas with regression (P < 0.01). The ratio CD123/TIA-1 was higher in melanomas than in halo nevi (1 vs. 0.67, P < 0.05). Regression in the 62 melanomas was categorized as early in 14 cases and late in 48 cases. Early regression was associated with a higher percentage of CD123, CD4, and TIA-1 staining than late regression. The inflammatory infiltrate found in halo nevi is characterized by a higher number of active cytotoxic T cells and regulatory PD1-positive T cells than the infiltrate found in melanoma with regression. CD123 staining was higher in early regression than in late regression, suggesting the presence of a tolerogenic mechanism in this phenomenon's initiation phase.

  1. CD44 and melanocytic tumors: a possible role for standard CD44 in the epidermotropic spread of melanoma.

    PubMed

    Fernández-Figueras, M T; Ariza, A; Calatrava, A; Puig, L; Fernández-Vasalo, A; Ferrándiz, C

    1996-04-01

    CD44 is a polymorphic family of cell membrane glycoproteins that mediate cell-matrix and cell-cell interactions involved in the mechanisms of tumor invasion and metastasis, and are subject to differential regulation during normal and malignant cell growth. We have investigated immunohistochemically the expression of CD44S and the variant isoforms CD44v3 and CD44v6 in paraffin-embedded tissue from 5 Spitz nevi, 3 compound melanocytic nevi, 2 blue nevi, 6 primary melanomas, 15 cutaneous metastases (three epidermotropic, nine dermal and three ulcerated) and 10 lymph node metastases of melanoma. Melanocytes were extensively positive for CD44S in primary melanomas and benign melanocytic proliferations. Among 15 cases of cutaneous metastases of melanoma, the three epidermotropic metastases, as well as one of the three ulcerated ones were positive for CD44S. CD44S expression was diminished or totally absent in six of the nine dermal metastases, in two of the ulcerated metastases and in seven of the ten lymph node metastases. CD44v3 and CD44v6 melanocytic expression was absent in all the lesions studied. According to our results, selective retention of CD44S expression by melanocytes in epidermotropic metastases of melanoma seems to indicate that preservation of CD44S may contribute to the intraepidermal spread of melanoma.

  2. Atypical histopathologic features in a melanocytic nevus after cryotherapy and pregnancy.

    PubMed

    Wilford, Casey E; Brantley, Julie S; Diwan, A Hafeez

    2014-10-01

    Melanocytic nevi can undergo clinical and histopathologic changes during pregnancy, as well as after various forms of surgical and nonsurgical trauma. We report the case of a 9-month postpartum 29-year-old female who presented to her dermatologist with a clinically worrisome nevus. This nevus had been treated with liquid nitrogen by her primary care physician 6 months prior to presentation. Histopathologic evaluation revealed a crowded proliferation of atypical melanocytes at the dermal-epidermal junction overlying a scar. The dermal component contained scattered mitotic figures. A combined MART-1, tyrosinase and Ki-67 immunohistochemical study showed foci of increased melanocytic proliferation. These atypical features were interpreted as associated with both the prior cryotherapy, as well as her recent pregnancy. Knowledge of the clinical context in evaluating difficult melanocytic lesions is essential.

  3. Terahertz spectroscopy of pigmentary skin nevi in vivo

    NASA Astrophysics Data System (ADS)

    Zaitsev, K. I.; Chernomyrdin, N. V.; Kudrin, K. G.; Reshetov, I. V.; Yurchenko, S. O.

    2015-09-01

    Pigmentary skin nevi are studied in vivo using terahertz pulsed spectroscopy. Dielectric parameters of healthy skin and dysplastic and nondysplastic nevi are reconstructed and analyzed. The fact that complex permittivities of the samples substantially differ in the terahertz spectral range can be used for early noninvasive diagnostics of dysplastic nevi, which are precursors of melanoma (the most dangerous skin cancer). A method is proposed to identify various dysplastic and nondysplastic nevi using the analysis of terahertz dielectric characteristics. It is demonstrated that terahertz pulsed spectroscopy is promising for early noninvasive diagnostics of dysplastic nevi and melanomas of the skin.

  4. THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

    PubMed Central

    Bastian, Boris C.

    2016-01-01

    Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

  5. TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF

    PubMed Central

    Loftus, Stacie K.; Liu, Huan; Sompallae, Ramakrishna; Gildea, Derek E.; Santana, Juan F.; Manak, J. Robert; Pavan, William J.; Williams, Trevor; Cornell, Robert A.

    2017-01-01

    Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa

  6. Melanocyte expression of Survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice

    PubMed Central

    Thomas, Joshua; Liu, Tong; Cotter, Murray A.; Florell, Scott R.; Robinette, Kyle; Hanks, Adrianne N.; Grossman, Douglas

    2008-01-01

    We previously found the apoptosis inhibitor Survivin to be expressed in melanocytic nevi and melanoma, but not in normal melanocytes. To investigate the role of Survivin in melanoma development and progression, we examined the consequences of forced Survivin expression in melanocytes in vivo. Transgenic (Tg) mouse lines (Dct-Survivin) were generated with melanocyte-specific expression of Survivin, and melanocytes grown from Dct-Survivin mice expressed Survivin. Dct-Survivin melanocytes exhibited decreased susceptibility to UV-induced apoptosis but no difference in proliferative capacity compared to melanocytes derived from non-Tg littermates. Induction of nevi in Dct-Survivin and non-Tg mice by topical application of DMBA did not reveal significant differences in lesion onset (median 10 wks) or density (4 lesions/mouse after 15 wks). Dct-Survivin mice were bred with melanoma-prone MH19/HGF-B6 Tg mice and all progeny expressing either individual, neither, or both (Survivin/HGF) transgenes were UV-treated as neonates and then monitored for 43 wks. Melanocytes in neonatal Survivin+/HGF+ mouse skin were less susceptible to UV-induced apoptosis than those from Survivin−/HGF+ mice. Onset of melanocytic tumors was earlier (median 18 vs. 24 wks, p = .01, log-rank test) and overall tumor density was greater (7.7 vs. 5.2 tumors/mouse, p = .04) in Survivin+/HGF+ compared to Survivin−/HGF+ mice. Strikingly, melanomas arising in Survivin+/HGF+ mice demonstrated a greater tendency for lymph node (35% vs. 0%, p = .04) and lung (53% vs. 22%) metastasis, and lower rates of spontaneous apoptosis, than those in Survivin−/HGF+ mice. These studies demonstrate a role for Survivin in promoting both early and late events of UV-induced melanoma development in vivo. PMID:17545596

  7. Usefulness of confocal microscopy in distinguishing between basal cell carcinoma and intradermal melanocytic nevus on the face.

    PubMed

    Gamo, R; Floristan, U; Pampín, A; Caro, D; Pinedo, F; López-Estebaranz, J L

    2015-10-01

    The clinical distinction between basal cell carcinoma (BCC) and intradermal melanocytic nevus lesions on the face can be difficult, particularly in young patients or patients with multiple nevi. Dermoscopy is a useful tool for analyzing characteristic dermoscopic features of BCC, such as cartwheel structures, maple leaf-like areas, blue-gray nests and dots, and ulceration. It also reveals arborizing telangiectatic vessels and prominent curved vessels, which are typical of BCC, and comma vessels, which are typical of intradermal melanocytic nevi. It is, however, not always easy to distinguish between these 2 conditions, even when dermoscopy is used. We describe 2 facial lesions that posed a clinical and dermoscopic challenge in two 38-year-old patients; confocal microscopy showed separation between tumor nests and stroma and polarized nuclei, which are confocal microscopy features of basal cell carcinoma.

  8. Differences in the melanosome distribution within the epidermal melanin units and its association with the impairing background of leukoderma in vitiligo and halo nevi: a retrospective study.

    PubMed

    Xiong, Xi-Xi; Ding, Gao-Zhong; Zhao, Wen-E; Li, Xue; Ling, Yu-Ting; Sun, Li; Gong, Qing-Li; Lu, Yan

    2017-03-17

    Skin color is determined by the number of melanin granules produced by melanocytes that are transferred to keratinocytes. Melanin synthesis and the distribution of melanosomes to keratinocytes within the epidermal melanin unit (EMU) within the skin of vitiligo patients have been poorly studied. The ultrastructure and distribution of melanosomes in melanocytes and surrounding keratinocytes in perilesional vitiligo and normal skin were investigated using transmission electron microscopy (TEM). Furthermore, we performed a quantitative analysis of melanosome distribution within the EMUs with scatter plot. Melanosome count within keratinocytes increased significantly compared with melanocytes in perilesional stable vitiligo (P < 0.001), perilesional halo nevi (P < 0.01) and the controls (P < 0.01), but not in perilesional active vitiligo. Furthermore, melanosome counts within melanocytes and their surrounding keratinocytes in perilesional active vitiligo skin decreased significantly compared with the other groups. In addition, taking the means-standard error of melanosome count within melanocytes and keratinocytes in healthy controls as a normal lower limit, EMUs were graded into 3 stages (I-III). Perilesional active vitiligo presented a significantly different constitution in stages compared to other groups (P < 0.001). The distribution and constitution of melanosomes were normal in halo nevi. Impaired melanin synthesis and melanosome transfer are involved in the pathogenesis of vitiligo. Active vitiligo varies in stages and in stage II, EMUs are slightly impaired, but can be resuscitated, providing a golden opportunity with the potential to achieve desired repigmentation with an appropriate therapeutic choice. Adverse milieu may also contribute to the low melanosome count in keratinocytes.

  9. Epithelioid melanocytic nevus with tubule and pseudoacini formation.

    PubMed

    Uhlenhake, Elizabeth E; Smoller, Bruce R; Gardner, Jerad M; Shalin, Sara C

    2015-03-01

    A 26-year-old female presented with a 7 mm irritated pink-red papule on the left posterior shoulder. A shave biopsy revealed a dermal proliferation of epithelioid cells arranged in small nests with central lumen-like structures resembling glands set in a densely sclerotic stroma. S100 and Melanoma antigen recognized by T cells 1 (MART-1) immunohistochemical positivity confirmed a dermal melanocytic neoplasm. Pan-cytokeratin and cytokeratin 7 were negative within the nests ruling out an adnexal neoplasm or metastatic adenocarcinoma. A Spitz nevus variant characterized by the presence of focal tubular structures (tubular epithelioid cell nevus) has rarely been described in the literature and is of uncertain biological significance. Similar structures have also been observed in Clark/dysplastic nevi and melanoma. Glandular differentiation is seen in a wide variety of benign and malignant epithelial neoplasms; however, melanocytes are not known to be capable of forming true glands. The exact mechanism and significance of this phenomenon are currently unknown. Certain postulations include central melanocyte apoptosis, autocrine or paracrine factor secretion or retraction artifact caused by tissue fixation. This distinctive finding is important to recognize in order to avoid misdiagnosis as a glandular neoplasm.

  10. Melanocytes: the new Black.

    PubMed

    Goding, Colin R

    2007-01-01

    Melanocytes, pigment-producing cells residing primarily in the hair follicle, epidermis and eye, are responsible for skin hair and eye pigmentation. Pigmentation is achieved by the highly regulated manufacture of the pigment melanin in specialised organelles, melanosomes that are transported along dendritic processes before being transferred to growing hair, or keratinocytes where melanin protects from UV-induced DNA damage. Because loss of melanocytes gives a clear pigmentation phenotype yet is non-lethal, over 130 genes implicated in the development or function of this cell type have been identified to date, and in humans the loss of melanocytes or their ability to produce pigment, or transport or transfer melanosomes is associated with several diseases such as vitiligo, albinism and Hermansky-Pudlak syndrome. Importantly, the effective combination of genetics, cell and molecular biology possible with this cell type is attracting an increasing number of researchers focussed on understanding how cells coordinate survival, proliferation, differentiation and stem cell maintenance.

  11. Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.

    PubMed

    Pawlikowski, Jeffrey S; Brock, Claire; Chen, Sheau-Chiann; Al-Olabi, Lara; Nixon, Colin; McGregor, Fiona; Paine, Simon; Chanudet, Estelle; Lambie, Wendy; Holmes, William M; Mullin, James M; Richmond, Ann; Wu, Hong; Blyth, Karen; King, Ayala; Kinsler, Veronica A; Adams, Peter D

    2015-08-01

    Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.

  12. Loss of p16 expression and copy number changes of CDKN2A in a spectrum of spitzoid melanocytic lesions.

    PubMed

    Harms, Paul W; Hocker, Thomas L; Zhao, Lili; Chan, May P; Andea, Aleodor A; Wang, Min; Harms, Kelly L; Wang, Michael L; Carskadon, Shannon; Palanisamy, Nallasivam; Fullen, Douglas R

    2016-12-01

    Spitzoid melanocytic lesions, including Spitz nevi (benign), spitzoid melanoma (malignant), and borderline atypical Spitz tumors (ASTs), frequently present challenges for accurate diagnosis and prognosis. Evaluation for loss of the tumor suppressor p16, encoded by CDKN2A gene on chromosome 9p21.3, has been proposed to be useful for evaluation of spitzoid melanocytic lesions. However, reports on the utility of p16 immunohistochemistry for spitzoid lesions have been conflicting, and few studies have directly compared p16 immunohistochemistry with fluorescence in situ hybridization (FISH) for CDKN2A genomic status. We analyzed a spectrum of benign (n=24), borderline (n=27), and malignant (n=19) spitzoid lesions for p16 protein expression by immunohistochemistry and CDKN2A copy number by FISH. Immunohistochemistry was evaluated by 2 scoring methods: H score and 2-tiered score (positive or negative for p16 loss). By immunohistochemistry, loss of p16 expression was not observed in Spitz nevi (0/24) but was seen in ASTs (7/27; 26%) and spitzoid melanomas (3/19; 16%). By H score, p16 expression was significantly higher in Spitz nevi relative to ASTs or spitzoid melanomas. Similarly, copy number aberrations of CDKN2A by FISH were absent in Spitz nevi but were found in 2 (9.5%) of 21 ASTs and 4 (33%) of 12 spitzoid melanomas. Our findings from this large cohort suggest that p16 aberrations are highly specific for borderline and malignant spitzoid neoplasms relative to Spitz nevi. Similar to ASTs, p16 loss in spitzoid melanomas may occur in the presence or absence of genomic CDKN2A loss.

  13. MITF accurately highlights epidermal melanocytes in atypical intraepidermal melanocytic proliferations.

    PubMed

    Nybakken, Grant E; Sargen, Michael; Abraham, Ronnie; Zhang, Paul J; Ming, Michael; Xu, Xiaowei

    2013-02-01

    Atypical intraepidermal melanocytic proliferations (AIMP) have random cytologic atypia and other histologic features that are concerning for malignancy and often require immunohistochemistry to differentiate from melanoma in situ. Immunostaining with S100, Melan-A, and microphthalmia-associated transcription factor (MITF) was performed for 49 morphologically well-characterized AIMP lesions. The percentage of cells in the basal layer of the epidermis that were identified as melanocytes by immunohistochemistry was compared with the percentage observed by morphology on hematoxylin and eosin staining, which is the gold standard stain for identifying cytologic atypia within an AIMP. Melan-A estimated the highest percentage of melanocytes and S100 the fewest in 47 of the 49 lesions examined. The estimated percentage of melanocytes was 23.3% (95% confidence interval: 18.6-28.1; P < 0.001) higher for Melan-A compared with hematoxylin and eosin staining. Melanocyte estimates were similar for hematoxylin and eosin and MITF (P = 0.15) although S100 estimated 21.8% (95% confidence interval: -27.2 to -16.4; P < 0.001) fewer melanocytes than hematoxylin and eosin. Melan-A staining produces higher estimates of epidermal melanocytes than S100 and MITF, which may increase the likelihood of diagnosing melanoma in situ. In contrast, melanoma in situ may be underdiagnosed with the use of S100, which results in lower estimates of melanocytes than the other 2 immunostains. Therefore, the best immunohistochemical marker for epidermal melanocytes is MITF.

  14. [CONGENITAL MELANOCYTIC NEVUS OF THE SHOULDER WITH RAPID GROWTH PROGRESSION DURING PREGNANCY. SUCCESSFUL SURGICAL APPROACH].

    PubMed

    Trayanov, I; Trayanova, E; Chokoeva, A; Tchernev, G

    2015-01-01

    Congenital melanocytic nevi are common subject of scientific debates nowadays, because of their possibility for transformation in malignant melanoma, although relatively rare. The diagnosis is difficult, due to their non-specific clinical and histological presentation, while the therapeutic methods are varied, depending on their size and localization. Surgical excision, however, is the most secure among them, because a complete removal of the lesion could be achieved, which, firstly provides a prevention of a possible malignant transformation, as well as this approach provides material for histological examination. We present a case of a 23-year-old female patient with congenital melanocytic nevus, located on the upper back, which increased significantly its size during her pregnancy, successfully treated by single surgical excision, with excellent aesthetic results.

  15. Metastatic melanoma in association with a giant congenital melanocytic nevus in an adult: controversial CGH findings.

    PubMed

    Machan, Salma; Molina-Ruiz, Ana M; Fernández-Aceñero, Maria J; Encabo, Beatriz; LeBoit, Philip; Bastian, Boris C; Requena, Luis

    2015-06-01

    Giant congenital melanocytic nevi (GCMNs) represent a distress to patients for 2 reasons: one is disfigurement, and the other is the increased risk of developing secondary melanocytic tumors, such as benign proliferative nodules (BPNs) and malignant melanoma (MM). BPN present as a rapid growth nodule arising within a congenital melanocytic nevus (CMN) that often ulcerates, occurs in children younger than 2 years of age. BPNs arising within a CMN are exceedingly rare after childhood, and very few cases have been described in adults. Despite the worrisome clinical and histologic findings of BPN, most laboratory investigations seem to support their benignity. The distinction between MM and BPN is extremely important, but the histopathology of BPN of GCMN can be a challenge to differentiate from MM. In the recent years, molecular tests that investigate DNA copy number alterations such as fluorescence in situ hybridization and comparative genomic hybridization have shown promise to help guide the diagnosis of ambiguous melanocytic proliferations arising within CMNs. We report the case of a 22-year-old woman with a nodule arising in a GCMN and with an axillary mass suggesting a nodal metastasis of melanoma, and discuss the unusual clinical, histopathologic, and molecular findings that make this case particularly interesting.

  16. VITILIGO AND THE MELANOCYTE RESERVOIR

    PubMed Central

    Falabella, Rafael

    2009-01-01

    Repigmentation of vitiligo depends on available melanocytes from three possible sources: from the hair follicle unit which is the main provider of pigment cells, from the border of vitiligo lesions, and from unaffected melanocytes within depigmented areas; pigment cells at these locations originate a perifollicular, border spreading and a diffuse repigmentation pattern. In order for repigmentation to take place under stimulation with diverse therapies, melanocytes should be present in appropriate numbers. Melanocyte tissue stem cells located in the niche at the bulge region of the hair follicle are the most important sources for providing immature pigment cells that undergo terminal differentiation and originate repigmentation, but cytokines, UVR and other molecules acting in melanogenesis with adequate regulation mechanisms contribute to successful recovery in vitiligo. The presence of keratinocyte stem cells in the interfollicular epidermis raises the question on the possibility of melanocyte stem cells in a similar location and the development of future strategies for therapeutic purposes. PMID:20101329

  17. The biology of melanocyte and melanocyte stem cell.

    PubMed

    Li, Ang

    2014-04-01

    The melanocyte stem cells of the hair follicle provide an attractive system for the study of the stem cells. Successful regeneration of a functional organ relies on the organized and timely orchestration of molecular events among distinct stem/progenitor cell populations. The stem cells are regulated by communication with their specialized microenvironment known as the niche. Despite remarkable progress in understanding stem cell-intrinsic behavior, the molecular nature of the extrinsic factors provided to the stem cells by the niche microenvironment remains poorly understood. In this regard, the bulge niche of the mammalian hair follicle offers an excellent model for study. It holds two resident populations of SCs: epidermal stem cells and melanocyte stem cells. While their behavior is tightly coordinated, very little of the crosstalk involved is known. This review summarized the recent development in trying to understand the regulation of melanocyte and melanocyte stem cells. A better understanding of the normal regulation and behaviors of the melanocytes and the melanocyte stem cells will help to improve the clinical applications in regenerative medicine, cancer therapy, and aging.

  18. Diagnosis and staging of female genital tract melanocytic lesions using pump-probe microscopy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Robles, Francisco E.; Selim, Maria A.; Warren, Warren S.

    2016-02-01

    Melanoma of the vulva is the second most common type of malignancy afflicting that organ. This disease caries poor prognosis, and shows tendencies to recur locally and develop distant metastases through hematogenous dissemination. Further, there exists significant clinical overlap between early-stage melanomas and melanotic macules, benign lesions that are believed to develop in about 10% of the general female population. In this work we apply a novel nonlinear optical method, pump-probe microscopy, to quantitatively analyze female genitalia tract melanocytic lesions. Pump-probe microscopy provides chemical information of endogenous pigments by probing their electronic excited state dynamics, with subcellular resolution. Using unstained biopsy sections from 31 patients, we find significant differences between melanin type and structure in tissue regions with invasive melanoma, melanoma in-situ and non-malignant melanocytic proliferations (e.g., nevi, melanocytic macules). The molecular images of non-malignant lesion have a well-organized structure, with relatively homogenous pigment chemistry, most often consistent with that of eumelanin with large aggregate size or void of metals, such as iron. On the other hand, pigment type and structure observed in melanomas in-situ and invasive melanomas is typically much more heterogeneous, with larger contributions from pheomelanin, melanins with larger metal content, and/or melanins with smaller aggregate size. Of most significance, clear differences can be observed between melanocytic macules and vulvar melanoma in-situ, which, as discussed above, can be difficult to clinically distinguish. This initial study demonstrates pump-probe microscopy's potential as an adjuvant diagnostic tool by revealing systematic chemical and morphological differences in melanin pigmentation among invasive melanoma, melanoma in-situ and non-malignant melanocytic lesions.

  19. Feline epidermal nevi resembling human inflammatory linear verrucous epidermal nevus.

    PubMed

    Sato, Masafumi; Kariya, Kazuhiro; Matsumoto, Munetaka; Itoh, Miyuki; Kobayashi, Yoshiyasu; Nishifuji, Koji; Kamiie, Junichi; Shirota, Kinji

    2012-10-01

    Multiple, pigmented, verrucous, cutaneous lesions in a 2-year-old female cat were pathologically examined. The lesions were linearly arranged on the right side of the body, and had developed along with moderate pruritus since infancy. Histologically, prominent exophytic, papillomatous outgrowths of the epidermis and acanthosis with intense ortho and parakeratotic hyperkeratosis were characteristic of the lesions. Dermal inflammation with mononuclear cells, neutrophils, and eosinophils was also noted. Inclusion bodies, cellular degeneration, and intranuclear viral particles suggesting papillomavirus infection in the keratinocytes were not observed. Papillomavirus antigen and DNA were not detected in the lesions by immunohistochemistry and polymerase chain reaction, respectively. In accordance with these clinical and histopathological features, the cutaneous lesions of the present cat were diagnosed as epidermal nevi, which were consistent with human inflammatory linear verrucous epidermal nevi.

  20. [Xanthofibrogranulomatosis, pontine glioma, multiple nevocytic nevi and albinism (authors transl)].

    PubMed

    Martin, U; Cremer, H; Klein, D; Kutzner, M

    1975-05-23

    A case of retroperitoneal fibrosis with ureter compression is reported. Clinical picture and course were determined by the presence of an additional tumor (astrospongoblastoma) of the pons. Extraretroperitoneal tissue changes found at post mortem examination were shown histologically to be foreign tissues of the same type deposited in the retroperitoneal space (disseminated xanthofibrogranuloma). Possible connections between the disseminated xanthofibrogranuloma, the pontine tumor and an albinism also present and multiple nevocytic nevi of the skin are discussed.

  1. Genetics Home Reference: giant congenital melanocytic nevus

    MedlinePlus

    ... noncancerous skin patch (nevus) that is composed of pigment-producing cells called melanocytes . It is present from ... called neurocutaneous melanosis, which is the presence of pigment-producing skin cells (melanocytes) in the tissue that ...

  2. Treatment of a giant congenital melanocytic nevus in the adult: review of the current management of giant congenital melanocytic nevus.

    PubMed

    Su, Jeannie J; Chang, Daniel K; Mailey, Brian; Gosman, Amanda

    2015-05-01

    Giant congenital melanocytic nevi (GCMNs) create cosmetic disfigurements and pose risk for malignant transformation. Adult GCMN cases are uncommon because most families opt for surgical treatment during childhood. We review the current literature on GCMN and present an interesting case of an adult with a GCMN encompassing the entire back with painful nodules exhibiting gross involvement of his back musculature, without pathologic evidence of malignancy. Surgical management was deferred in childhood because of parental desires to allow the patient to make his own decision, and treatment in adulthood was pursued on the basis of the significant impairment of the patient's quality of life and self-esteem due to the massive size and deforming nature of the nevus. The treatment strategy used for this young adult male patient involved a massive en bloc excision of the GCMN with partial resection of the latissimus dorsi, followed by a 5-week staged reconstructive process using dermal regenerative matrices and split-thickness skin grafting. Because of the shift in GCMN management from early surgical management to more conservative management, we may see an increase in adult cases of GCMN. Thus, it is critical to better understand the controversy surrounding early versus delayed management of GCMN.

  3. Intramedullary and retroperitoneal melanocytic tumor associated with congenital blue nevus and nevus flammeus: an uncommon combination of neurocutaneous melanosis and phacomatosis pigmentovascularis--case report.

    PubMed

    Kurokawa, Ryu; Kim, Phyo; Kawamoto, Toshiki; Matsuda, Hadzki; Hayashi, Shujiro; Yamazaki, Soji; Hatamochi, Atsushi; Mori, Shozo; Shimoda, Mitsugi; Kubota, Keiichi

    2013-01-01

    Neurocutaneous melanosis (NCM) is a rare condition characterized by central nervous system melanocytic tumors associated with congenital melanocytic nevi. Phacomatosis pigmentovascularis (PPV) is an association of vascular nevus with pigmentary nevus. Aberrant maturation of neural crest-derived cells is considered to be related to pathogenesis in both conditions. However, association of NCM and PPV has not been reported to the best of our knowledge. Melanocytoma, which usually involves the leptomeninges or spinal cord, is extremely rare in the retroperitoneum. We present here a case of a patient with NCM, PPV, and melanocytic tumors in the spinal cord and retroperitoneum, which were treated surgically. A 40-year-old woman had a 2-year history of dysesthesia and weakness in the left leg. History included congenital giant blue nevus-like lesion in the trunk, a port-wine stain in the sacral area, and Caesarean section performed 8 years before, when diffuse pigmentation in the peritoneum was noted. Magnetic resonance (MR) imaging of the spine revealed an intramedullary tumor at T10 level with paramagnetic signal characteristics. The spinal cord tumor was totally removed, and the histological diagnosis was melanocytoma. Three months later, a left retroperitoneal mass with histological features of melanocytic tumor was removed. Neither tumors recurred and the patient stays ambulatory 4 years after the surgery. Multiple subtypes of melanocytic tumors with distinctive features of NCM and PPV can develop simultaneously, mimicking malignant melanoma. Gross total resection of each tumor, when indicated, is beneficial.

  4. Neuroendocrine activity of the melanocyte

    PubMed Central

    Slominski, Andrzej

    2009-01-01

    More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress. Examples of the above are catecholamines, serotonin, N-acetyl-serotonin, melatonin, proopiomelanocortin-derived adrenocorticotropic hormone, β-endorphin or melanocyte-stimulating hormone peptides, corticotropin releasing factor, related urocortins and corticosteroids including cortisol and corticosterone as well as their precursors. Furthermore, their production is not random, but hierarchical and follows the structures of classical neuroendocrine organizations such as hypothalamic-pituitary-adrenal axis, serotoninergic, melatoninergic and catecholaminergic systems. An example of an intrinsic but overlooked neuroendocrine activity is production and secretion of melanogenesis intermediates including L-DOPA or its derivatives that could enter circulation and act on distant sites. Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis. PMID:19558501

  5. Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study

    PubMed Central

    Zhang, Mingfeng; Zhang, Xuehong; Qureshi, Abrar A.; Eliassen, A. Heather; Hankinson, Susan E.; Han, Jiali

    2014-01-01

    Background Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk. Methods and Findings We followed 74,523 female nurses for 24 y (1986–2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98–1.10 for 1–5 nevi; 1.15, 95% CI, 1.00–1.31 for 6–14 nevi, and 1.35, 95% CI, 1.04–1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%–9.33%) for women with 1–5 nevi, 9.75% (95% CI, 8.48%–11.11%) for women with 6–14 nevi, and 11.4% (95% CI, 8.82%–14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)–positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02–1.16 for ER+/progesterone receptor [PR]–positive tumors; 1.08, 95% CI, 0.94–1.24 for ER+/PR− tumors; and 0.99, 95% CI, 0.86–1.15 for ER−/PR− tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched

  6. Sox proteins in melanocyte development and melanoma

    PubMed Central

    Harris, Melissa L.; Baxter, Laura L.; Loftus, Stacie K.; Pavan, William J.

    2010-01-01

    Over ten years has passed since the first Sox gene was implicated in melanocyte development. Since then, we have discovered that SOX5, SOX9, SOX10 and SOX18 all participate as transcription factors that affect key melanocytic genes in both regulatory and modulatory fashions. Both SOX9 and SOX10 play major roles in the establishment and normal function of the melanocyte; SOX10 has been shown to heavily influence melanocyte development and SOX9 has been implicated in melanogenesis in the adult. Despite these advances, the precise cellular and molecular details of how these SOX proteins are regulated and interact during all stages of the melanocyte life cycle remain unknown. Improper regulation of SOX9 or SOX10 is also associated with cancerous transformation, and thus understanding the normal function of SOX proteins in the melanocyte will be key to revealing how these proteins contribute to melanoma. PMID:20444197

  7. The melanocyte lineage in development and disease

    PubMed Central

    Mort, Richard L.; Jackson, Ian J.; Patton, E. Elizabeth

    2015-01-01

    Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma. PMID:25670789

  8. Understanding Melanocyte Stem Cells for Disease Modeling and Regenerative Medicine Applications.

    PubMed

    Mull, Amber N; Zolekar, Ashwini; Wang, Yu-Chieh

    2015-12-21

    Melanocytes in the skin play an indispensable role in the pigmentation of skin and its appendages. It is well known that the embryonic origin of melanocytes is neural crest cells. In adult skin, functional melanocytes are continuously repopulated by the differentiation of melanocyte stem cells (McSCs) residing in the epidermis of the skin. Many preceding studies have led to significant discoveries regarding the cellular and molecular characteristics of this unique stem cell population. The alteration of McSCs has been also implicated in several skin abnormalities and disease conditions. To date, our knowledge of McSCs largely comes from studying the stem cell niche of mouse hair follicles. Suggested by several anatomical differences between mouse and human skin, there could be distinct features associated with mouse and human McSCs as well as their niches in the skin. Recent advances in human pluripotent stem cell (hPSC) research have provided us with useful tools to potentially acquire a substantial amount of human McSCs and functional melanocytes for research and regenerative medicine applications. This review highlights recent studies and progress involved in understanding the development of cutaneous melanocytes and the regulation of McSCs.

  9. "Compound blue nevus": a reappraisal of "superficial blue nevus with prominent intraepidermal dendritic melanocytes" with emphasis on dermoscopic and histopathologic features.

    PubMed

    Ferrara, Gerardo; Argenziano, Giuseppe; Zgavec, Borut; Bartenjev, Igor; Staibano, Stefania; De Rosa, Gaetano; Soyer, H Peter

    2002-01-01

    We describe 5 cases of "compound blue nevus" (CBN) ("superficial blue nevus with prominent intraepidermal dendritic melanocytes," "Kamino nevus"). Dermoscopically in 2 of 4 cases the bluish pigmentation characteristic of blue nevi was centrally replaced by a black lamella, with black dots and brown globules also observed in one case, thus revealing a structural asymmetry suggestive of melanoma. Histopathologically, pigmented parakeratosis was the underlying histopathologic finding of black lamella and dots/globules. Immunohistochemistry highlighted the unique histopathologic feature of CBN, namely, single dendritic melanocytes at the dermoepidermal junction with striking intraepidermal prolongations. Our findings confirm that CBN is a distinctive variant of blue nevus that may mimic cutaneous melanoma both clinically and dermoscopically.

  10. Clinical, pathological, and etiologic aspects of acquired dermal melanocytosis.

    PubMed

    Mizoguchi, M; Murakami, F; Ito, M; Asano, M; Baba, T; Kawa, Y; Kubota, Y

    1997-06-01

    To study the pathogenesis of acquired dermal melanocytosis (ADM), we reviewed the clinical, immunohistochemical, and ultrastructural features of 34 cases (female, 33, and male, 1) of ADM. The patients' ages at onset ranged from 8 to 51 years and averaged 26.8 +/- 12.7 years. There was a positive family history. Gray-brown macules were mostly recognized on the face. Not only active dermal melanocytes but also non-pigmented c-KIT- and TRP-2-positive immature melanocytes were detected in the dermis. Taken together those clinical and histological findings, activation of pre-existing immature melanocytes by sunlight, estrogen, and/or progesterone, and some other factors, may be the most likely mode of the development of ADM. Moreover, using cultured murine neural crest cells as a model of c-KIT-positive immature melanocytes, we confirmed that endothelin-1, which is produced and secreted by keratinocytes after UV-irradiation, affects melanocytes and accelerated melanogenesis.

  11. Patterns in melanocytic lesions: impact of the geometry on growth and transport inside the epidermis

    PubMed Central

    Balois, Thibaut; Chatelain, Clément; Ben Amar, Martine

    2014-01-01

    In glabrous skin, nevi and melanomas exhibit pigmented stripes during clinical dermoscopic examination. They find their origin in the basal layer geometry which periodically exhibits ridges, alternatively large (limiting ridges) and thin (intermediate ridges). However, nevus and melanoma lesions differ by the localization of the pigmented stripes along furrows or ridges of the epidermis surface. Here, we propose a biomechanical model of avascular tumour growth which takes into account this specific geometry in the epidermis where both kinds of lesions first appear. Simulations show a periodic distribution of tumour cells inside the lesion, with a global contour stretched out along the ridges. In order to be as close as possible to clinical observations, we also consider the melanin transport by the keratinocytes. Our simulations show that reasonable assumptions on melanocytic cell repartition in the ridges favour the limiting ridges of the basal compared with the intermediate ones in agreement with nevus observations but not really with melanomas. It raises the question of cell aggregation and repartition of melanocytic cells in acral melanomas and requires further biological studies of these cells in situ. PMID:24872499

  12. Microtubule-associated protein light chain 3 is involved in melanogenesis via regulation of MITF expression in melanocytes

    PubMed Central

    Yun, Woo Jin; Kim, Eun-Young; Park, Ji-Eun; Jo, Soo Youn; Bang, Seung Hyun; Chang, Eun-Ju; Chang, Sung Eun

    2016-01-01

    Although autophagy plays a role in melanogenesis by regulating melanosome degradation and biogenesis in melanocytes, a detailed understanding of the regulatory functions of autophagy factors is lacking. Here, we report a mechanistic link between microtubule-associated protein light chain 3 (LC3) activation and melanogenesis. We observed high expression of LC3 in melanosome-associated pigment-rich melanocytic nevi of sun-exposed skin, as indicated by patterns of melanosomal protein MART1 expression. Rapamycin-induced autophagy significantly increased the melanin index, tyrosinase activity and expression of several proteins linked to melanosome biogenesis, including microphthalmia transcription factor (MITF), pre-melanosome protein and tyrosinase, in Melan-a melanocytes. siRNA-mediated knockdown of LC3, but not beclin-1 or ATG5, decreased melanin content and tyrosinase activity. LC3 knockdown also markedly inhibited MITF expression and subsequent rapamycin-induced melanosome formation. More importantly, LC3 knockdown suppressed α-MSH-mediated melanogenesis by attenuating cAMP response element-binding protein (CREB) phosphorylation and MITF expression in Melan-a cells via decreased extracellular signal-regulated kinase (ERK) activity. Overexpression of constitutively active ERK reversed the effect of LC3 knockdown on CREB phosphorylation and MITF expression. These findings demonstrate that LC3 contributes to melanogenesis by increasing ERK-dependent MITF expression, thereby providing a mechanistic insight into the signaling network that links autophagy to melanogenesis. PMID:26814135

  13. Biological characteristics of mouse skin melanocytes.

    PubMed

    Shi, Zhanquan; Ji, Kaiyuan; Yang, Shanshan; Zhang, Junzhen; Yao, Jianbo; Dong, Changsheng; Fan, Ruiwen

    2016-04-01

    The objective of this research was to evaluate the optimal passage number according to the biological characteristics of mouse skin melanocytes from different passages. Skin punch biopsies harvested from the dorsal region of 2-day old mice were used to establish melanocyte cultures. The cells from passage 4, 7, 10 and 13 were collected and evaluated for their melanogenic activity. Histochemical staining for tyrosinase (TYR) activity and immunostaining for the melanocyte specific markers including S-100 antigen, TYR, tyrosinase related protein 1 (TYRP1), tyrosinase related protein 2 (TYRP2) and micropthalmia associated transcription factor (MITF) confirmed purity and melanogenic capacity of melanocytes from different passages, with better melanogenic activity of passage 10 and 13 cells being observed. Treatment of passage 13 melanocytes with α-melanocyte stimulating hormone (α-MSH) showed increased expression of MITF, TYR and TYRP2 mRNA. However, considering the TYR mRNA dramatically high expression which is the characteristics of melanoma cells, melanocytes from passage 10 was the optimal passage number for the further research. Our results demonstrate culture of pure populations of mouse melanocytes to at least 10 passages and illustrate the potential utility of passage 10 cells for studies of intrinsic and extrinsic regulation of genes controlling pigmentation and coat color in mouse.

  14. GI tract tumors with melanocytic differentiation.

    PubMed

    Karamchandani, Dipti M; Patil, Deepa T; Goldblum, John R

    2013-11-01

    Gastrointestinal (GI) tract tumors with melanocytic differentiation may present significant diagnostic challenges both for the pathologist and the clinician. This comprehensive review discusses the relatively common as well as rare entities that have melanocytic differentiation in the GI tract. Clinical, histologic, immunohistochemical and molecular features are discussed along with prognosis and differential diagnosis.

  15. In vivo terahertz pulsed spectroscopy of dysplastic and non-dysplastic skin nevi

    NASA Astrophysics Data System (ADS)

    Zaytsev, Kirill I.; Chernomyrdin, Nikita V.; Kudrin, Konstantin G.; Gavdush, Arseniy A.; Nosov, Pavel A.; Yurchenko, Stanislav O.; Reshetov, Igor V.

    2016-08-01

    The results of the in vivo terahertz (THz) pulsed spectroscopy (TPS) of pigmentary skin nevi are reported. Observed THz dielectric permittivity of healthy skin and dysplastic and non-dysplastic skin nevi exhibits significant contrast in THz frequency range. Dysplastic skin nevus is a precursor of melanoma, which is reportedly the most dangerous cancer of the skin. Therefore, the THz dielectric spectroscopy is potentially an effective tool for non-invasive early diagnosis of melanomas of the skin.

  16. Chemical Bum from Vinegar Following an Internet-based Protocol for Self-removal of Nevi

    PubMed Central

    Feldstein, Stephanie; Afshar, Maryam

    2015-01-01

    “Natural home remedies” for nevi removal found on the Internet can be ineffective, or worse, dangerous. Children and teens, in particular, may be more likely to attempt self-treatment in order to avoid discussing their concerns with their parents. Here, the authors report a case of an adolescent who presented with a chemical burn after following an Internet-based protocol for nevi removal using apple cider vinegar. PMID:26155328

  17. Chemical Burn from Vinegar Following an Internet-based Protocol for Self-removal of Nevi.

    PubMed

    Feldstein, Stephanie; Afshar, Maryam; Krakowski, Andrew C

    2015-06-01

    "Natural home remedies" for nevi removal found on the Internet can be ineffective, or worse, dangerous. Children and teens, in particular, may be more likely to attempt self-treatment in order to avoid discussing their concerns with their parents. Here, the authors report a case of an adolescent who presented with a chemical burn after following an Internet-based protocol for nevi removal using apple cider vinegar.

  18. Automatic nevi segmentation using adaptive mean shift filters and feature analysis

    NASA Astrophysics Data System (ADS)

    King, Michael A.; Lee, Tim K.; Atkins, M. Stella; McLean, David I.

    2004-05-01

    A novel automatic method of segmenting nevi is explained and analyzed in this paper. The first step in nevi segmentation is to iteratively apply an adaptive mean shift filter to form clusters in the image and to remove noise. The goal of this step is to remove differences in skin intensity and hairs from the image, while still preserving the shape of nevi present on the skin. Each iteration of the mean shift filter changes pixel values to be a weighted average of pixels in its neighborhood. Some new extensions to the mean shift filter are proposed to allow for better segmentation of nevi from the skin. The kernel, that describes how the pixels in its neighborhood will be averaged, is adaptive; the shape of the kernel is a function of the local histogram. After initial clustering, a simple merging of clusters is done. Finally, clusters that are local minima are found and analyzed to determine which clusters are nevi. When this algorithm was compared to an assessment by an expert dermatologist, it showed a sensitivity rate and diagnostic accuracy of over 95% on the test set, for nevi larger than 1.5mm.

  19. Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes

    PubMed Central

    Qiao, Zhuhui; Wang, Xiuxiu; Xiang, Leihong

    2016-01-01

    Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of functional melanocytes from the epidermis and follicular reservoir. Among multiple hypotheses which have been proposed in the pathogenesis of vitiligo, autoimmunity and oxidative stress-mediated toxicity in melanocytes remain most widely accepted. Macroautophagy is a lysosome-dependent degradation pathway which widely exists in eukaryotic cells. Autophagy participates in the oxidative stress response in many cells, which plays a protective role in preventing damage caused by oxidative stress. Recent studies have enrolled autophagy as an important regulator in limiting damage caused by UV light and lipid oxidation, keeping oxidative stress in a steady state in epidermal keratinocytes and maintaining normal proliferation and aging of melanocytes. Impairment of autophagy might disrupt the antioxidant defense system which renders melanocytes to oxidative insults. These findings provide supportive evidence to explore new ideas of the pathogenesis of vitiligo and other pigmentation disorders. PMID:28018522

  20. Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes.

    PubMed

    Qiao, Zhuhui; Wang, Xiuxiu; Xiang, Leihong; Zhang, Chengfeng

    2016-01-01

    Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of functional melanocytes from the epidermis and follicular reservoir. Among multiple hypotheses which have been proposed in the pathogenesis of vitiligo, autoimmunity and oxidative stress-mediated toxicity in melanocytes remain most widely accepted. Macroautophagy is a lysosome-dependent degradation pathway which widely exists in eukaryotic cells. Autophagy participates in the oxidative stress response in many cells, which plays a protective role in preventing damage caused by oxidative stress. Recent studies have enrolled autophagy as an important regulator in limiting damage caused by UV light and lipid oxidation, keeping oxidative stress in a steady state in epidermal keratinocytes and maintaining normal proliferation and aging of melanocytes. Impairment of autophagy might disrupt the antioxidant defense system which renders melanocytes to oxidative insults. These findings provide supportive evidence to explore new ideas of the pathogenesis of vitiligo and other pigmentation disorders.

  1. Isolation, culture, and transfection of melanocytes.

    PubMed

    Godwin, Lauren S; Castle, Joanna T; Kohli, Jaskaren S; Goff, Philip S; Cairney, Claire J; Keith, W Nicol; Sviderskaya, Elena V; Bennett, Dorothy C

    2014-06-03

    Located in the basal epidermis and hair follicles, melanocytes of the integument are responsible for its coloration through production of melanin pigments. Melanin is produced in lysosomal-like organelles called melanosomes. In humans, this skin pigmentation acts as an ultraviolet radiation filter. Abnormalities in the division of melanocytes are quite common, with potentially oncogenic growth usually followed by cell senescence producing benign naevi (moles), or occasionally melanoma. Therefore, melanocytes are a useful model for studying melanoma, as well as pigmentation and organelle transport and the diseases affecting these mechanisms. This chapter focuses on the isolation, culture, and transfection of human and murine melanocytes. The first basic protocol describes the primary culture of melanocytes from human skin and the maintenance of growing cultures. The second basic protocol details the subculture and preparation of mouse keratinocyte feeder cells. The primary culture of melanocytes from mouse skin is described in the third basic protocol, and, lastly, the fourth basic protocol outlines a technique for transfecting melanocytes and melanoma cells.

  2. Hair follicle nevi and accessory tragi: variable quantity of adipose tissue in connective tissue framework.

    PubMed

    Ban, M; Kamiya, H; Yamada, T; Kitajima, Y

    1997-01-01

    Controversy exists about the histologic differences between hair follicle nevi and accessory tragi. We examined 10 congenital lesions histologically, possible diagnoses of which were hair follicle nevi or accessory tragi. Two specimens out of the 10 had tiny, mature hair follicles surrounded by thick fibrous root sheaths, a few fat cells, and no cartilage. The subcutaneous fat cells of their bases were segmented by a connective tissue framework. They had histologic features of hair follicle nevi. One specimen had cartilage and abundant fat cells with a connective tissue framework in the nodule, as well as a conglomeration of numerous well-differentiated hair follicles. It possessed both elements of a hair follicle nevus and an accessory tragus. Seven specimens had abundant subcutaneous fat and showed a prominent connective tissue framework. These were typical accessory tragi. The present study suggests that the number of fat cells in the nodule or papule differs between these two conditions. All the lesions studied revealed a connective tissue framework in the subcutaneous fat. Histologic features of both hair follicle nevi and accessory tragi can coexist in a single lesion. Hair follicle nevi may represent incomplete accessory tragi with scant fat cells.

  3. HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

    PubMed

    Damm, Sabine; Koefinger, Petra; Stefan, Martina; Wels, Christian; Mehes, Gabor; Richtig, Erika; Kerl, Helmut; Otte, Marcus; Schaider, Helmut

    2010-07-01

    The regulation of CD44v6, a variant of the CD44 family of glycosylated adhesion molecules, through hepatocyte growth factor (HGF) has implications for motility in primary human melanocytes. We show that exposure of primary human melanocytes to HGF results in an increase of CD44v6 expression. Immunostaining of melanocytic lesions revealed low cytoplasmic positivity of CD44v6 in some nevi but high membranous expression in primary cutaneous melanomas, and cutaneous and lymph node metastases. HGF-dependent CD44v6 regulation in melanocytes is NF-kappaB dependent because BAY 11-7082, an inhibitor of NF-kappaB activation, but not interference with the mitogen-activated protein kinase or phosphatidylinositol 3-kinase cascade, antagonized HGF-induced CD44v6 expression. NF-kappaB-mediated transcriptional regulation of CD44v6 involves the transcription factors Egr-1 and CCAAT enhancer-binding protein-beta (C/EBP-beta). In gel shift assays, the initial binding of p100/p52 NF-kappaB, C/EBP-beta, and Egr-1 to the CD44 promoter experienced reshuffling toward increased affinity of C/EBP-beta after HGF stimulation. A blocking antibody to CD44v6 decreased HGF-induced c-Met phosphorylation as well as enhanced random- and site-directed migration. Our data show that HGF-induced motility in primary human melanocytes depends on c-Met-CD44v6 interaction, and that HGF-enhanced CD44v6 expression is required for motility and transcriptional upregulation of CD44v6, presumably mediated through a complex comprising NF-kappaB/C/EBP-beta and Egr-1.

  4. "Melanocytic Nests Arising in Lichenoid Inflammation": Reappraisal of the Terminology "Melanocytic Pseudonests".

    PubMed

    Chung, Hye Jin; Simkin, A David; Bhawan, Jag; Wolpowitz, Deon

    2015-12-01

    Pseudonests or pseudomelanocytic nests represent aggregates of cells and cell fragments, including keratinocytes, macrophages, lymphocytes, and occasional melanocytes. Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Several reports documented nonspecific staining of pseudonests with melanoma antigen recognized by T cells-1/Melan-A, which can be detected in the cytoplasm of nonmelanocytic cells. In contrast, nuclear stains, such as MITF and SOX10, avoid this nonmelanocyte cytoplasmic staining. The authors have previously proposed the term melanocytic pseudonests to describe junctional nests with numerous (>2) true melanoma antigen recognized by T cells-1/Melan-A, SOX10, and MITF in a nonmelanocytic lesion with lichenoid inflammation (unilateral lichen planus pigmentosus/erythema dyschromicum perstans). In this study, the authors report another case of this phenomenon arising in a different lichenoid inflammatory dermatitis (lichen planus). The immunophenotype and number of clustered true melanocytes indicate that these dermoepidermal aggregates represent true melanocytic nests and not pseudonests of any type. Therefore, the authors propose the revised terminology of "melanocytic nests arising in lichenoid inflammation" to describe this novel pattern of benign melanocytic reorganization or proliferation in a subset of lichenoid dermatitides. Because this phenomenon can mimic atypical melanocytic proliferations, clinicopathologic correlation is essential for the correct diagnosis.

  5. Melanocytic Nests Arising in Lichenoid Inflammation”: Reappraisal of the Terminology “Melanocytic Pseudonests”

    PubMed Central

    Chung, Hye Jin; Simkin, A. David; Bhawan, Jag

    2015-01-01

    Abstract: Pseudonests or pseudomelanocytic nests represent aggregates of cells and cell fragments, including keratinocytes, macrophages, lymphocytes, and occasional melanocytes. Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Several reports documented nonspecific staining of pseudonests with melanoma antigen recognized by T cells-1/Melan-A, which can be detected in the cytoplasm of nonmelanocytic cells. In contrast, nuclear stains, such as MITF and SOX10, avoid this nonmelanocyte cytoplasmic staining. The authors have previously proposed the term melanocytic pseudonests to describe junctional nests with numerous (>2) true melanoma antigen recognized by T cells-1/Melan-A, SOX10, and MITF in a nonmelanocytic lesion with lichenoid inflammation (unilateral lichen planus pigmentosus/erythema dyschromicum perstans). In this study, the authors report another case of this phenomenon arising in a different lichenoid inflammatory dermatitis (lichen planus). The immunophenotype and number of clustered true melanocytes indicate that these dermoepidermal aggregates represent true melanocytic nests and not pseudonests of any type. Therefore, the authors propose the revised terminology of “melanocytic nests arising in lichenoid inflammation” to describe this novel pattern of benign melanocytic reorganization or proliferation in a subset of lichenoid dermatitides. Because this phenomenon can mimic atypical melanocytic proliferations, clinicopathologic correlation is essential for the correct diagnosis. PMID:26588340

  6. Non pigmented melanocytic nevus of the oral cavity: a case report with emphasis on the surgical excision procedures.

    PubMed

    Porrini, R; Valente, G; Colombo, E; Cannas, M; Sabbatini, M

    2013-01-01

    We report a case of a 37-year-old caucasian woman presenting a 1 cm pinkish nodular asymptomatic lesion of the hard palate, slowly growing in the last years. The lesion underwent to biopsy. Histological analysis showed the nevus tissue layered under a continuous squamous epithelium. The stroma contained nests of medium-sized round cells, with regular monomorphous nuclei. The nevus cells were immunohistochemically positive for S-100 protein, while melanin, visualized by Masson-Fontana silver staining, was absent. Therefore a diagnosis of non pigmented melanocytic nevus was formulated. Because of its rarity and to avoid any risk of malignant transformation, a surgical treatment with wide excision was chosen; the surgical wound was previously covered with a membrane of fibrin and autologous platelets, and subsequently sutured, resulting in a total heal. This procedure seems to be the most reliable to approach melanocytic lesions of the oral cavity. Clinical diagnosis of non-pigmented nevi, either flat or protruding, is difficult, because the nevus shows a pinkish colour that is indistinguishable from that of the surrounding mucosa. Moreover, attention is required when similar clinical evidence occurs, because the localization inside the oral cavity may offer several problems of differential diagnosis.

  7. Nuclear to non-nuclear Pmel17/gp100 expression (HMB45 staining) as a discriminator between benign and malignant melanocytic lesions.

    PubMed

    Rothberg, Bonnie E Gould; Moeder, Christopher B; Kluger, Harriet; Halaban, Ruth; Elder, David E; Murphy, George F; Lazar, Alexander; Prieto, Victor; Duncan, Lynn McDivitt; Rimm, David L

    2008-09-01

    HMB45 is a mouse monoclonal antibody raised against Pmel17/gp100, a melanoma-specific marker, which is routinely used in the diagnosis of primary cutaneous malignant melanoma. The standard expression pattern for a positive HMB45 staining result on immunohistochemistry is based upon the results of chromogenic-based methods. We re-evaluated the patterns of HMB45 staining across the 480-core 'SPORE melanoma progression array' containing lesions representing the spectrum of melanocytic lesions ranging from thin nevus to visceral metastasis using the fluorescence-based staining technique and automated quantitative analysis (AQUA) of the obtained digital images. The methods validated the expected cytoplasmic HMB45 staining pattern in 70/108 malignant lesions and in the epithelial components of nevus specimens. However, the fluorescence-based approach revealed a nuclear gp100 localization present in the dermal component of all nevi that was not seen before. This nuclear localization could not be observed on routine chromogenic stains, because the standard hematoxylin nuclear counterstain overwhelms the weak nuclear HMB45 stain. The thin (0.450+/-0.253) and thick (0.513+/-0.227) nevi had strongly positive mean ln(nuclear/non-nuclear AQUA score ratios), which are significantly higher than those from the group of malignant lesions (P<0.0001). This finding was reproduced on a smaller but independent progression array composed of nevi and melanomas from the Yale Pathology archives (P<0.01). The odds ratio associated with a sample being a nevus was 2.24 (95% CI: 1.87-2.69, P<0.0001) for each 0.1 unit increase of the ln(nuclear/non-nuclear AQUA score ratio) to yield an ROC curve with 0.93 units of area and a simultaneously maximized sensitivity of 0.92 and specificity of 0.80 for distinguishing benign nevi from malignant melanomas. On the basis of this preliminary study, we propose that the ratio of nuclear to non-nuclear HMB45 staining may be useful for diagnostic challenges in

  8. Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall.

    PubMed

    Nguyen, Thuy L T; Theos, Amy; Kelly, David R; Busam, Klaus; Andea, Aleodor A

    2013-02-01

    Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result.

  9. Links between Schwann cells and melanocytes in development and disease.

    PubMed

    Van Raamsdonk, Catherine D; Deo, Mugdha

    2013-09-01

    Melanocytes are pigment-producing cells that reside in the skin, eyes, ears, heart, and central nervous system meninges of mammals. Schwann cells are glial cells, which closely associate with peripheral nerves, myelinating, and sheathing them. Melanocytes and Schwann cells both arise from the neural crest during development, and some melanocytes arise directly from Schwann cell precursors lining developing spinal nerves. In this review, we explore the connections between melanocytes and Schwann cells in development and transformation.

  10. Treatment of nasal ala nodular congenital melanocytic naevus with carbon dioxide laser and Q-switched Nd:YAG laser.

    PubMed

    Zeng, Ying; Ji, Chenyang; Zhan, Kui; Weng, Weili

    2016-11-01

    Total excision of congenital melanocytic nevi (CMN) is not always feasible. We here present our experience of using carbon dioxide laser and Q-switched neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser to treat nodular CMN of the nasal ala. Q-switched Nd:YAG laser and/or carbon dioxide laser were used to treat eight cases of nasal ala nodular CMN. Carbon dioxide laser was utilized to ablate all visible melanocytic tissue within one session. Ablation was performed so as to reproduce the original anatomical contours as closely as possible. Recurrences were treated in the same way. Q-switched Nd:YAG laser was also used to irradiate all target lesions to achieve the desired end point within one session. The intervals between treatments were at least 8 weeks. Recurrence of melanocytic tissue, scar formation, pigmentation, depigmentation, and the degree of patient satisfaction were recorded at every visit. Two of the eight patients were treated with Q-switched Nd:YAG laser. Although, the lesion lightened in one of them, the hyperplastic tissue persisted. Eventually, these two patients, along with the remaining six patients, were successfully treated with a carbon dioxide laser. We recommend carbon dioxide laser treatment for nodular nasal CMN. This simple treatment does not involve skin flap transplantation and has good cosmetic outcomes. Although Q-switched Nd:YAG laser does lighten some nasal nodular CMNs, it does not eradicate the hyperplastic tissue, and is therefore not an effective treatment for nodular nasal CMN.

  11. Vulnerability Assessment of Selected Buildings Designated as Shelters: St. Kitts--Nevis.

    ERIC Educational Resources Information Center

    Gibbs, Tony

    Educational facilities in the Caribbean often serve roles as shelters during natural hazards, but they often sustain as much damage as other buildings. This study investigated the physical vulnerability of schools located on St. Kitts and Nevis to wind forces, torrential rain, and seismic forces in order to provide relevant local agencies with…

  12. UV light phototransduction depolarizes human melanocytes.

    PubMed

    Bellono, Nicholas W; Oancea, Elena

    2013-01-01

    Exposure of human skin to low doses of solar UV radiation (UVR) causes increased pigmentation, while chronic exposure is a powerful risk factor for skin cancers. The mechanisms mediating UVR detection in skin, however, remain poorly understood. Our recent studies revealed that UVR activates a retinal-dependent G protein-coupled signaling pathway in melanocytes. This phototransduction pathway leads to the activation of transient receptor potential A1 (TRPA1) ion channels, elevation of intracellular calcium (Ca( 2+)) and rapid increase in cellular melanin content. Here we report that physiological doses of solar-like UVR elicit a retinal-dependent membrane depolarization in human epidermal melanocytes. This transient depolarization correlates with delayed inactivation time of the UVR-evoked photocurrent and with sustained Ca( 2+) responses required for early melanin synthesis. Thus, the cellular depolarization induced by UVR phototransduction in melanocytes is likely to be a critical signaling mechanism necessary for the protective response represented by increased melanin content.

  13. Congenital Melanocytic Nevus Syndrome: A Case Series.

    PubMed

    Recio, A; Sánchez-Moya, A I; Félix, V; Campos, Y

    2017-01-19

    Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies.

  14. Near-infrared reflectance and autofluorescence imaging characteristics of choroidal nevi.

    PubMed

    Vallabh, N A; Sahni, J N; Parkes, C K; Czanner, G; Heimann, H; Damato, B

    2016-12-01

    PurposeTo report near-infrared reflectance (NIR-R), near-infrared autofluorescence (NIR-AF) and blue wave autofluorescence (BW-AF) appearance of choroidal nevi using a confocal scanning laser ophthalmoscope (cSLO).Patients and methodsNIR-R, NIR-AF and BW-AF images of choroidal nevi were compared with color fundus photos (CF). Images were graded as hyperreflective if reflectance was much greater than background, hyporeflective if less than background, and isoreflective if the same as the background.ResultsForty-two nevi of 39 patients were imaged. When compared with CF, nevi could be identified on 95% (40/42) NIR-R images (95% CI: 83.5-99.3). On NIR-R 71% (30/42) demonstrated hyperreflectance and 24% (10/42) were hyporeflective. Hyperreflectivity was demonstrated in 96% (23/24) of NIR-AF images (95% CI: 79.1-99.9) and 34% (14/41) of BW-AF images (95% CI: 20.0-50.5). On NIR-R, 29/40 (73%) were apparently smaller in comparison with CF and 11/40 (28%) had the same area. A correlation was found between NIR-R and NIR-AF (P=0.02) but not with BW-AF (P=0.15).ConclusionsNevi can be visualized well using NIR-R and NIR-AF imaging modalities, but are less frequently visible using BW-AF. These changes may be related to melanin within the choroid or chronic changes of the overlying retinal pigment epithelium.

  15. A Mosquito Survey of the Twin-Island Caribbean Nation of Saint Kitts and Nevis, 2010.

    PubMed

    Mohammed, Hamish; Evanson, Jessica; Revan, Floyd; Lee, Elise; Krecek, Rosina C; Smith, Joshua

    2015-12-01

    Adult mosquito surveys of Saint Kitts and Nevis (SKN) were performed in the dry season (March 16-23, 2010) in Saint Kitts, and the rainy season (October 18-25, 2010) in SKN. Biogents (BG) Sentinel Traps were set with CO₂and BG Lure in urban, rural, mangrove, and dry forest habitats. Mosquitoes were identified to species, and reverse transcription-polymerase chain reaction was performed on potential vector species for dengue virus (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV). The most abundant species during both seasons in St. Kitts were Culex quinquefasciatus, Aedes taeniorhynchus, and Aedes aegypti. There were 3 new records for Saint Kitts: Aedes tortilis, Anopheles albimanus, and Culex nigripalpus. Traps were also set in Nevis. No mosquito pool tested positive for DENV, CHIKV, or WNV.

  16. Study of Nevi in Children (SONIC): baseline findings and predictors of nevus count.

    PubMed

    Oliveria, Susan A; Satagopan, Jaya M; Geller, Alan C; Dusza, Stephen W; Weinstock, Martin A; Berwick, Marianne; Bishop, Marilyn; Heneghan, Maureen K; Halpern, Allan C

    2009-01-01

    The authors report baseline findings and predictors of nevus count (log total nevi) at the completion of year 1 (2004) of the first known population-based, prospective study of nevi in a US cohort of children. Overall, 64% (n = 443/691) of grade 5 students and their parents in Framingham, Massachusetts, completed surveys and underwent digital photography. Total nevus count was associated with skin and hair color and tendency to burn, as measured by a sun sensitivity index. In multivariate analyses, male gender (rate ratio (RR) = 1.38, 95% confidence interval (CI): 1.22, 1.55; P < 0.0001), spending 5-6 weekly hours outdoors between 10 AM and 4 PM (RR = 1.13, 95% CI: 1.00, 1.28; P = 0.051), getting a painful sunburn once (RR = 1.24, 95% CI: 0.98, 1.57; P = 0.073) and at least twice (RR = 1.34, 95% CI: 0.99, 1.82; P = 0.061), and wearing a shirt at the beach or pool rarely (RR = 1.29, 95% CI: 1.08, 1.54; P = 0.005), sometimes (RR = 1.26, 95% CI: 1.01, 1.57; P = 0.041), and often and always (RR = 1.32, 95% CI: 1.13, 1.54; P = 0.001) were associated with increased number of nevi. Identifying factors that predict the development of nevi will improve primary prevention efforts during early life.

  17. Immunohistochemical study of melanocyte-melanocyte stem cell lineage in vitiligo; a clue to interfollicular melanocyte stem cell reservoir.

    PubMed

    Seleit, Iman; Bakry, Ola Ahmed; Abdou, Asmaa Gaber; Dawoud, Noha Mohammed

    2014-05-01

    There has been a long lasting controversy over whether melanocytes (MCs) in vitiligo are actually lost or still present but functionally inactive. We aimed to evaluate the MC cell lineage in follicular and interfollicular vitiliginous epidermis through immunohistochemical localization of Human Melanoma Black-45 (HMB-45) and Tyrosinase Related Protein 2 (TRP2) and to correlate it with clinicopathologic parameters. Using immunohistochemical techniques, skin biopsies from 50 vitiligo patients and 20 age- and gender-matched healthy subjects were examined. Differentiated active MCs were detected in 44% of interfollicular epidermis (IFE) and 46.7% of follicular epidermis (FE) in lesional skin. Melanocyte precursors/stem cells were detected in 54% of IFE and 63.3% of FE in lesional skin. Melanocyte precursors/stem cells of IFE were significantly associated with residual melanin pigment (p = 0.007) and with absence of angiogenesis (p = 0.05). HMB-45 percentage of expression in IFE was positively correlated with MC precursors/stem cells percentage in FE (r = +0.65, p < 0.001) and IFE (r = +0.33, p = 0.01). Melanocyte precursors/stem cells positivity (p < 0.001) was progressively decreasing with advanced histopathologic grading. There was no significant association between interfollicular or follicular expression of HMB-45, TRP2 or MC precursors/stem cells and the clinical type of vitiligo or its duration. In conclusion, functioning MCs may exist in vitiligo. The presence of MC precursors/stem cells in IFE may provide an additional reservoir needed for repigmentation.

  18. Apoptosis of melanocytes in vitiligo results from antibody penetration.

    PubMed

    Ruiz-Argüelles, Alejandro; Brito, Gustavo Jiménez; Reyes-Izquierdo, Paola; Pérez-Romano, Beatriz; Sánchez-Sosa, Sergio

    2007-12-01

    Vitiligo is a rather common disease characterized by depigmentation of skin and mucosae due to the loss of melanocytes, most likely as a result of autoimmune phenomena. In this study we demonstrated apoptotic markers in residual melanocytes in skin biopsies of patients with vitiligo, as well as the presence of serum antibodies to melanocyte-specific antigens in the vast majority of patients. Moreover, we were able to prove that serum IgG antibodies from vitiligo patients, but not from healthy controls, were capable to penetrate into cultured melanocytes in vitro, and trigger them to engage in apoptosis. Our results are consonant with the theory that melanocyte-specific antibodies are responsible for the deletion of melanocytes through antibody penetration and apoptosis.

  19. Growth of melanocytes in human epidermal cell cultures

    SciTech Connect

    Staiano-Coico, L.; Hefton, J.M.; Amadeo, C.; Pagan-Charry, I.; Madden, M.R.; Cardon-Cardo, C. )

    1990-08-01

    Epidermal cell cultures were grown in keratinocyte-conditioned medium for use as burn wound grafts; the melanocyte composition of the grafts was studied under a variety of conditions. Melanocytes were identified by immunohistochemistry based on a monoclonal antibody (MEL-5) that has previously been shown to react specifically with melanocytes. During the first 7 days of growth in primary culture, the total number of melanocytes in the epidermal cultures decreased to 10% of the number present in normal skin. Beginning on day 2 of culture, bipolar melanocytes were present at a mean cell density of 116 +/- 2/mm2; the keratinocyte to melanocyte ratio was preserved during further primary culture and through three subpassages. Moreover, exposure of cultures to mild UVB irradiation stimulated the melanocytes to proliferate, suggesting that the melanocytes growing in culture maintained their responsiveness to external stimuli. When the sheets of cultured cells were enzymatically detached from the plastic culture flasks before grafting, melanocytes remained in the basal layer of cells as part of the graft applied to the patient.

  20. A unique opportunity to reconstruct the volcanic history of the island of Nevis, Lesser Antilles

    NASA Astrophysics Data System (ADS)

    Saginor, I.; Gazel, E.

    2012-12-01

    We report twelve new ICP-MS analyses and two 40Ar/39Ar ages for the Caribbean island of Nevis, located in the Lesser Antilles. These data show a very strong fractionation trend, suggesting that along strike variations may be primarily controlled by the interaction of rising magma with the upper plate. If this fractionation trend is shown to correlate with age, it may suggest that underplating of the crust is responsible for variations in the makeup of erupted lava over time, particularly with respect to silica content. We have recently been given permission to sample a series of cores being drilled by a geothermal company with the goal of reconstructing the volcanic history of the island. Drilling is often cost-prohibitive, making this a truly unique opportunity. Nevis has received little recent attention from researchers due to the fact that it has not been active for at least 100,000 years and also because of its proximity to the highly active Montserrat, which boasts its very own volcano observatory. However, there are a number of good reasons that make this region and Nevis in particular an ideal location for further analysis. First, and most importantly, is the access to thousands of meters of drill cores that is being provided by a local geothermal company. Second, a robust earthquake catalog exists (Bengoubou-Valerius et al., 2008), so the dip and depth to the subducting slab is well known. These are fundamental parameters that influence the mechanics of a subduction zone, therefore it would be difficult to proceed if they were poorly constrained. Third, prior sampling of Nevis has been limited since Hutton and Nockolds (1978) published the only extensive petrologic study ever performed on the island. This paper contained only 43 geochemical analyses and 6 K-Ar ages, which are less reliable than more modern Ar-Ar ages. Subsequent studies tended to focus on water geochemistry (GeothermEx, 2005), geothermal potential (Geotermica Italiana, 1992; Huttrer, 1998

  1. Evaluation of electrical impedance spectroscopy as an adjunct to dermoscopy in short-term monitoring of atypical melanocytic lesions

    PubMed Central

    Ceder, Hannah; Hylén, Alexandra Sjöholm; Larkö, Ann-Marie Wennberg; Paoli, John

    2016-01-01

    Background Early detection of melanoma is vital for treatment outcome and survival. Short-term sequential digital dermoscopic monitoring (ST-SDDM) involves the capture and assessment of dermoscopic images of one or more atypical melanocytic lesions (AMLs), at baseline and after four months, in order to detect early morphologic changes. Electrical impedance spectroscopy (EIS) is a diagnostic tool with high sensitivity for the detection of malignant melanocytic lesions. Objectives The aim of this study was to assess whether EIS, in addition to ST-SDDM, could improve the selection of AMLs requiring surgery. Methods In this retrospective descriptive study, 22 AMLs in 19 patients were monitored with both ST-SDDM and EIS. A modified EIS decision-making algorithm was established. AMLs were excised if any dermoscopic changes were seen and/or if the EIS score had increased significantly at follow-up. Statistical analyses were made including sensitivity, specificity, PPV and NPV. Results A total of seven lesions (32%) were excised. Four lesions (57%) were excised solely because of dermoscopic changes including a 0.4 mm-thick melanoma and three benign nevi. Three benign lesions (43%) were excised because of increased EIS scores without any dermoscopic changes. The EIS scores at follow-up showed high variability as compared to the initial scores. Conclusion The addition of EIS to ST-SDDM did not identify additional malignant lesions. There was no correlation between dermoscopic changes seen with ST-SDDM and increased EIS scores. Three histopathologically benign lesions were needlessly excised. Moreover, the low reproducibility and the possible interoperator variability of the method raised concerns. PMID:27867738

  2. In vitro dedifferentiation of melanocytes from adult epidermis.

    PubMed

    Kormos, Bernadett; Belso, Nóra; Bebes, Attila; Szabad, Gábor; Bacsa, Sarolta; Széll, Márta; Kemény, Lajos; Bata-Csörgo, Zsuzsanna

    2011-02-23

    In previous work we described a novel culture technique using a cholera toxin and PMA-free medium (Mel-mix) for obtaining pure melanocyte cultures from human adult epidermis. In Mel-mix medium the cultured melanocytes are bipolar, unpigmented and highly proliferative. Further characterization of the cultured melanocytes revealed the disappearance of c-Kit and TRP-1 and induction of nestin expression, indicating that melanocytes dedifferentiated in this in vitro culture. Cholera toxin and PMA were able to induce c-Kit and TRP-1 protein expressions in the cells, reversing dedifferentiation. TRP-1 mRNA expression was induced in dedifferentiated melanocytes by UV-B irradiated keratinocyte supernatants, however direct UV-B irradiation of the cells resulted in further decrease of TRP-1 mRNA expression. These dedifferentiated, easily accessible cultured melanocytes provide a good model for studying melanocyte differentiation and possibly transdifferentiation. Because melanocytes in Mel-mix medium can be cultured with human serum as the only supplement, this culture system is also suitable for autologous cell transplantation.

  3. Meningeal Melanocytes in the Mouse: Distribution and Dependence on Mitf

    PubMed Central

    Gudjohnsen, Stefán A. H.; Atacho, Diahann A. M.; Gesbert, Franck; Raposo, Graca; Hurbain, Ilse; Larue, Lionel; Steingrimsson, Eirikur; Petersen, Petur Henry

    2015-01-01

    Summary: Melanocytes are pigment producing cells derived from the neural crest. They are primarily found in the skin and hair follicles, but can also be found in other tissues including the eye, ear and heart. Here, we describe the distribution of pigmented cells in C57BL/6J mouse meninges, the membranes that envelope the brain. These cells contain melanosomes of all four stages of development and they depend on Microphthalmia associated transcription factor (MITF), the master regulator of melanocyte development, suggesting that they are bona-fide melanocytes. The location of these pigmented cells is consistent with the location of meningeal melanomas in humans and animal models. Significance: Here, we document and define pigmented cells in the meninges of the mouse brain and confirm that they are melanocytes. This is important for understanding the role of this cell type and for understanding primary meningeal melanoma, a rare disease that likely arises from normal meningeal melanocytes. PMID:26635543

  4. Exosomes released by keratinocytes modulate melanocyte pigmentation

    PubMed Central

    Cicero, Alessandra Lo; Delevoye, Cédric; Gilles-Marsens, Floriane; Loew, Damarys; Dingli, Florent; Guéré, Christelle; André, Nathalie; Vié, Katell; van Niel, Guillaume; Raposo, Graça

    2015-01-01

    Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states. PMID:26103923

  5. Exosomes released by keratinocytes modulate melanocyte pigmentation.

    PubMed

    Lo Cicero, Alessandra; Delevoye, Cédric; Gilles-Marsens, Floriane; Loew, Damarys; Dingli, Florent; Guéré, Christelle; André, Nathalie; Vié, Katell; van Niel, Guillaume; Raposo, Graça

    2015-06-24

    Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states.

  6. Cytoskeleton alterations in melanoma: aberrant expression of cortactin, an actin-binding adapter protein, correlates with melanocytic tumor progression

    PubMed Central

    Xu, Xu-Zhi; Garcia, Marileila Varella; Li, Tian-yu; Khor, Li-Yan; Gajapathy, R Sujatha; Spittle, Cindy; Weed, Scott; Lessin, Stuart R; Wu, Hong

    2010-01-01

    Cortactin is a multidomain actin-binding protein important for the functions of cytoskeleton by regulating cortical actin dynamics. It is involved in a diverse array of basic cellular functions. Tumorigenesis and tumor progression involves alterations in actin cytoskeleton proteins. We sought to study the role of cortactin in melanocytic tumor progression using immunohistochemistry on human tissues. The results reveal quantitative differences between benign and malignant lesions. Significantly higher cortactin expression is found in melanomas than in nevi (P<0.0001), with levels greater in metastatic than in invasive melanomas (P<0.05). Qualitatively, tumor tissues often show aberrant cortactin localization at the cell periphery, corresponding to its colocalization with filamentous actin in cell cortex of cultured melanoma cells. This suggests an additional level of protein dysregulation. Furthermore, in patients with metastatic disease, high-level cortactin expression correlates with poor disease-specific survival. Our data, in conjunction with outcome data on several other types of human cancers and experimental data from melanoma cell lines, supports a potential role of aberrant cortactin expression in melanoma tumor progression and a rational for targeting key elements of actin-signaling pathway for developmental therapeutics in melanomas. PMID:19898426

  7. Effects of hydroxybenzyl alcohols on melanogenesis in melanocyte-keratinocyte co-culture and monolayer culture of melanocytes.

    PubMed

    Liu, Szu-Hsiu; Chu, I-Ming; Pan, I-Horng

    2008-08-01

    In mammalian skin, melanocyte proliferation and melanogenesis can be stimulated by keratinocytes, fibroblasts and other regulatory factors. To determine whether hydroxybenzyl alcohols (HBAs) show more inhibitory in melanocytes cultured alone or in melanocytes co-cultured with keratinocytes, we developed a murine melanocyte-keratinocyte co-culture model to investigate the pigmentation regulators in company with other melanogenic inhibitors and stimulators. It was found that the effects of HBAs and melanogenic factors were more evident in melanocytes co-cultured with keratinocytes. Keratinocytes may play a synergistic role in melanocyte melanogenesis and influence the pigment production. The tests in the co-culture model also imply that the inhibitory effects of HBAs on melanogenesis are due to the direct inhibition of melanosomal tyrosinase activity. HBAs showed a low cytotoxicity. The eventual results proved that HBAs are promising and safe agents for skin whitening in melanocyte alone and in co-culture systems. The co-culture model provides a more physiologically realistic condition to study the interaction between melanocytes and keratinocytes, which enables a reliable screening system for depigmenting compounds.

  8. [Iris heterochromia in acquired Horner's syndrome].

    PubMed

    Beynat, J; Soichot, P; Bidot, S; Dugas, B; Creuzot-Garcher, C; Bron, A

    2007-09-01

    Horner's syndrome (HS) is related to an interruption of the oculosympathetic nerve pathway. The classic clinical findings associated with this condition are ptosis, miosis, and enophthalmos. Heterochromia is typically described in congenital HS, but it is an uncommon finding in acquired HS. We report a case of post-traumatic HS associated with heterochromia. A literature review indicates that this type of heterochromia may be related to a reduction in the number of iris melanocytes. This mechanism may be the same in the physiological iris color modifications in adulthood.

  9. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  10. Positive and negative elements regulate a melanocyte-specific promoter.

    PubMed Central

    Lowings, P; Yavuzer, U; Goding, C R

    1992-01-01

    Melanocytes are specialized cells residing in the hair follicles, the eye, and the basal layer of the human epidermis whose primary function is the production of the pigment melanin, giving rise to skin, hair, and eye color. Melanogenesis, a process unique to melanocytes that involves the processing of tyrosine by a number of melanocyte-specific enzymes, including tyrosinase and tyrosinase-related protein 1 (TRP-1), occurs only after differentiation from the melanocyte precursor, the melanoblast. In humans, melanogenesis is inducible by UV irradiation, with melanin being transferred from the melanocyte in the epidermis to the surrounding keratinocytes as protection from UV-induced damage. Excessive exposure to UV, however, is the primary cause of malignant melanoma, an increasingly common and highly aggressive disease. As an initial approach to understanding the regulation of melanocyte differentiation and melanocyte-specific transcription, we have isolated the gene encoding TRP-1 and examined the cis- and trans-acting factors required for cell-type-specific expression. We find that the TRP-1 promoter comprises both positive and negative regulatory elements which confer efficient expression in a TRP-1-expressing, pigmented melanoma cell line but not in NIH 3T3 or JEG3 cells and that a minimal promoter extending between -44 and +107 is sufficient for cell-type-specific expression. Assays for DNA-protein interactions coupled with extensive mutagenesis identified three factors, whose binding correlated with the function of two positive and one negative regulatory element. One of these factors, termed M-box-binding factor 1, binds to an 11-bp motif, the M box, which acts as a positive regulatory element both in TRP-1-expressing and -nonexpressing cell lines, despite being entirely conserved between the melanocyte-specific tyrosinase and TRP-1 promoters. The possible mechanisms underlying melanocyte-specific gene expression are discussed. Images PMID:1321344

  11. Multiple roles of NF1 in the melanocyte lineage.

    PubMed

    Larribère, Lionel; Utikal, Jochen

    2016-07-01

    NF1 is a tumour suppressor gene, germline mutations of which lead to neurofibromatosis type 1 syndrome. Patients develop benign tumours from several types of cells including neural crest-derived cells. NF1 somatic mutations also occur in 15% of sporadic melanoma, a cancer originating from melanocytes. Evidence now suggests the involvement of NF1 mutations in melanoma resistance to targeted therapies. Although NF1 is ubiquitously expressed, genetic links between NF1 and genes involved in melanocyte biology have been described, implying the lineage-specific mechanisms. In this review, we summarize and discuss the latest advances related to the roles of NF1 in melanocyte biology and in cutaneous melanoma.

  12. Comparative Study of Efficacy of Epidermal Melanocyte Transfer Versus Hair Follicular Melanocyte Transfer in Stable Vitiligo

    PubMed Central

    Donaparthi, Navya; Chopra, Ajay

    2016-01-01

    Background: Vitiligo surgery has come up a long way from punch skin grafts to epidermal cell suspension and latest to the extracted hair follicle outer root sheath cell suspension (EHFORSCS) transplantation. The progressive development from one technique to the other is always on a quest for the best. In the latest development, EHFORSCS, which is an enriched source of follicular inactive melanocyte (melanocyte stem cells), seems to be a good addition to the prevailing cell-based therapies for vitiligo. However, it needs to be explored further in larger, clinical trials. Methodology: A total of 11 patients with sixty stable vitiligo sites attending dermatology outpatient department were included for the open-labeled, prospective, comparative study. The sites were sequentially distributed into two groups of thirty each. Sites of one group were subjected to epidermal melanocyte transfer (EMT) and the others to hair follicular melanocyte transfer (HFMT). Response to treatment was evaluated on the basis of degree of repigmentation; final evaluation of area of involvement was done after completion of 6 months. Results: At the end of 6 months, repigmentation >90% was observed in 83.33% patches of EMT group and 43.33% in HFMT group. Repigmentation >75% was observed in 90% of patches in Group A and 43.34% of patches in Group B, respectively. There was statistically significant difference in the overall pigmentation between these two groups. Conclusion: Both noncultured autologous epidermal cell suspension transfer and noncultured EHFORSCS transfer are safe and effective surgical modalities in the management of stable vitiligo though EMT has shown a better response in the present study. Outer root sheath cell suspension transfer is a novel, minimally invasive technique in its nascent stage in the surgical management of vitiligo which requires further larger clinical trials for evaluation of its efficacy. PMID:27904182

  13. Cutaneous malignant melanoma arising in an acquired naevus of Ota.

    PubMed

    Patterson, Clare R S; Acland, Katharine; Khooshabeh, Ramona

    2009-11-01

    Naevus of Ota is a dermal melanocytosis most commonly found in black or Asian skin and is usually a benign malformation, but with a low risk of melanoma. We describe a 32-year-old Caucasian man with an acquired naevus of Ota with subtle pigmentation, in which a melanocytic papule developed. The lesion, deceptively, had no clinically suspicious features, but investigation revealed an aggressive cutaneous malignant melanoma, extensive orbital ring melanocytosis and metastatic brain and subsequent liver disease.

  14. Situation Report--Burma, Chile, German Democratic Republic, Indonesia, Jamaica, Poland, Singapore, St. Christopher/Nevis, Trinidad & Tobago, Venezuela.

    ERIC Educational Resources Information Center

    International Planned Parenthood Federation, London (England).

    Data relating to population and family planning in ten foreign countries are presented in these situation reports. Countries included are Burma, Chile, German Democratic Republic, Indonesia, Jamaica, Poland, Singapore, St. Christopher/Nevis, Trinidad and Tobago, and Venezuela. Information is provided, where appropriate and available, under two…

  15. Moles (Nevi)

    MedlinePlus

    ... Us Media contacts Advertising contacts AAD logo Advertising, marketing and sponsorships Legal notice Copyright © 2017 American Academy ... prohibited without prior written permission. AAD logo Advertising, marketing and sponsorships Legal notice Copyright © 2017 American Academy ...

  16. Radioimmunoassay for. gamma. -melanocyte stimulating hormone

    SciTech Connect

    Shibasaki, T.; Ling, N.; Guillemin, R.

    1980-05-26

    A specific radioimmunoassay for ..gamma..-melanocyte stimulating hormone-like peptides was developed. An antiserum raised in rabbit to synthetic bovine ..gamma../sub 3/-MSH, one of the possible ..gamma..-MSH peptides, specifically recognizes the portion between His/sup 5/ and Arg/sup 14/ of ..gamma../sub 3/-MSH without significant cross-reaction with other synthetic ..gamma..-MSH-like peptides, ..cap alpha..-, ..beta..-MSH, adrenocorticotropin, and ..beta..-endorphin. The usable range of this RIA is 10 pg to 600 pg of synthetic ..gamma../sub 3/-MSH. Three immunoreactive ..gamma..-MSH peaks were thus found in gel permeation chromatography of the whole bovine pituitary extract.

  17. Congenital melanocytic nevus: two clinicopathological forms.

    PubMed

    Magaña, Mario; Sánchez-Romero, Elizabeth; Magaña, Pablo; Beck-Magaña, Andrés; Magaña-Lozano, Mario

    2015-01-01

    Congenital melanocytic nevus (CMN) is a hamartomatous disease for which many attempts at classification have been proposed. This disease is relevant not only because of its functional and esthetic implications but also because it is a well-documented precursor to malignant melanoma. We performed a clinical and pathological prospective study of 200 cases of CMN and were able to identify 2 different forms of CMN, each one with biological, clinical, and histopathological features and criteria that are consistent and repeatable. We propose to name them types I and II. Type I CMN is the most common, usually, if not always, a single lesion, it consists of a plaque that involves only 1 anatomic region and does not go beyond it; type I CNM grows in proportion to the growth of the child, melanoma rarely develops from it, and when it does it usually arises at the dermoepidermal junction. Its histopathology shows cords, strands, nests, and single units of melanocytes spreading between collagen bundles only in the dermis and frequently the epidermis too, but without trespassing to the hypodermis, that is, it is superficial. Type II CMN is always made up of many lesions, one of them being very large and surrounded by many lesions; histopathologically, it involves not only the skin but also deeper structures, sometimes bone and central nervous system; therefore, it is deep; when melanoma develops, it does in the dermal component and usually from the largest plaque. This type of CMN is the one that develops neurocutaneous melanocytosis. This system is not only easy and logical but it also has biologic advantages and the clinical-pathological correlation and criteria are repeatable by clinicians and pathologists.

  18. Monitoring human melanocytic cell responses to piperine using multispectral imaging

    NASA Astrophysics Data System (ADS)

    Samatham, Ravikant; Phillips, Kevin G.; Sonka, Julia; Yelma, Aznegashe; Reddy, Neha; Vanka, Meenakshi; Thuillier, Philippe; Soumyanath, Amala; Jacques, Steven

    2011-03-01

    Vitiligo is a depigmentary disease characterized by melanocyte loss attributed most commonly to autoimmune mechanisms. Currently vitiligo has a high incidence (1% worldwide) but a poor set of treatment options. Piperine, a compound found in black pepper, is a potential treatment for the depigmentary skin disease vitiligo, due to its ability to stimulate mouse epidermal melanocyte proliferation in vitro and in vivo. The present study investigates the use of multispectral imaging and an image processing technique based on local contrast to quantify the stimulatory effects of piperine on human melanocyte proliferation in reconstructed epidermis. We demonstrate the ability of the imaging method to quantify increased pigmentation in response to piperine treatment. The quantization of melanocyte stimulation by the proposed imaging technique illustrates the potential use of this technology to quickly assess therapeutic responses of vitiligo tissue culture models to treatment non-invasively.

  19. Immunohistochemical diagnosis of canine oral amelanotic melanocytic neoplasms.

    PubMed

    Smedley, R C; Lamoureux, J; Sledge, D G; Kiupel, M

    2011-01-01

    Definitive diagnosis of canine oral melanocytic neoplasms is often difficult because of variability in pigmentation and cellular pleomorphism. These neoplasms can resemble carcinomas, sarcomas, and round cell neoplasms, which differ in prognosis and treatment. A variety of immunohistochemical antibodies have been used for diagnosis of melanocytic neoplasms in humans and dogs; however, sensitivity and specificity of many markers have not been determined in amelanotic melanocytic neoplasms in dogs. The authors investigated a comprehensive panel of immunohistochemical markers in 49 canine oral amelanotic melanocytic neoplasms--namely, Melan-A, PNL2, HMB-45, microphthalmia transcription factor (MiTF), S-100, tyrosine hydroxylase, tyrosinase, tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2), and CD34. Ten well-differentiated cutaneous soft tissue spindle cell sarcomas were negative controls. Melan-A, PNL2, TRP-1, and TRP-2 were highly sensitive and 100% specific for the diagnosis of canine oral amelanotic melanocytic neoplasms. S-100 and MiTF showed high sensitivity but were less specific; that is, they also labeled a proportion of the soft tissue spindle cell sarcomas. HMB-45, tyrosinase, and tyrosine hydroxylase were 100% specific but had low sensitivities. CD34 did not label any of the melanocytic neoplasms but did label 80% of the soft tissue spindle cell sarcomas. A cost-effective and efficient immunodiagnostic cocktail containing antibodies against PNL2, Melan-A, TRP-1, and TRP-2 was created that had 100% specificity and 93.9% sensitivity in identifying canine oral amelanotic melanocytic neoplasms. The spindloid variant was the variant with the lowest sensitivity to the cocktail. The likelihood of correctly diagnosing canine oral amelanotic melanocytic neoplasms was dramatically higher when biopsy samples contained ample overlying and adjacent epithelium.

  20. Distinctive molecular responses to ultraviolet radiation between keratinocytes and melanocytes

    PubMed Central

    Sun, Xiaoyun; Kim, Arianna; Nakatani, Masashi; Shen, Yao; Liu, Liang

    2017-01-01

    Solar ultraviolet radiation (UVR) is the major risk factor for skin carcinogenesis. To gain new insights into the molecular pathways mediating UVR effects in the skin, we performed comprehensive transcriptomic analyses to identify shared and distinctive molecular responses to UVR between human keratinocytes and melanocytes. Keratinocytes and melanocytes were irradiated with varying doses of UVB (10, 20 and 30 mJ/cm2) then analysed by RNA-Seq at different time points post-UVB radiation (4, 24 and 72 h). Under basal conditions, keratinocytes and melanocytes expressed similar number of genes, although they each expressed a distinctive subset of genes pertaining to their specific cellular identity. Upon UVB radiation, keratinocytes displayed a clear pattern of time- and dose-dependent changes in gene expression that was different from melanocytes. The early UVB-responsive gene set (4 h post-UVR) differed significantly from delayed UVB-responsive gene sets (24 and 72 h). We also identified multiple novel UVB signature genes including PRSS23, SERPINH1, LCE3D and CNFN, which were conserved between melanocyte and keratinocyte lines from different individuals. Taken together, our findings elucidated both common and distinctive molecular features between melanocytes and keratinocytes and uncovered novel UVB signature genes that might be utilized to predict UVB photobiological effects on the skin. PMID:27119462

  1. Parents' attitudes related to melanocytic nevus count in children.

    PubMed

    de Maleissye, Marie-Florence; Beauchet, Alain; Aegerter, Philippe; Saiag, Philippe; Mahé, Emmanuel

    2010-11-01

    Sun exposure, fair phototype, and a high common melanocytic nevus (MN) count have been identified as the most important risk factors for melanoma. MN are mainly acquired during childhood, and their relationship to sun exposure, sunburn, and light skin complexion is well documented. The purpose of this study was to investigate how the sun protection attitudes of parents and their offspring affect MN development in children. We designed a cross-sectional study in 828 9-year-old school children. Trained nurses counted the MN on each child's back and arms, depending on their size. Questionnaires filled by children and parents provided information about sun exposure, attitude towards the sun, and sun-protection behaviors. Multivariate analysis showed that the childhood MN count was linked to fair phenotype--fair skin: rate ratio (RR)=3.80, 95% confidence interval (CI)=2.25-6.41; blue/green eyes: RR=1.2, 95% CI=1.11-1.34; blond hair: RR=1.25, 95% CI=1.10-1.41; history of sunburn: RR=1.13, 95% CI=1.03-1.23, seaside sun exposure--RR=1.14, 95% CI=1.01-1.28, and to their parents' behaviors during exposure to the sun--increase in the number of MN when parents used sunscreen: RR=1.23, 95% CI=1.08-1.40; decrease in MN count when parents wore a tee-shirt: RR=0.86, 95% CI=0.79-0.93. In conclusion, fair phenotype and sun exposure are known major risk factors for MN. Parents' behaviors influence their children and appeared in our analysis as another determinant predictor of MN count, being protective against (wearing a tee-shirt when exposed to sun) or increasing the risk (sunscreen use, reflecting higher sun exposure) for childhood MN development.

  2. Nanostructural change of human melanocytes stimulated with α-melanocyte stimulating hormone observed by atomic force microscopy.

    PubMed

    Shin, Min Kyung; Lim, Hee Kyeong; Kang, Boo Kyoung; Lee, Gi-Ja; Uhm, Yun-Kyung; Lee, Mu-Hyoung

    2014-01-01

    It is well known that α-melanocyte stimulating hormone (α-MSH) induces melanization, but structural changes of melanocytes after α-MSH exposure are not well known. This study investigated the serial morphologic changes of human cultured melanocytes after stimulation with α-MSH using atomic force microscopy (AFM). Cultured human melanocytes were treated with α-MSH for 7 days. Contact mode AFM images were obtained using a NANOstation II and fixed melanocytes were scanned in PBS solution at a resolution of 512 × 512 pixels, at a scan speed of 0.4 line/s. The surface roughness and pore-like structures of the melanocytes were measured from topographic images using the Scanning Probe Imaging Processor. The surface roughness of cell body did not change significantly over time. All three roughness parameters (Sa, Sq, Sz) inside the pore-like structures on the dendrites increased significantly. The number of pore-like structures increased and the length and the breadth of pore-like structures also increased gradually. Pore-like structures changed statistically significantly in response to α-MSH stimulation. Further study will be needed to clarify whether the nature of pore-like structures is related to movement of melanosomes.

  3. Muse Cells Derived from Dermal Tissues Can Differentiate into Melanocytes.

    PubMed

    Tian, Ting; Zhang, Ru-Zhi; Yang, Yu-Hua; Liu, Qi; Li, Di; Pan, Xiao-Ru

    2017-02-07

    The objective of the authors has been to obtain multilineage-differentiating stress-enduring cells (Muse cells) from primary cultures of dermal fibroblasts, identify their pluripotency, and detect their ability to differentiate into melanocytes. The distribution of SSEA-3-positive cells in human scalp skin was assessed by immunohistochemistry, and the distribution of Oct4, Sox2, Nanog, and SSEA-3-positive cells was determined by immunofluorescence staining. The expression levels of Sox2, Oct4, hKlf4, and Nanog mRNAs and proteins in Muse cells were determined by reverse transcription polymerase chain reaction (RT-PCR) analyses and Western blots, respectively. These Muse cells differentiated into melanocytes in differentiation medium. The SSEA-3-positive cells were scattered in the basement membrane zone and the dermis, with comparatively more in the sebaceous glands, vascular and sweat glands, as well as the outer root sheath of hair follicles, the dermal papillae, and the hair bulbs. Muse cells, which have the ability to self-renew, were obtained from scalp dermal fibroblasts by flow cytometry sorting with an anti-SSEA-3 antibody. The results of RT-PCR, Western blot, and immunofluorescence staining showed that the expression levels of Oct4, Nanog, Sox2, and Klf4 mRNAs and proteins in Muse cells were significantly different from their parental dermal fibroblasts. Muse cells differentiated into melanocytes when cultured in melanocyte differentiation medium, and the Muse cell-derived melanocytes expressed the melanocyte-specific marker HMB45. Muse cells could be obtained by flow cytometry from primary cultures of scalp dermal fibroblasts, which possessed the ability of pluripotency and self-renewal, and could differentiate into melanocytes in vitro.

  4. Wnt inhibitory factor (WIF)-1 promotes melanogenesis in normal human melanocytes.

    PubMed

    Park, Tae Jun; Kim, Misun; Kim, Hyeran; Park, Sun Yi; Park, Kyoung-Chan; Ortonne, Jean-Paul; Kang, Hee Young

    2014-01-01

    Wnt signaling plays a role in the differentiation as well as the development of melanocytes. Using a microarray analysis, hyperpigmentary skin of melasma expressed high levels of Wnt inhibitory factor-1 (WIF-1) compared with perilesional normal skin. In this study, the expression and functional roles of WIF-1 on melanocytes were investigated. WIF-1 was expressed both in the melanocytes of normal human skin and in cultured melanocytes. The upregulation of WIF-1 on cultured normal human melanocytes significantly induced expressions of MITF and tyrosinase, which were associated with increased melanin content and tyrosinase activity. Consistent with the stimulatory effect of WIF-1, WIF-1 siRNA reduced melanogenesis in the cells. Moreover, WIF-1 increases pigmentation in melanocytes co-cultured with WIF-1-overexpressed fibroblasts and of organ-cultured human skin. These findings suggest that melanocytes express WIF-1 constitutively in vivo and in vitro and that WIF-1 promotes melanogenesis in normal human melanocytes.

  5. Alpha-melanocyte-stimulating hormone suppresses oxidative stress through a p53-mediated signaling pathway in human melanocytes.

    PubMed

    Kadekaro, Ana Luisa; Chen, Juping; Yang, Jennifer; Chen, Shuna; Jameson, Joshua; Swope, Viki B; Cheng, Tan; Kadakia, Madhavi; Abdel-Malek, Zalfa

    2012-06-01

    Epidermal melanocytes are skin cells specialized in melanin production. Activation of the melanocortin 1 receptor (MC1R) on melanocytes by α-melanocyte-stimulating hormone (α-MSH) induces synthesis of the brown/black pigment eumelanin that confers photoprotection from solar UV radiation (UVR). Contrary to keratinocytes, melanocytes are slow proliferating cells that persist in the skin for decades, in an environment with high levels of UVR-induced reactive oxygen species (ROS). We previously reported that in addition to its role in pigmentation, α-MSH also reduces oxidative stress and enhances the repair of DNA photoproducts in melanocytes, independent of melanin synthesis. Given the significance of ROS in carcinogenesis, here we investigated the mechanisms by which α-MSH exerts antioxidant effects in melanocytes. We show that activation of the MC1R by α-MSH contributes to phosphorylation of p53 on serine 15, a known requirement for stabilization and activation of p53, a major sensor of DNA damage. This effect is mediated by the cAMP/PKA pathway and by the activation of phosphoinositide 3-kinase (PI3K) ATR and DNA protein kinase (DNA-PK). α-MSH increases the levels of 8-oxoguanine DNA glycosylase (OGG1) and apurinic apyrimidinic endonuclease 1 (APE-1/Ref-1), enzymes essential for base excision repair. Nutlin-3, an HDM2 inhibitor, mimicked the effects of α-MSH resulting in reduced phosphorylation of H2AX (γ-H2AX), a marker of DNA damage. Conversely, the p53 inhibitor pifithrin-α or silencing of p53 abolished the effects of α-MSH and augmented oxidative stress. These results show that p53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes.

  6. Transplantation of cultured autologous melanocytes: hope or danger?

    PubMed

    Czajkowski, Rafal; Pokrywczynska, Marta; Placek, Waldemar; Zegarska, Barbara; Tadrowski, Tadeusz; Drewa, Tomasz

    2010-01-01

    Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.

  7. Effect of streptomycin on melanogenesis and antioxidant status in melanocytes.

    PubMed

    Wrześniok, Dorota; Beberok, Artur; Otręba, Michał; Buszman, Ewa

    2013-11-01

    Streptomycin is an aminoglycoside antibiotic with an antituberculosis activity commonly used in clinical practice due to its good antimicrobial characteristics. A well-known undesirable side effect of this drug is ototoxicity, which may be caused by overproduction of reactive oxygen species and loss of melanocytes in the inner ear. The aim of this study was to examine the effect of streptomycin on melanogenesis and antioxidant defense system in cultured normal human melanocytes (HEMa-LP). Streptomycin induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be ~5.0 mM. It has been shown that streptomycin causes inhibition of tyrosinase activity and reduces melanin content in human melanocytes in a concentration-dependent manner. Significant changes in the activity of cellular antioxidant enzymes: superoxide dismutase, catalase, and glutathione peroxidase were also stated. The results obtained in vitro may explain a potential role of melanocytes and melanin in the causative mechanisms of aminoglycosides ototoxic effects in vivo.

  8. Hesperetin induces melanin production in adult human epidermal melanocytes.

    PubMed

    Usach, Iris; Taléns-Visconti, Raquel; Magraner-Pardo, Lorena; Peris, José-Esteban

    2015-06-01

    One of the major sources of flavonoids for humans are citrus fruits, hesperidin being the predominant flavonoid. Hesperetin (HSP), the aglycon of hesperidin, has been reported to provide health benefits such as antioxidant, anti-inflammatory and anticarcinogenic effects. However, the effect of HSP on skin pigmentation is not clear. Some authors have found that HSP induces melanogenesis in murine B16-F10 melanoma cells, which, if extrapolated to in vivo conditions, might protect skin against photodamage. Since the effect of HSP on normal melanocytes could be different to that observed on melanoma cells, the described effect of HSP on murine melanoma cells has been compared to the effect obtained using normal human melanocytes. HSP concentrations of 25 and 50 µM induced melanin synthesis and tyrosinase activity in human melanocytes in a concentration-dependent manner. Compared to control melanocytes, 25 µM HSP increased melanin production and tyrosinase activity 1.4-fold (p < 0.01) and 1.1-fold (p < 0.01), respectively, and the corresponding increases in the case of 50 µM HSP were 1.9-fold (p < 0.001) and 1.3-fold (p < 0.001). Therefore, HSP could be considered a valuable photoprotective substance if its capacity to increase melanin production in human melanocyte cultures could be reproduced on human skin.

  9. Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation.

    PubMed

    Feller, Liviu; Masilana, Aubrey; Khammissa, Razia A G; Altini, Mario; Jadwat, Yusuf; Lemmer, Johan

    2014-03-24

    The presence of melanocytes in the oral epithelium is a well-established fact, but their physiological functions are not well defined. Melanin provides protection from environmental stressors such as ultraviolet radiation and reactive oxygen species; and melanocytes function as stress-sensors having the capacity both to react to and to produce a variety of microenvironmental cytokines and growth factors, modulating immune, inflammatory and antibacterial responses. Melanocytes also act as neuroendocrine cells producing local neurotransmitters including acetylcholine, catecholamines and opioids, and hormones of the melanocortin system such as proopiomelanocortin, adrenocorticotropic hormone and α-melanocyte stimulating hormone, that participate in intracellular and in intercellular signalling pathways, thus contributing to tissue homeostasis.There is a wide range of normal variation in melanin pigmentation of the oral mucosa. In general, darker skinned persons more frequently have oral melanin pigmentation than light-skinned persons. Variations in oral physiological pigmentation are genetically determined unless associated with some underlying disease.In this article, we discuss some aspects of the biophysiology of oral melanocytes, of the functions of melanin, and of physiological oral pigmentation.

  10. Proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type Ia

    PubMed Central

    Peralta, Rosario; Sabban, Emilia Cohen; Friedman, Paula; Marcucci, Carolina; Bollea Garlatti, Luis A.; Galimberti, Gastón; Cabo, Horacio

    2017-01-01

    Albino patients are at great risk for developing cutaneous neoplasms, including melanomas. In this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type Ia (OCA-Ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. We propose managing these patients with dermoscopy, using the comparative approach, digital follow up (DFU), and reflectance confocal microscopy as a complementary tool for difficult cases. PMID:28243493

  11. Verification of the Inactivation of Melanocytic Nevus in vitro Using a Newly Developed Portable High Hydrostatic Pressure Device.

    PubMed

    Morimoto, Naoki; Jinno, Chizuru; Mahara, Atsushi; Kakudo, Natsuko; Fujisato, Toshia; Kusumoto, Kenji; Suzuki, Shigehiko; Yamaoka, Tetsuji

    2016-01-01

    High hydrostatic pressure (HHP) technology is a physical method for inactivating tissue. We reported that nevus specimens were inactivated after HHP at 200 MPa and that the inactivated nevus could be used as autologous dermis for covering skin defects. In this study, we verified the inactivation of nevus specimens using a newly developed portable HHP device which will be used in a clinical trial. Nevus tissue specimens were obtained from 5 patients (mean age 7.2 years, range 1-19). We cultured fibroblasts and nevus cells from the tissue specimens and then evaluated their inactivation after HHP at 200 MPa by confirming the attachment of the suspensions and by the live/dead staining of the suspensions, through the dissociation of the cells on chamber slides and by the live/dead staining of the remaining cells. The cells were also quantitatively evaluated by WST-8 assay. We then confirmed the inactivation of the nevus specimens after HHP using explant culture. Our results indicated that fibroblasts and nevus cells were inactivated after HHP at 200 MPa, with the exception of a small percentage of green-colored cells, which reflected the remaining activity of the cellular esterases after HHP. No cells migrated from the nevus specimens after HHP at 200 MPa. We verified the inactivation of fibroblasts and nevus cells cultured from nevus specimens, and in the nevus samples themselves after pressurization at 200 MPa using this device. This device could be used in clinical trials for giant congenital melanocytic nevi and may thus become useful in various medical fields.

  12. Induction of nerve growth factor receptors on cultured human melanocytes

    SciTech Connect

    Peacocke, M.; Yaar, M.; Mansur, C.P.; Chao, M.V.; Gilchrest, B.A. )

    1988-07-01

    Normal differentiation and malignant transformation of human melanocytes involve a complex series of interactions during which both genetic and environmental factors play roles. At present, the regulation of these processes is poorly understood. The authors have induced the expression of nerve growth factor (NGF) receptors on cultured human melanocytes with phorbol 12-tetradecanoate 13-acetate and have correlated this event with the appearance of a more differentiated, dendritic morphology. Criteria for NGF receptor expression included protein accumulation and cell-surface immunofluorescent staining with a monoclonal antibody directed against the human receptor and induction of the messenger RNA species as determined by blot-hybridization studies. The presence of the receptor could also be induced by UV irradiation or growth factor deprivation. The NGF receptor is inducible in cultured human melanocytes, and they suggest that NGF may modulate the behavior of this neural crest-derived cell in the skin.

  13. Metaplastic breast carcinoma; melanocytic variant, a very rare tumour

    PubMed Central

    Nzegwu, Martin A.; Sule, Emmanuel; Uzoigwe, Joseph; Achi, Franklyn

    2015-01-01

    Metaplastic breast carcinoma (MBC) is a rare heterogeneous malignancy, accounting for <1% of all invasive breast carcinomas, in which adenocarcinoma is found to coexist with an admixture of spindle, squamous, chondroid or bone-forming neoplastic cells. Melanocytic variant was first described by Ruffolo et al. in 1997. We report a case of MBC, melanocytic variant, in a 57-year-old Nigerian female who presented with a left breast mass 8 cm in diameter in the upper outer quadrant, hard and gradually increase in size to become painful. Breast examination showed gross asymmetry. Left breast was oedematous and shiny with extensive peau d'orange. No palpable axillary nodes were seen. Chest X-ray and abdominal ultrasound scan showed no involvement. Breast biopsy revealed an invasive metaplastic ductal carcinoma with melanocytic differentiation. PMID:25666364

  14. A new transgenic mouse line for tetracycline inducible transgene expression in mature melanocytes and the melanocyte stem cells using the Dopachrome tautomerase promoter.

    PubMed

    Woods, Susan L; Bishop, J Michael

    2011-04-01

    We have generated a novel transgenic mouse to direct inducible and reversible transgene expression in the melanocytic compartment. The Dopachrome tautomerase (Dct) control sequences we used are active early in the development of melanocytes and so this system was designed to enable the manipulation of transgene expression during development in utero and in the melanocyte stem cells as well as mature melanocytes. We observed inducible lacZ and GFP reporter transgene activity specifically in melanocytes and melanocyte stem cells in mouse skin. This mouse model will be a useful tool for the pigment cell community to investigate the contribution of candidate genes to normal melanocyte and/or melanoma development in vivo. Deregulated expression of the proto-oncogene MYC has been observed in melanoma, however whether MYC is involved in tumorigenesis in pigment cells has yet to be directly investigated in vivo. We have used our system to over-express MYC in the melanocytic compartment and show for the first time that increased MYC expression can indeed promote melanocytic tumor formation.

  15. Traumatic iridial extrusion mimicking a conjunctival melanocytic neoplasm

    PubMed Central

    Zoroquiain, Pablo; Ganimi, Maria SB; Alghamdi, Sarah; Burnier, Julia V; Aldrees, Sultan S; Burnier, Miguel N

    2016-01-01

    Conjunctival melanoma is a rare malignant tumour of the eye. Its diagnosis represents a challenge for general pathologists due to low exposure to ocular biopsies and a broad differential diagnosis. In addition, conjunctival samples are often small and are associated with a high frequency of artefacts due to their processing. Here, we present the first case to date of a traumatic iridial extrusion masquerading as a conjunctival melanocytic neoplasm. An 83-year-old Asian man presented with a conjunctival-pigmented nodule surrounded by an area of diffuse pigmentation. Histopathology revealed in the nodule a well-demarcated lesion composed of spindle shaped melanocytes with thick-walled blood vessels. At higher magnification, the blood vessels were composed of thick walls with collagen fibres in an onion-skin-like arrangement. The histological findings were consistent with extruded iridial tissue. The map biopsies of the flat, pigmented lesion showed melanocytic cell proliferation with dendritic processes restricted to the lamina propria without any epithelial involvement, consistent with ocular melanocytosis. The diagnosis of conjunctival melanocytic lesions is challenging, and non-neoplastic conditions should always be included in the differential diagnosis. Pathologists should correlate clinicopathological findings and be familiar with the normal histology in order to achieve the correct diagnosis. PMID:26913071

  16. Molecular biology of normal melanocytes and melanoma cells.

    PubMed

    Bandarchi, Bizhan; Jabbari, Cyrus Aleksandre; Vedadi, Ali; Navab, Roya

    2013-08-01

    Malignant melanoma is one of the most aggressive malignancies in humans and is responsible for 60-80% of deaths from skin cancers. The 5-year survival of patients with metastatic malignant melanoma is about 14%. Its incidence has been increasing in the white population over the past two decades. The mechanisms leading to malignant transformation of melanocytes and melanocytic lesions are poorly understood. In developing malignant melanoma, there is a complex interaction of environmental and endogenous (genetic) factors, including: dysregulation of cell proliferation, programmed cell death (apoptosis) and cell-to-cell interactions. The understanding of genetic alterations in signalling pathways of primary and metastatic malignant melanoma and their interactions may lead to therapeutics modalities, including targeted therapies, particularly in advanced melanomas that have high mortality rates and are often resistant to chemotherapy and radiotherapy. Our knowledge regarding the molecular biology of malignant melanoma has been expanding. Even though several genes involved in melanocyte development may also be associated with melanoma cell development, it is still unclear how a normal melanocyte becomes a melanoma cell. This article reviews the molecular events and recent findings associated with malignant melanoma.

  17. Genome-wide transcriptome analysis of human epidermal melanocytes

    PubMed Central

    Haltaufderhyde, Kirk D.; Oancea, Elena

    2015-01-01

    Because human epidermal melanocytes (HEMs) provide critical protection against skin cancer, sunburn, and photoaging, a genome-wide perspective of gene expression in these cells is vital to understanding human skin physiology. In this study we performed high throughput sequencing of HEMs to obtain a complete data set of transcript sizes, abundances, and splicing. As expected, we found that melanocyte specific genes that function in pigmentation were among the highest expressed genes. We analyzed receptor, ion channel and transcription factor gene families to get a better understanding of the cell signalling pathways used by melanocytes. We also performed a comparative transcriptomic analysis of lightly versus darkly pigmented HEMs and found 16 genes differentially expressed in the two pigmentation phenotypes; of those, only one putative melanosomal transporter (SLC45A2) has known function in pigmentation. In addition, we found 166 genes with splice isoforms expressed exclusively in one pigmentation phenotype, 17 of which are genes involved in signal transduction. Our melanocyte transcriptome study provides a comprehensive view and may help identify novel pigmentation genes and potential pharmacological targets. PMID:25451175

  18. Adipose-Derived Stem Cells Improve Efficacy of Melanocyte Transplantation in Animal Skin

    PubMed Central

    Lim, Won-Suk; Kim, Chang-Hyun; Kim, Ji-Young; Do, Byung-Rok; Kim, Eo Jin; Lee, Ai-Young

    2014-01-01

    Vitiligo is a pigmentary disorder induced by a loss of melanocytes. In addition to replacement of pure melanocytes, cocultures of melanocytes with keratinocytes have been used to improve the repigmentation outcome in vitiligo treatment. We previously identified by in vitro studies, that adipose-derived stem cells (ADSCs) could be a potential substitute for keratinocytes in cocultures with melanocytes. In this study, the efficacy of pigmentation including durability of grafted melanocytes and short-term safety was examined in the nude mouse and Sprague-Dawley rat after grafting of primary cultured human melanocytes, with or without different ratios of primary cultured human ADSCs. Simultaneous grafting of melanocytes and ADSCs, which were separately cultured and mixed on grafting at the ratios of 1:1, 1:2, or 1:3, showed better efficacy than that of pure melanocytes. Grafting of melanocytes cocultured with ADSCs resulted in a similar outcome as the grafting of cell mixtures. Skin pigmentation by melanocytes : ADSCs at the ratios of 1:1 and 1:2 was better than at 1:3. No significant difference was observed between the 1-week and 2-week durations in coculturing. Time-course microscopic examination showed that the grafted melanocytes remained a little longer than 6-week post-grafting. No inflammatory cell infiltration was observed in the grafted skin and no melanocytes were detectable in other organs. Collectively, grafting of melanocytes and ADSCs was equally safe and more effective than grafting of melanocytes alone. Despite the absence of significant differences in efficacy between the group of 1:1 and that of 1:2 ratio, 1:2 ratio for 1-week coculturing may be better for clinical use from the cost-benefit viewpoint. PMID:25143812

  19. A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation.

    PubMed

    Molven, Anders; Grimstvedt, Magne B; Steine, Solrun J; Harland, Mark; Avril, Marie-Françoise; Hayward, Nicholas K; Akslen, Lars A

    2005-09-01

    Mutations in two loci encoding cell-cycle-regulatory proteins have been shown to cause familial malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus, which encodes two unrelated proteins, p16INK4A and p14ARF. Mutations in the other locus, CDK4, are much rarer and have been linked to the disease in only three families worldwide. In the 1960s, a large Norwegian pedigree with multiple atypical nevi and malignant melanomas was identified. Subsequently, six generations and more than 100 family members were traced and 20 cases of melanoma verified. In this article, we report that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. Intriguingly, one of the family members had ocular melanoma, but the CDK4 mutation could not be detected in archival tissue samples from this subject. Thus, the case of ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. The CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England. Haplotype analysis using microsatellite markers flanking the CDK4 gene and single-nucleotide polymorphisms within the gene did not support the possibility that there was a common founder, but rather indicated at least two independent mutational events. All CDK4 melanoma families known to date have a substitution of amino acid 24. In addition to resulting from selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hot spot in the CDK4 gene.

  20. Acquired Cystic Kidney Disease

    MedlinePlus

    ... They Work Kidney Disease A-Z Acquired Cystic Kidney Disease What is acquired cystic kidney disease? Acquired cystic kidney disease happens when a ... cysts. What are the differences between acquired cystic kidney disease and polycystic kidney disease? Acquired cystic kidney ...

  1. The historical archaeology of the 17th- and 18th-century Jewish community of Nevis, British West Indies

    NASA Astrophysics Data System (ADS)

    Terrell, Michelle M.

    2000-11-01

    This is an historical archaeological examination of a 17th- and 18th-century Jewish community on the island of Nevis in the British West Indies. Unlike earlier archaeological studies of the Jewish Caribbean Diaspora that focused on single sites, this investigation used a community-wide approach to elucidate the daily experience of Sephardic Jews within the colonial Caribbean. This project included an archaeological excavation at the purported location of the community's synagogue, an electrical resistivity survey of the surviving cemetery, the construction of a map of property ownership in 18th-century Charlestown, and archival research. This study was carded out within a multiscalar and contextual framework that emphasized the importance of understanding the diaspora that brought the Jews to the West Indies, the development of the colonial Caribbean, and the surrounding environs of the port city of Charlestown, Nevis. The archaeological analysis of the supposed site of the synagogue proved that it was in fact that of a late 18th-century townhouse, but the associated land record research revealed the actual location of the community's former synagogue. Furthermore, the reconstruction of the physical layout of colonial-period Charlestown from the land records indicated the presence of a distinct Jewish quarter in the undesirable southern portion of the town. Evidence from the public records of Nevis and the social history of the members of the Jewish population unveiled external social and political pressures placed upon the Sephardim as well as internal religious and ethnic ties dig bound the community together. It is argued in closing that the archival evidence, in conjunction with the continued presence of a clustered settlement pattern like that of European Jewish communities during the medieval period, indicates that the Jews of the Caribbean were not fully integrated socially or politically into British colonial society. This examination of the Nevis community

  2. Altered E-Cadherin Levels and Distribution in Melanocytes Precede Clinical Manifestations of Vitiligo.

    PubMed

    Wagner, Roselyne Y; Luciani, Flavie; Cario-André, Muriel; Rubod, Alain; Petit, Valérie; Benzekri, Laila; Ezzedine, Khaled; Lepreux, Sébastien; Steingrimsson, Eirikur; Taieb, A; Gauthier, Yvon; Larue, Lionel; Delmas, Véronique

    2015-07-01

    Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes, as well as oxidative and mechanical stress. It is important to identify early events in vitiligo to clarify pathogenesis, improve diagnosis, and inform therapy. Here, we show that E-cadherin (Ecad), which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to the suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective Ecad expression in melanocytes, we demonstrated that Ecad is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/preclinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness that, under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.

  3. The "Umbrella Sign": A Useful Clue in the Diagnosis of Melanocytic Lesions in Sun Damaged Skin.

    PubMed

    Wood, Benjamin A; Harvey, Nathan T

    2016-07-01

    As ultraviolet radiation is an important aetiological agent in melanoma development, the presence of solar elastosis is an important factor in the assessment of any melanocytic lesion. However, melanocytic naevi are also seen in chronically sun damaged skin, particularly in regions with high levels of ultraviolet exposure and fair skinned populations. It has previously been noted that the relationship of a melanocytic proliferation to elastic fibers in the dermis can be of discriminatory value in the separation of melanoma from melanocytic naevus, in particular, it has been proposed that naevi act as a "sunscreen," which may result in a histological clue that the authors colloquially refer to in practice as "the umbrella sign." The aim of this study was to evaluate the patterns of solar elastosis within and beneath melanocytic proliferations developing in sun damaged skin and to determine the utility of the "umbrella sign" in diagnostic practice. We assessed 81 melanocytic proliferations in sun damaged skin for the presence of an umbrella sign, that was present in 49/53 melanocytic naevi (92%) compared with only 2/28 melanomas (7%, P < 0.05). In addition, entrapped elastotic fibers displaying distinct purple discolouration were identified in 16 melanocytic naevi. This finding was not identified in any of the melanomas. The umbrella sign appears to be a useful clue in the distinction of melanoma from melanocytic naevus in sun damaged skin, although as with all histological features in melanocytic pathology, it requires interpretation within a multifactorial assessment cognizant of potential diagnostic pitfalls.

  4. Consolidating Social Achievements & Meeting the Challenges of the 21st Century Child Survival, Development & Protection in St. Kitts and Nevis. 1991-96 Situation Analysis of Children and Their Families.

    ERIC Educational Resources Information Center

    Halliday, Joseph; Harris, Vernon

    This report details an assessment of the state of children and their families in St. Kitts and Nevis in the Caribbean. The assessment was conducted by a team from St. Kitts in consultation with government officials and non-governmental organizations in St. Kitts and Nevis. Following an executive summary, the report's chapters are: (1)…

  5. Endothelin-1 increases melanin synthesis in an established sheep skin melanocyte culture.

    PubMed

    Pang, Yamiao; Geng, Jianjun; Qin, Yilong; Wang, Haidong; Fan, Ruiwen; Zhang, Ying; Li, Hongquan; Jiang, Shan; Dong, Changsheng

    2016-08-01

    The aims of the study were to establish a culture system for sheep skin melanocytes and uncover the effects of endothelin-1 on melanin synthesis in cultured melanocytes in order to provide an optimal cell system and a theoretical basis for studying the regulatory mechanism of coat color in sheep. In this study, skin punch biopsies were harvested from the dorsal region of 1-3-yr-old sheep, and skin melanocytes were then obtained by the two-step digestion using dispase II and trypsin/ethylene diamine tetraacetic acid (EDTA). The primary cultures of the melanocytes were established and characterized by dopa-staining, immunocytochemical localization of melanocyte markers, and RT-polymerase chain reaction (PCR) analysis of coat color genes. To determine the effect of endothelin-1 on proliferation and melanin synthesis of melanocytes, the cultured cells were treated with different doses of endothelin-1 (10(-7), 10(-8), 10(-9), 10(-10), and 0 mol/L), and the growth rate of melanocytes, production of melanin, expression of related genes, and location of related protein in cultured cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ultraviolet spectrophotometry, qRT-PCR, and immunocytochemical localization, respectively. The results showed that the established melanocyte culture functions properly. Endothelin-1 treatment increased markedly the number of melanocytes and melanin content. In responding to this treatment, expressions of microphthalmia-associated transcription factor (MITF), melanocortin 1 receptor (MC1R), tyrosinase (TYR), and endothelin receptor B (EDNRB) in the melanocytes were significantly up regulated (P < 0.05). Immunocytochemical localization revealed that TYR was mainly localized in the cytoplasm. Positive staining of TYR in the melanocytes was significant. The findings demonstrated that the culture system of sheep skin melanocytes was established successfully in vitro, and endothelin-1 promotes the

  6. Cellular origin and developmental mechanisms during the formation of skin melanocytes

    SciTech Connect

    Ernfors, Patrik

    2010-05-01

    Melanocytes are derived from the neural crest (NC), which are transient multipotent cells arising by delamination from the developing dorsal neural tube. During recent years, signaling systems and molecular mechanisms of melanocyte development have been studied in detail, but the exact diversification of the NC into melanocytes and how they migrate, expand and disperse in the skin have not been fully understood. The recent finding that Schwann cell precursors (SCPs) of the growing nerve represents a stem cell niche from which various cell types, including Schwann cells, endoneural fibroblasts and melanocytes arise has exposed new knowledge on the cellular basis for melanocyte development. This opens for the identification of new factors and reinterpretation of old data on cell fate instructive, proliferative, survival and cell homing factors participating in melanocyte development.

  7. Paracrine Secreted Frizzled-Related Protein 4 Inhibits Melanocytes Differentiation in Hair Follicle

    PubMed Central

    Guo, Haiying; Lei, Mingxing; Li, Yuhong; Liu, Yingxin; Tang, Yinhong; Xing, Yizhan; Deng, Fang

    2017-01-01

    Wnt signaling plays crucial role in regulating melanocyte stem cells/melanocyte differentiation in the hair follicle. However, how the Wnt signaling is balanced to be overactivated to control follicular melanocytes behavior remains unknown. Here, by using immunofluorescence staining, we showed that secreted frizzled-related protein 4 (sFRP4) is preferentially expressed in the skin epidermal cells rather than in melanocytes. By overexpression of sFRP4 in skin cells in vivo and in vitro, we found that sFRP4 attenuates activation of Wnt signaling, resulting in decrease of melanocytes differentiation in the regenerating hair follicle. Our findings unveiled a new regulator that involves modulating melanocytes differentiation through a paracrine mechanism in hair follicle, supplying a hope for potential therapeutic application to treat skin pigmentation disorders. PMID:28337220

  8. Spontaneous Involution of Congenital Melanocytic Nevus With Halo Phenomenon.

    PubMed

    Lee, Noo Ri; Chung, Hee-Chul; Hong, Hannah; Lee, Jin Wook; Ahn, Sung Ku

    2015-12-01

    Congenital melanocytic nevus (CMN) is a neural crest-derived hamartoma, which appear at or soon after birth. CMN has a dynamic course and may show variable changes over time, including spontaneous involution. Spontaneous involution of CMN is a rare phenomenon and is often reported in association with halo phenomenon or vitiligo. The mechanism of halo phenomenon is yet to be investigated but is suggested to be a destruction of melanocytes by immune responses of cytotoxic T cells or IgM autoantibodies. Here, the authors report an interesting case of spontaneously regressed medium-sized CMN with halo phenomenon and without vitiligo, which provides evidence that cytotoxic T cells account for the halo formation and pigmentary regression of CMN.

  9. Ultraviolet radiation directly induces pigment production by cultured human melanocytes

    SciTech Connect

    Friedmann, P.S.; Gilchrest, B.A.

    1987-10-01

    In humans the major stimulus for cutaneous pigmentation is ultraviolet radiation (UVR). Little is known about the mechanism underlying this response, in part because of the complexity of interactions in whole epidermis. Using a recently developed culture system, human melanocytes were exposed daily to a physiologic range of UVR doses from a solar simulator. Responses were determined 24 hours after the last exposure. There was a dose-related increase in melanin content per cell and uptake of /sup 14/C-DOPA, accompanied by growth inhibition. Cells from donors of different racial origin gave proportionately similar increases in melanin, although there were approximately tenfold differences in basal values. Light and electron microscopy revealed UVR-stimulated increases in dendricity as well as melanosome number and degree of melanization, analogous to the well-recognized melanocyte changes following sun exposure of intact skin. Similar responses were seen with Cloudman S91 melanoma cells, although this murine cell line required lower UVR dosages and fewer exposures for maximal stimulation. These data establish that UVR is capable of directly stimulating melanogenesis. Because cyclic AMP elevation has been associated in some settings with increased pigment production by cultured melanocytes, preliminary experiments were conducted to see if the effects of UVR were mediated by cAMP. Both alpha-MSH and isobutylmethylxanthine (IBMX), as positive controls, caused a fourfold increase in cAMP level in human melanocytes and/or S91 cells, but following a dose of UVR sufficient to stimulate pigment production there was no change in cAMP level up to 4 hours after exposure. Thus, it appears that the UVR-induced melanogenesis is mediated by cAMP-independent mechanisms.

  10. Clues to the diagnosis of atypical melanocytic lesions.

    PubMed

    McKee, Phillip H

    2010-01-01

    This review, based on a lecture given at the 2009 Update in Dermatopathology meeting held at the Institute of Dermatology (London, UK), discusses the problem of misdiagnosing atypical benign melanocytic lesions as melanoma and the alternative problem of interpreting naevoid melanoma as a banal naevus. Consequences are considered. Brief consideration of a range of other melanoma variants that may be a source of diagnostic difficulty is also included.

  11. Expression profiling of human melanocytes in response to UV-B irradiation

    PubMed Central

    López, Saioa; Smith-Zubiaga, Isabel; Alonso, Santos

    2015-01-01

    A comprehensive gene expression analysis of human melanocytes was performed assessing the transcriptional profile of dark melanocytes (DM) and light melanocytes (LM) at basal conditions and after UV-B irradiation at different time points (6, 12 and 24 h), and in culture with different keratinocyte-conditioned media (KCM + and KCM −). The data, previously published in [1], have been deposited in NCBI's Gene Expression Omnibus (GEO accession number: GSE70280). PMID:26697372

  12. The optical properties and spectral features of malignant skin melanocytes in the terahertz frequency range

    NASA Astrophysics Data System (ADS)

    Goryachuk, A. A.; Begaeva, V. A.; Khodzitsky, M. K.; Truloff, A. S.

    2016-08-01

    The samples of cells of mice's melanocytes have been investigated. Their optical properties and spectral features were investigated by terahertz time-domain spectroscopy (TDS) in transmission mode. It was found that the optical properties of oncological melanocytes and normal cells are different and oncological cells have spectral features of absorption coefficient so it can be concluded that it is easy to discriminate mice's oncological skin melanocytes by using THz TDS.

  13. UVA phototransduction drives early melanin synthesis in human melanocytes.

    PubMed

    Wicks, Nadine L; Chan, Jason W; Najera, Julia A; Ciriello, Jonathan M; Oancea, Elena

    2011-11-22

    Exposure of human skin to solar ultraviolet radiation (UVR), a powerful carcinogen [1] comprising ~95% ultraviolet A (UVA) and ~5% ultraviolet B (UVB) at the Earth's surface, promotes melanin synthesis in epidermal melanocytes [2, 3], which protects skin from DNA damage [4, 5]. UVB causes DNA lesions [6] that lead to transcriptional activation of melanin-producing enzymes, resulting in delayed skin pigmentation within days [7]. In contrast, UVA causes primarily oxidative damage [8] and leads to immediate pigment darkening (IPD) within minutes, via an unknown mechanism [9, 10]. No receptor protein directly mediating phototransduction in skin has been identified. Here we demonstrate that exposure of primary human epidermal melanocytes (HEMs) to UVA causes calcium mobilization and early melanin synthesis. Calcium responses were abolished by treatment with G protein or phospholipase C (PLC) inhibitors or by depletion of intracellular calcium stores. We show that the visual photopigment rhodopsin [11] is expressed in HEMs and contributes to UVR phototransduction. Upon UVR exposure, significant melanin production was measured within one hour; cellular melanin continued to increase in a retinal- and calcium-dependent manner up to 5-fold after 24 hr. Our findings identify a novel UVA-sensitive signaling pathway in melanocytes that leads to calcium mobilization and melanin synthesis and may underlie the mechanism of IPD in human skin.

  14. Automatic Classification of Specific Melanocytic Lesions Using Artificial Intelligence

    PubMed Central

    Jaworek-Korjakowska, Joanna; Kłeczek, Paweł

    2016-01-01

    Background. Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. Different computer-aided diagnosis (CAD) systems have been proposed to increase the specificity and sensitivity of melanoma detection. Although such computer programs are developed for different diagnostic algorithms, to the best of our knowledge, a system to classify different melanocytic lesions has not been proposed yet. Method. In this research we present a new approach to the classification of melanocytic lesions. This work is focused not only on categorization of skin lesions as benign or malignant but also on specifying the exact type of a skin lesion including melanoma, Clark nevus, Spitz/Reed nevus, and blue nevus. The proposed automatic algorithm contains the following steps: image enhancement, lesion segmentation, feature extraction, and selection as well as classification. Results. The algorithm has been tested on 300 dermoscopic images and achieved accuracy of 92% indicating that the proposed approach classified most of the melanocytic lesions correctly. Conclusions. A proposed system can not only help to precisely diagnose the type of the skin mole but also decrease the amount of biopsies and reduce the morbidity related to skin lesion excision. PMID:26885520

  15. Ultrastructural changes in the melanocytes of aging human choroid.

    PubMed

    Nag, Tapas Chandra

    2015-12-01

    Retinal pigment epithelial cells as well as choroidal melanocytes (CM) possess melanin granules. The former show clear, age-related changes (formation of lipofuscin granules with a concomitant decrease in melanin content); however, data on changes in the CM with aging are fairly limited. We examined CM in human macular and mid-peripheral areas by light- and transmission electron microscopy in 50-94 year-old donor eyes (N=12). Unlike in the choroid of lower ages, the melanocytes from aging choroid (>75 years) showed partial fusion of about 8-15 melanosomes, forming rosettes-like structures. Besides, there was evidence of emptiness in cytoplasm caused by the loss of melanosomes in aged CM, as was confirmed by quantification in macular part of choroid. In advanced aged eyes (85-94-year-old), the CM possessed many lipid droplets as well as irregular lipofuscin granules, the latter had a tendency to fuse with melanosomes, as happens in aged retinal pigment epithelium. Macrophages in their cytoplasm contained abundant irregular as well as clumped melanosomes of variable size, suggesting that damaged granules/melanocytes are cleared by these phagocytes. These obvious changes in the CM are likely to make the choroid prone to damage by visible light.

  16. Intelligent bioengineering in vitiligo treatment: transdermal protein transduction of melanocyte-lineage-specific genes.

    PubMed

    Mou, Yi; Jiang, Xian; Du, Yu; Xue, Li

    2012-12-01

    Vitiligo is a common, incurable skin disease with a prevalence of about 1%. Although many vitiligo therapies are available in clinics, there is almost no one method that causes significant improvement in all vitiligo patients. Some have hypothesized that melanocyte dysfunction or deficiency underlies the loss of skin pigmentation observed in vitiligo. The autoimmune-mediated apoptosis of melanocytes might be an important part of the etiology of vitiligo, which prevents the formation of melanocytes in the skin. Here we propose a novel hypothesis for vitiligo treatment using in situ melanocyte regeneration induced by melanocyte-lineage-specific genes (MLSGs). This may serve as an intelligent bioengineering prototype. The hypothesis is based on the fact that MLSGs regulate melanocyte differentiation through epigenetic reprogramming, which includes microphthalmia-associated transcription factor (MITF), paired box 3 (PAX3), and Notch signaling. MITF directs the terminal differentiation of melanocytes, and PAX3 helps to establish the properties of the melanocyte stem cells. Notch signaling promotes adult stem cell proliferation and self-renewal. This process could be mimicked by Notch intracellular domain (NICD). MLSGs could also stimulate anti-apoptotic gene expression. Recent improvements in relevant biotechniques allow the transdermal delivery of MLSG proteins into the patient, where they enter cells through protein transduction. This process may promote melanocyte regeneration in situ with little impact on the hair follicular cycle or on carcinogenesis. This simple and efficient treatment may have significant impact on the treatment of vitiligo patients.

  17. Differential PAX3 functions in normal skin melanocytes and melanoma cells

    SciTech Connect

    Medic, Sandra; Rizos, Helen; Ziman, Mel

    2011-08-12

    Highlights: {yields} PAX3 retains embryonic roles in adult melanocytes and melanoma cells. {yields} Promotes 'stem' cell-like phenotype via NES and SOX9 in both cells types. {yields} Regulates melanoma and melanocyte migration through MCAM and CSPG4. {yields} PAX3 regulates melanoma but not melanocyte proliferation via TPD52. {yields} Regulates melanoma cell (but not melanocyte) survival via BCL2L1 and PTEN. -- Abstract: The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as 'stem' cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated 'stem' cell like phenotype, PAX3 may contribute to melanoma development and progression.

  18. Melanocytes in the Skin – Comparative Whole Transcriptome Analysis of Main Skin Cell Types

    PubMed Central

    Reemann, Paula; Reimann, Ene; Ilmjärv, Sten; Porosaar, Orm; Silm, Helgi; Jaks, Viljar; Vasar, Eero; Kingo, Külli; Kõks, Sulev

    2014-01-01

    Melanocytes possess several functions besides a role in pigment synthesis, but detailed characteristics of the cells are still unclear. We used whole transcriptome sequencing (RNA-Seq) to assess differential gene expression of cultivated normal human melanocytes with respect to keratinocytes, fibroblasts and whole skin. The present results reveal cultivated melanocytes as highly proliferative cells with possible stem cell-like properties. The enhanced readiness to regenerate makes melanocytes the most vulnerable cells in the skin and explains their high risk of developing into malignant melanoma. PMID:25545474

  19. Melanocytes in the skin--comparative whole transcriptome analysis of main skin cell types.

    PubMed

    Reemann, Paula; Reimann, Ene; Ilmjärv, Sten; Porosaar, Orm; Silm, Helgi; Jaks, Viljar; Vasar, Eero; Kingo, Külli; Kõks, Sulev

    2014-01-01

    Melanocytes possess several functions besides a role in pigment synthesis, but detailed characteristics of the cells are still unclear. We used whole transcriptome sequencing (RNA-Seq) to assess differential gene expression of cultivated normal human melanocytes with respect to keratinocytes, fibroblasts and whole skin. The present results reveal cultivated melanocytes as highly proliferative cells with possible stem cell-like properties. The enhanced readiness to regenerate makes melanocytes the most vulnerable cells in the skin and explains their high risk of developing into malignant melanoma.

  20. Dysregulated autophagy increased melanocyte sensitivity to H2O2-induced oxidative stress in vitiligo

    PubMed Central

    He, Yuanmin; Li, Shuli; Zhang, Weigang; Dai, Wei; Cui, Tingting; Wang, Gang; Gao, Tianwen; Li, Chunying

    2017-01-01

    In vitiligo, melanocytes are particularly vulnerable to oxidative stress owing to the pro-oxidant state generated during melanin synthesis and to the genetic antioxidant defects. Autophagy is a controlled self-digestion process which can protect cells against oxidative damage. However, the exact role of autophagy in vitiligo melanocytes in response to oxidative stress and the mechanism involved are still not clear. To determine the implications of autophagy for melanocyte survival in response to oxidative stress, we first detected the autophagic flux in normal melanocytes exposure to H2O2, and found that autophagy was significantly enhanced in normal melanocytes, for protecting cells against H2O2-induced oxidative damage. Nevertheless, vitiligo melanocytes exhibited dysregulated autophagy and hypersensitivity to H2O2-induced oxidative injury. In addition, we confirmed that the impairment of Nrf2-p62 pathway is responsible for the defects of autophagy in vitiligo melanocytes. Noteworthily, upregulation of the Nrf2-p62 pathway or p62 reduced H2O2-induced oxidative damage of vitiligo melanocytes. Therefore, our data demonstrated that dysregulated autophagy owing to the impairment of Nrf2-p62 pathway increase the sensitivity of vitiligo melanocytes to oxidative stress, thus promote the development of vitiligo. Upregulation of p62-dependent autophagy may be applied to vitiligo treatment in the future. PMID:28186139

  1. Narrow Band Ultraviolet B Treatment for Human Vitiligo Is Associated with Proliferation, Migration, and Differentiation of Melanocyte Precursors.

    PubMed

    Goldstein, Nathaniel B; Koster, Maranke I; Hoaglin, Laura G; Spoelstra, Nicole S; Kechris, Katerina J; Robinson, Steven E; Robinson, William A; Roop, Dennis R; Norris, David A; Birlea, Stanca A

    2015-08-01

    In vitiligo, the autoimmune destruction of epidermal melanocytes produces white spots that can be repigmented by melanocyte precursors from the hair follicles, following stimulation with UV light. We examined by immunofluorescence the distribution of melanocyte markers (C-KIT, DCT, PAX3, and TYR) coupled with markers of proliferation (KI-67) and migration (MCAM) in precursors and mature melanocytes from the hair follicle and the epidermis of untreated and narrow band UVB (NBUVB)-treated human vitiligo skin. NBUVB was associated with a significant increase in the number of melanocytes in the infundibulum and with restoration of the normal melanocyte population in the epidermis, which was lacking in the untreated vitiligo. We identified several precursor populations (melanocyte stem cells, melanoblasts, and other immature phenotypes), and progressively differentiating melanocytes, some with putative migratory and/or proliferative abilities. The primary melanocyte germ was present in the untreated and treated hair follicle bulge, whereas a possible secondary melanocyte germ composed of C-KIT+ melanocytes was found in the infundibulum and interfollicular epidermis of UV-treated vitiligo. This is an exceptional model for studying the mobilization of melanocyte stem cells in human skin. Improved understanding of this process is essential for designing better treatments for vitiligo, ultimately based on melanocyte stem cell activation and mobilization.

  2. Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human epidermal keratinocytes and melanocytes modulated by alpha-melanocyte-stimulating hormone

    PubMed Central

    Böhm, Markus; Hill, Helene Z.

    2016-01-01

    Alpha-melanocyte-stimulating hormone (alpha-MSH) increases melanogenesis and protects from UV-induced DNA damage. However, its effect on mitochondrial DNA (mtDNA) damage is unknown. We have addressed this issue in a pilot study using human epidermal keratinocytes and melanocytes incubated with alpha-MSH and irradiated with UVB. Real-time touchdown PCR was used to quantify total and deleted mtDNA. The deletion detected encompassed the common deletion but was more sensitive to detection. There were 4.4 times more mtDNA copies in keratinocytes than in melanocytes. Irradiation alone did not affect copy numbers. Alpha-MSH slightly increased copy numbers in both cell types in the absence of UVB and caused a similar small decrease in copy number with dose in both cell types. Deleted copies were nearly twice as frequent in keratinocytes as in melanocytes. Alpha-MSH reduced the frequency of deleted copies by half in keratinocytes but not in melanocytes. UVB dose dependently led to an increase in the deleted copy number in alpha-MSH-treated melanocytes. UVB irradiation had little effect on deleted copy number in alpha-MSH-treated keratinocytes. In summary, alpha-MSH enhances mtDNA damage in melanocytes presumably by increased melanogenesis, while α-MSH is protective in keratinocytes, the more so in the absence of irradiation. PMID:27303631

  3. New melanogenesis and photobiological processes in activation and proliferation of precursor melanocytes after UV-exposure: ultrastructural differentiation of precursor melanocytes from Langerhans cells

    SciTech Connect

    Jimbow, K.; Uesugi, T.

    1982-02-01

    Photobiological processes involving new melanogenesis after exposure to ultraviolet (UV) light were experimentally studied in C57 black adult mice by histochemistry, cytochemistry, and autoradiography. The trunk and the plantar region of the foot, where no functioning melanocytes were present before exposure, were exposed to UV-A for 14 consecutive days. Both regions revealed a basically similar pattern for new melanogenesis which involved an activation of precursor melanocytes. Essentially all of ''indeterminate'' cells appeared to be precursor melanocytes, the fine structure of which could be differentiated even from poorly developed Langerhans cells. New melanogenesis was manifested by 4 stages of cellular and subcellular reactions of these cells as indicated by histochemistry of dihydroxyphenylalanine (dopa) and autoradiography of thymidine incorporation: (a) an initial lag in the activation of precursor melanocytes with development of Golgi cisternae and rough endoplasmic reticulum followed by formation of unmelanized melanosomes (day 0 to 2); (b) synthesis of active tyrosinase accumulated in Golgi cisternae and vesicles with subsequent formation of melanized melanosomes in these cells (day 3 to 5); (c) mitotic proliferation of many of these activated cells, followed by an exponential increase of new melanocytes (day 6 to 7); and (d) melanosome transfer with differentiation of 10 nm filaments and arborization of dendrites, but without any significant change in the melanocyte population (day 8 to 14). The melanosome transfer was, however, not obvious until after 7 days of exposure. The size of newly synthesized melanosomes was similar to that of tail skin where native melanocytes were present before exposure.

  4. Study of Health Outcomes in School Children: Key Challenges and Lessons Learned from the Framingham Schools' Natural History of Nevi Study

    ERIC Educational Resources Information Center

    Geller, Alan C.; Oliveria, Susan A.; Bishop, Marilyn; Buckminster, Marcia; Brooks, Katie R.; Halpern, Allan C.

    2007-01-01

    Background: We describe the planning, recruitment, key challenges, and lessons learned in the development of a study of the evolution of nevi (moles) among children in a school setting. Methods: This population-based study of digital photography and dermoscopy of the child's back (overview, close-up, and dermoscopic images) and genetic specimens…

  5. Detection of auto antibodies and transplantation of cultured autologous melanocytes for the treatment of vitiligo

    PubMed Central

    Zhu, Mei-Cai; Ma, Hong-Yu; Zhan, Zhi; Liu, Cheng-Gang; Luo, Wei; Zhao, Guang

    2017-01-01

    The aim of the present study was to establish an immunofluorescence method of antibody detection to identify melanocytes in the serum of vitiligo patients. Furthermore, we aimed to establish a method for the culture and proliferation of autologous pure melanocytes and to observe the effect of their transplantation for the treatment of vitiligo. Suspension of epidermal cells with melanocytes was performed using trypsin digestion of normal epiderm from eyelid operation and melanocytes were selectively cultured and proliferated in serum-free M2 medium. FITC-labeled rabbit anti-human antibody was used to detect the relative fluorescence intensity of the melanocytes. After identification with immunological and biological examinations, the melanocytes were transplanted to depigmented areas of vitiligo. Repigmentation was observed continuously. The results indicated that melanocytes could be selectively proliferated in the medium. Subsequently, pure melanocytes without contamination of fibroblast and keratinocyte were harvested. A total of 34 patients suffering vitiligo for between 3 months and 20 years with depigmented area (between 4 cm2 and 70% of body surface) were divided into 19 cases of developing stage and 15 cases of stable stage, according to the change of depigmentation. A total of 15 developing cases were positive for the antibody against melanocytes, with the positive rate of 79%. The titers of serum was >1:50 in 10 patients at the developing stage, and 5 developing patients were 1:10. Among the 15 stable cases, four were positive, with a positive rate of 27%. Fluorescence of antibody was localized in the cytoplasm of the melanocytes. Autologous melanocytes of vitiligo patients could be selectively proliferated in the medium. Next, pure melanocytes without contamination with fibroblasts and keratinocytes were harvested. A total of 16 vitiligo patients with 28 depigmented areas (2–200 cm2) were treated with transplantation of melanocytes. Repigmentation of

  6. Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes.

    PubMed

    Soong, Joanne; Scott, Glynis

    2013-01-15

    Plexin B1, the receptor for Semaphorin 4D (Sema4D), is expressed by melanocytes in the skin. We recently showed that Sema4D suppresses activation of the hepatocyte growth factor receptor, MET, in melanocytes, and that knockdown of Plexin B1 results in activation of MET. MET signaling mediates proliferation, survival and migration in melanocytes, and its activation is associated with transformation of melanocytes to melanoma. In this report we investigated the mechanism by which Plexin B1 inhibits MET activation. Our results show that Plexin B1 and MET exist as an oligomeric receptor-receptor complex in melanocytes, and that receptor association is increased by Sema4D. MET and Plexin B1 receptor complexes were identified along the cell body of melanocytes, and Sema4D increased receptor association on dendrites, suggesting that Sema4D regulates MET-dependent processes at precise locations on the melanocyte. Despite activation of MET, Plexin B1 knockdowns proliferated slowly and showed increased apoptosis compared with controls. Shp2, a non-receptor protein tyrosine phosphatase, translates growth and survival signals from MET and other receptor tyrosine kinases. Plexin B1 knockdowns had markedly lower levels of Shp2 compared with controls, and Sema4D upregulated Shp2 expression at the protein and message level in normal melanocytes. Functional studies showed that blockade of Shp2 activity abrogated MET-dependent activation of Erk1/Erk2 and Akt in melanocytes. These results suggest a complex role for Sema4D and Plexin B1 in orchestrating signaling from the MET receptor in melanocytes. Because Shp2 is a downstream adaptor protein for multiple receptors, Sema4D may control the effects of several growth factors on melanocytes through regulation of Shp2.

  7. Isolating RNA from precursor and mature melanocytes from human vitiligo and normal skin using laser capture microdissection

    PubMed Central

    Goldstein, Nathaniel B.; Koster, Maranke I.; Hoaglin, Laura G.; Wright, Michael J.; Robinson, Steven E.; Robinson, William A.; Roop, Dennis R.; Norris, David A.; Birlea, Stanca A.

    2017-01-01

    To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1 and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in both NBUVB-treated vitiligo skin and normal skin, when bulge melanocytes were compared with epidermal melanocytes, we found significantly lower expression of melanocyte-specific genes and significantly higher expression of three melanocytic stem cell genes (SOX9, WIF1 and SFRP1), while ALCAM and ALDH1A1 transcripts did not show significant variation. We found significantly higher expression of melanocyte-specific genes in the epidermis of NBUVB-treated vitiligo, as compared to the normal skin. When comparing bulge melanocyte samples from untreated vitiligo, NBUVB-treated vitiligo and normal skin, we did not find significant differences in the expression of melanocyte-specific genes or melanocytic stem cell genes. These techniques offer valuable opportunities to study melanocytes and their precursors in vitiligo and other pigmentation disorders. PMID:27193292

  8. Relationships between melanocytes, mechanical properties and extracellular matrix composition in mouse heart valves.

    PubMed

    Carneiro, Flavia; Kruithof, Boudewijn Pt; Balani, Kanthesh; Agarwal, Arvind; Gaussin, Vinciane; Kos, Lidia

    2015-01-01

    Heart valves are complex structures composed of organized layers of extracellular matrix, and interstitial and overlying endothelial cells. In this article, we present the specific localization of a population of melanocytes within the murine heart valves at ages important for their post-natal development. In all stages analyzed in our study, melanocytes were found in high numbers populating the atrial aspect of the tricuspid and mitral leaflets. The pulmonary valve did not present melanocytes. To characterize a putative role for the valve melanocytes, the dynamic nanomechanical properties of tricuspid leaftets containing large numbers or no melanocytes were measured. The stiffness coefficient of hyperpigmented leaflets was higher (11.5 GPa) than the ones from wild-type (7.5 GPa) and hypopigmented (5.5 GPa) leaflets. These results suggest that melanocytes may contribute to the mechanical properties of the heart valves. The arrangement of extracellular matrix molecules such as Collagen I and Versican B is responsible for the mechanical characteristics of the leaflets. Melanocytes were found to reside primarily in areas of Versican B expression. The patterns of expression of Collagen I and Versican B were not, however, disrupted in hyper or hypopigmented leaflets. Melanocytes may affect other extracellular matrix molecules to alter the valves' microenvironment.

  9. Keratinocytes and fibroblasts in a human skin equivalent model enhance melanocyte survival and melanin synthesis after ultraviolet irradiation.

    PubMed

    Archambault, M; Yaar, M; Gilchrest, B A

    1995-05-01

    To investigate paracrine effects of fibroblasts and keratinocytes on melanocyte behavior after ultraviolet (UV) irradiation, we compared an in vitro skin equivalent model with melanocyte cultures. Human melanocytes were maintained alone in monolayer cultures or on dermal equivalents with or without keratinocytes and were irradiated daily with solar-simulated light. After seven daily UV irradiations, monolayer melanocytes displayed dose-dependent increases in cellular damage. In contrast, melanocytes on dermal equivalents survived strikingly better. Moreover, UV-irradiated skin equivalent melanocytes became highly dendritic as compared with sham-irradiated cells, closely mimicking their morphology in UV-irradiated skin. In addition, in skin equivalents melanocytes migrated from the center to the periphery of the keratinocyte layer after UV irradiation. Melanin production per culture, as measured by 14C-dihydroxyphenylalanine incorporation, was consistently higher in skin equivalent melanocytes than in monolayer melanocytes from the same donor, and it was highest in melanocytes from skin equivalents containing both keratinocytes and fibroblasts. Our data strongly suggest that fibroblasts and keratinocytes modulate melanocyte function in skin. The skin equivalent is a valuable model for investigating paracrine effects on melanocytes after UV irradiation.

  10. Repression of genes involved in melanocyte differentiation in uveal melanoma

    PubMed Central

    Bergeron, Marjorie-Allison; Champagne, Sophie; Gaudreault, Manon; Deschambeault, Alexandre

    2012-01-01

    Purpose Uveal melanoma (UM) has been the subject of intense interest due to its distinctive metastatic pattern, which involves hematogenous dissemination of cancerous cells toward the liver in 50% of patients. To search for new UM prognostic markers, the Suppressive Subtractive Hybridization (SSH) technique was used to isolate genes that are differentially expressed between UM primary tumors and normal uveal melanocytes (UVM). Methods A subtracted cDNA library was prepared using cDNA from uncultured UM primary tumors and UVM. The expression level of selected genes was further validated by cDNA microarray, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence analyses. Results One hundred-fifteen genes were identified using the SSH technique. Microarray analyses comparing the gene expression profiles of UM primary tumors to UVM validated a significant differential expression for 48% of these genes. The expression pattern of selected genes was then analyzed by semi-quantitative RT–PCR and was found to be consistent with the SSH and cDNA microarray findings. A down-regulation of genes associated with melanocyte differentiation was confirmed in UM primary tumors. Presence of undifferentiated cells in the UM was demonstrated by the expression of stem cell markers ATP-binding cassette sub-family G member 2 (ABCG2) and octamer-binding protein 4 (OCT4). Conclusions We demonstrated that the SSH technique is efficient to detect differentially expressed genes between UM and UVM. The genes identified in this study represent valuable candidates for further functional analysis in UM and should be informative in studying the biology of this tumor. In addition, deregulation of the melanocyte differentiation pathway revealed the presence of UM cells exhibiting a stem cell-like phenotype. PMID:22815634

  11. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes.

    PubMed

    Thompson, Benjamin C; Surjana, Devita; Halliday, Gary M; Damian, Diona L

    2014-07-01

    Cutaneous melanoma is a significant cause of morbidity and mortality. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. Here, we report the effect of nicotinamide on DNA damage and repair in primary human melanocytes. Nicotinamide significantly enhanced the repair of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine) and cyclobutane pyrimidine dimers induced by UV exposure. It also enhanced the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine induced by the culture conditions in unirradiated melanocytes. A significant increase in the percentage of melanocytes undergoing unscheduled but not scheduled DNA synthesis was observed, confirming that nicotinamide enhances DNA repair in human melanocytes. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma.

  12. The most common mistakes on dermatoscopy of melanocytic lesions.

    PubMed

    Kamińska-Winciorek, Grażyna; Placek, Waldemar

    2015-02-01

    Dermatoscopy is a method of in vivo evaluation of the structures within the epidermis and dermis. Currently, it may be the most precise pre-surgical method of diagnosing melanocytic lesions. Diagnostic errors may result in unnecessary removal of benign lesions or what is even worse, they can cause early and very early melanomas to be overlooked. Errors in assessment of dermatoscopy can be divided into those arising from failure to maintain proper test procedures (procedural and technical errors) and knowledge based mistakes related to the lack of sufficient familiarity and experience in dermatoscopy. The article discusses the most common mistakes made by beginner or inexperienced dermatoscopists.

  13. Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes.

    PubMed

    Chen, Tianzhi; Wang, Haidong; Liu, Yu; Zhao, Bingling; Zhao, Yuanyuan; Fan, Ruiwen; Wang, Pengchao; Dong, Changsheng

    2016-09-27

    To investigate whether ocular albinism type 1 (OA1) is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR), immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes' pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TRP1) and premelanosome protein (PMEL). However, the tyrosinase-related protein 2 (TRP2) level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB) was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may participate in the

  14. The most common mistakes on dermatoscopy of melanocytic lesions

    PubMed Central

    Kamińska-Winciorek, Grażyna

    2015-01-01

    Dermatoscopy is a method of in vivo evaluation of the structures within the epidermis and dermis. Currently, it may be the most precise pre-surgical method of diagnosing melanocytic lesions. Diagnostic errors may result in unnecessary removal of benign lesions or what is even worse, they can cause early and very early melanomas to be overlooked. Errors in assessment of dermatoscopy can be divided into those arising from failure to maintain proper test procedures (procedural and technical errors) and knowledge based mistakes related to the lack of sufficient familiarity and experience in dermatoscopy. The article discusses the most common mistakes made by beginner or inexperienced dermatoscopists. PMID:25821425

  15. Presence of cytoadhesins (IIb-IIIa-like glycoproteins) on human metastatic melanomas but not on benign melanocytes.

    PubMed

    McGregor, B C; McGregor, J L; Weiss, L M; Wood, G S; Hu, C H; Boukerche, H; Warnke, R A

    1989-10-01

    Glycoproteins IIb and IIIa, a heterodimer complex, play a vital role in blood platelet aggregation and are members of a wide family of membrane receptors known as integrins or cytoadhesins. Cellular interaction to extracellular matrix (ECM) adhesive proteins is mediated by integrins. Certain tumor cells are known to interact with ECM and blood platelets in the process of metastasis. However, it is not known if tumor cells, compared with their normal counterparts, acquire IIb-IIIa-like receptors to help them in their metastatic spread. In this study, monoclonal antibodies directed against the IIb-IIIa platelet glycoprotein complex were used on frozen biopsies of normal and various tumor tissues to detect the presence of these integrins. These studies demonstrate the presence of IIb-IIIa-like glycoproteins on the cells of metastatic malignant melanoma but not on benign melanocytes and rarely on other tumors. The presence of integrins on melanomas may help explain their propensity for frequent metastasis.

  16. Neuroendocrine functions of melanocytes: beyond the skin-deep melanin maker.

    PubMed

    Takeda, Kazuhisa; Takahashi, Na-Ho; Shibahara, Shigeki

    2007-03-01

    The skin is armored with "dead cells", the stratum corneum, and is continuously exposed to external stressful environments, such as atmospheric oxygen, solar radiations, and thermal and chemical insults. Melanocytes of neural crest origin are located in the skin, eye, inner ear, and leptomeninges. Melanin pigment in the skin is produced by melanocytes under the influence of various endogenous factors, derived from neighboring keratinocytes and underlying fibroblasts. The differentiation and functions of melanocytes are regulated at multiple processes, including transcription, RNA editing, melanin synthesis, and the transport of melanosomes to keratinocytes. Impairment at each step causes the pigmentary disorders in humans, with the historical example of oculocutaneous albinism. Moreover, heterozygous mutations in the gene coding for microphthalmia-associated transcription factor, a key regulator for melanocyte development, are associated with Waardenburg syndrome type 2, an auditory-pigmentary disorder. Sun tanning, melasma, aging spots (lentigo senilis), hair graying, and melanoma are well-known melanocyte-related pathologies. Melanocytes therefore have attracted much attention of many ladies, makeup artists and molecular biologists. More recently, we have shown that lipocalin-type prostaglandin D synthase (L-PGDS) is expressed in melanocytes but not in other skin cell types. L-PGDS generates prostaglandin D2 and also functions as an inter-cellular carrier protein for lipophilic ligands, such as bilirubin and thyroid hormones. Thus, melanocytes may exert hitherto unknown functions through L-PGDS and prostaglandin D2. Here we update the neuroendocrine functions of melanocytes and discuss the possible involvement of melanocytes in the control of the central chemosensor that generates respiratory rhythm.

  17. Increased endogenous DNA oxidation correlates to increased iron levels in melanocytes relative to keratinocytes.

    PubMed

    Pelle, Edward; Huang, Xi; Zhang, Qi; Pernodet, Nadine; Yarosh, Daniel B; Frenkel, Krystyna

    2014-01-01

    The endogenous oxidative state of normal human epidermal melanocytes was investigated and compared to normal human epidermal keratinocytes (NHEKs) in order to gain new insight into melanocyte biology. Previously, we showed that NHEKs contain higher levels of hydrogen peroxide (H2O2) than melanocytes and that it can migrate from NHEKs to melanocytes by passive permeation. Nevertheless, despite lower concentrations of H2O2, we now report higher levels of oxidative DNA in melanocytes as indicated by increased levels of 8-oxo-2'-deoxyguanosine (8-oxo-dG): 4.49 (±0.55 SEM) 8-oxo-dG/10(6) dG compared to 1.49 (±0.11 SEM) 8-oxo-dG/10(6) dG for NHEKs. An antioxidant biomarker, glutathione (GSH), was also lower in melanocytes (3.14 nmoles (±0.15 SEM)/cell) in comparison to NHEKs (5.98 nmoles (±0.33 SEM)/cell). Intriguingly, cellular bioavailable iron as measured in ferritin was found to be nearly fourfold higher in melanocytes than in NHEKs. Further, ferritin levels in melanocytes were also higher than in hepatocarcinoma cells, an iron-rich cell, and it indicates that higher relative iron levels may be characteristic of melanocytes. To account for the increased oxidative DNA and lower GSH and H2O2 levels that we observe, we propose that iron may contribute to higher levels of oxidation by reacting with H2O2 through a Fenton reaction leading to the generation of DNA-reactive hydroxyl radicals. In conclusion, our data support the concept of elevated oxidation and high iron levels as normal parameters of melanocytic activity. We present new evidence that may contribute to our understanding of the melanogenic process and lead to the development of new skin care products.

  18. S100B as a potential biomarker for the detection of cytotoxicity of melanocytes.

    PubMed

    Cheong, Kyung Ah; Noh, Minsoo; Kim, Chang-Hyun; Lee, Ai-Young

    2014-03-01

    Skin irritation is one of the most common adverse reactions in hydroquinone (HQ) and retinoic acid (RA). Although melanocytes have rarely been considered to be involved in skin irritation, RA and particularly HQ could induce melanocyte toxicity, resulting in depigmentation. We chose S100B as a candidate gene for melanocytotoxicity from a genome-wide transcriptional profiling analysis after applying irritant doses of HQ, RA and sodium lauryl sulphate (SLS) to cultures of keratinocytes and/or melanocytes. In this study, the role of S100B on melanocyte viability and cytotoxicity was examined. S100B was detected in melanocytes, but not in keratinocytes or fibroblasts. Melanocytes after treatment with increasing concentrations of HQ, RA, SLS and urushiol showed significant increases in intracellular and extracellular S100B expression with reduced viable cell number and increased release of lactate dehydrogenase. No RAGE expression and no significant function of CD166/ALCAM in melanocyte survival and cytotoxicity favoured the role of intracellular S100B in chemically irritated melanocytes. S100B knock-down increased apoptosis through inhibition of PI3K/AKT, NF-κB and ERK activation, suggesting the increased intracellular S100B expression by chemical irritation as a compensatory reaction to reduce cytotoxicity. The numerical decrease in S100B/c-kit-double-positive melanocytes was also examined in human skin epidermis irritated by HQ or RA with stronger staining intensities of S100B. Collectively, the decrease in viable cell number by reduced intracellular S100B levels in vitro and by chemical irritation in vivo suggests that S100B could be a potential biomarker for melanocytes cytotoxicity.

  19. PGE2 is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation

    PubMed Central

    Starner, Renny J.; McClelland, Lindy; Abdel-Malek, Zalfa; Fricke, Alex; Scott, Glynis

    2013-01-01

    Melanocyte proliferation, dendrite formation, and pigmentation are controlled by paracrine factors, particularly following exposure to ultraviolet radiation (UVR). Little is known about autocrine factors for melanocytes. Prostaglandins activate signaling pathways involved in growth, differentiation and apoptosis. Prostaglandin E2 (PGE2) is the most abundant prostaglandin released by keratinocytes following UVR, and stimulates the formation of dendrites in melanocytes. Synthesis of PGE2 is controlled by cPLA2, which releases arachidonic acid from membranes, and COX-2 and prostaglandin E2 synthases (PGES), which convert arachidonic acid to PGH2 and PGH2 to PGE2, respectively. In this report we show that multiple irradiations of human melanocytes with UVR stimulates tyrosinase activity, independent of expression of a functional melanocortin 1 receptor, suggesting the presence of a non-melanocortin autocrine factor. Irradiation of melanocytes activated cPLA2, the rate-limiting step in eicosanoid synthesis, and stimulated PGE2 secretion. PGE2 increased cAMP production, tyrosinase activity and proliferation in melanocytes. PGE2 binds to four distinct G-protein coupled receptors (EP1–4). We show that EP4 receptor signaling stimulates cAMP production in melanocytes. Conversely, stimulation of the EP3 receptor lowered basal cAMP levels. These data suggest that relative levels or activity of these receptors controls effects of PGE2 on cAMP in melanocytes. The data are the first to identify PGE2 as an UVR-inducible autocrine factor for melanocytes that stimulates tyrosinase activity and proliferation, and to show that EP3 and EP4 receptor signaling have opposing effects on cAMP production, a critical signaling pathway that regulates proliferation and melanogenesis in melanocytes. PMID:20500768

  20. The actions of melanin and melanocyte stimulating hormone (MSH).

    PubMed

    Rasmussen, Natalie; Nelson, Francine; Govitrapong, Piyarat; Ebadi, Manuchair

    1999-01-01

    The skin, the largest organ of the body, plays an important role in the total metabolism of several hormones. Melanin, the major product of the melanocyte, is largely responsible for the coloring of skin. Melanin is a complex of insoluble, polyquinone, brown or red pigment and protein, formed by the oxidation of tyrosine and 3,4-dihydroxyphenylalanine in the presence of tyrosinase. There exists two main groups of melanin: the black to dark-brown insoluble eumelanins and the yellow to reddish brown, alkali-soluble pheomelanins. MSH, ACTH and beta-lipoprotein are able to influence skin pigmentation. The functions attributed to melanins are acting as a barrier against ionizing radiation; participating in developmental processes, serving as a cosmetic entity, and scavenging cytotoxic radicals and intermediates. Melanocytes express numerous receptors that allow interaction with other cells in their microenvironment, including keratinocytes and the immune component of the skin Langerhans cells. Albinism represents a group of inherited abnormalities that present with congenital hypopigmentation that can involve the skin, hair, and eyes (oculocutaneous albinism) or be limited primarily to the eyes (ocular albinism). The inherited disorders of keratin include epidermolysis bullosu simplex causing cell degeneration within the basal layer. Sunlight and ultraviolet radiation from artificial light sources could be tonic or toxic to human skin. The harmful effects of solar radiation are skin cancer, photosensitivity diseases, sunburn, photoallergy, photoimmunologic alterations, cataracts, mutations, skin aging and phototoxicity. Sunscreen chemicals protect the skin against ultraviolet radiation.

  1. Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates UV induced melanocyte homeostasis

    PubMed Central

    Hyter, Stephen; Coleman, Daniel J.; Ganguli-Indra, Gitali; Merrill, Gary F.; Ma, Steven; Yanagisawa, Masashi; Indra, Arup K.

    2013-01-01

    Summary Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of EDN1 in murine epidermis (EDN1ep−/−) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage and apoptosis after UVB irradiation. Expression of other keratinocyte derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV induced melanocyte activation and recapitulated the phenotype seen in EDN1ep−/− mice. Altogether, present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV induced melanocyte homeostasis in vivo. PMID:23279852

  2. Cutaneous photobiology. The melanocyte vs. the sun: who will win the final round?

    PubMed

    Kadekaro, Ana Luisa; Kavanagh, Renny J; Wakamatsu, Kazumasa; Ito, Shosuke; Pipitone, Michelle A; Abdel-Malek, Zalfa A

    2003-10-01

    Solar ultraviolet radiation (UV) is a major environmental factor that dramatically alters the homeostasis of the skin as an organ by affecting the survival, proliferation and differentiation of various cutaneous cell types. The effects of UV on the skin include direct damage to DNA, apoptosis, growth arrest, and stimulation of melanogenesis. Long-term effects of UV include photoaging and photocarcinogenesis. Epidermal melanocytes synthesize two main types of melanin: eumelanin and pheomelanin. Melanin, particularly eumelanin, represents the major photoprotective mechanism in the skin. Melanin limits the extent of UV penetration through the epidermal layers, and scavenges reactive oxygen radicals that may lead to oxidative DNA damage. The extent of UV-induced DNA damage and the incidence of skin cancer are inversely correlated with total melanin content of the skin. Given the importance of the melanocyte in guarding against the adverse effects of UV and the fact that the melanocyte has a low self-renewal capacity, it is critical to maintain its survival and genomic integrity in order to prevent malignant transformation to melanoma, the most fatal form of skin cancer. Melanocyte transformation to melanoma involves the activation of certain oncogenes and the inactivation of specific tumor suppressor genes. This review summarizes the current state of knowledge about the role of melanin and the melanocyte in photoprotection, the responses of melanocytes to UV, the signaling pathways that mediate the biological effects of UV on melanocytes, and the most common genetic alterations that lead to melanoma.

  3. Race Does Not Predict Melanocyte Heterogeneous Responses to Dermal Fibroblast-Derived Mediators

    PubMed Central

    Sirimahachaiyakul, Pornthep; Sood, Ravi F.; Muffley, Lara A.; Seaton, Max; Lin, Cheng-Ta; Qiao, Liang; Armaly, Jeffrey S.; Hocking, Anne M.; Gibran, Nicole S.

    2015-01-01

    Introduction Abnormal pigmentation following cutaneous injury causes significant patient distress and represents a barrier to recovery. Wound depth and patient characteristics influence scar pigmentation. However, we know little about the pathophysiology leading to hyperpigmentation in healed shallow wounds and hypopigmentation in deep dermal wound scars. We sought to determine whether dermal fibroblast signaling influences melanocyte responses. Methods and Materials Epidermal melanocytes from three Caucasians and three African-Americans were genotyped for single nucleotide polymorphisms (SNPs) across the entire genome. Melanocyte genetic profiles were determined using principal component analysis. We assessed melanocyte phenotype and gene expression in response to dermal fibroblast-conditioned medium and determined potential mesenchymal mediators by proteome profiling the fibroblast-conditioned medium. Results Six melanocyte samples demonstrated significant variability in phenotype and gene expression at baseline and in response to fibroblast-conditioned medium. Genetic profiling for SNPs in receptors for 13 identified soluble fibroblast-secreted mediators demonstrated considerable heterogeneity, potentially explaining the variable melanocyte responses to fibroblast-conditioned medium. Discussion Our data suggest that melanocytes respond to dermal fibroblast-derived mediators independent of keratinocytes and raise the possibility that mesenchymal-epidermal interactions influence skin pigmentation during cutaneous scarring. PMID:26418010

  4. Preferential secretion of inducible HSP70 by vitiligo melanocytes under stress.

    PubMed

    Mosenson, Jeffrey A; Flood, Kelsey; Klarquist, Jared; Eby, Jonathan M; Koshoffer, Amy; Boissy, Raymond E; Overbeck, Andreas; Tung, Rebecca C; Le Poole, I Caroline

    2014-03-01

    Inducible HSP70 (HSP70i) chaperones peptides from stressed cells, protecting them from apoptosis. Upon extracellular release, HSP70i serves an adjuvant function, enhancing immune responses to bound peptides. We questioned whether HSP70i differentially protects control and vitiligo melanocytes from stress and subsequent immune responses. We compared expression of HSP70i in skin samples, evaluated the viability of primary vitiligo and control melanocytes exposed to bleaching phenols, and measured secreted HSP70i. We determined whether HSP70i traffics to melanosomes to contact immunogenic proteins by cell fractionation, western blotting, electron microscopy, and confocal microscopy. Viability of vitiligo and control melanocytes was equally affected under stress. However, vitiligo melanocytes secreted increased amounts of HSP70i in response to MBEH, corroborating with aberrant HSP70i expression in patient skin. Intracellular HSP70i colocalized with melanosomes, and more so in response to MBEH in vitiligo melanocytes. Thus, whereas either agent is cytotoxic to melanocytes, MBEH preferentially induces immune responses to melanocytes.

  5. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma.

    PubMed

    Laugier, Florence; Finet-Benyair, Adeline; André, Jocelyne; Rachakonda, P Sivaramakrishna; Kumar, Rajiv; Bensussan, Armand; Dumaz, Nicolas

    2015-09-29

    Several studies have highlighted the importance of the PI3K pathway in melanocytes and its frequent over-activation in melanoma. However, little is known about regulation of the PI3K pathway in melanocytic cells. We showed that normal human melanocytes are less sensitive to selective PI3K or mTOR inhibitors than to dual PI3K/mTOR inhibitors. The resistance to PI3K inhibitor was due to a rapid AKT reactivation limiting the inhibitor effect on proliferation. Reactivation of AKT was linked to a feedback mechanism involving the mTORC2 complex and in particular its scaffold protein RICTOR. RICTOR overexpression in melanocytes disrupted the negative feedback, activated the AKT pathway and stimulated clonogenicity highlighting the importance of this feedback to restrict melanocyte proliferation. We found that the RICTOR locus is frequently amplified and overexpressed in melanoma and that RICTOR over-expression in NRAS-transformed melanocytes stimulates their clonogenicity, demonstrating that RICTOR amplification can cooperate with NRAS mutation to stimulate melanoma proliferation. These results show that RICTOR plays a central role in PI3K pathway negative feedback in melanocytes and that its deregulation could be involved in melanoma development.

  6. Human melanocytes mitigate keratinocyte-dependent contraction in an in vitro collagen contraction assay.

    PubMed

    Rakar, Jonathan; Krammer, Markus P; Kratz, Gunnar

    2015-08-01

    Scarring is an extensive problem in burn care, and treatment can be especially complicated in cases of hypertrophic scarring. Contraction is an important factor in scarring but the contribution of different cell types remains unclear. We have investigated the contractile behavior of keratinocytes, melanocytes and fibroblasts by using an in vitro collagen gel assay aimed at identifying a modulating role of melanocytes in keratinocyte-mediated contraction. Cells were seeded on a collagen type I gel substrate and the change in gel dimensions were measured over time. Hematoxylin & Eosin-staining and immunohistochemistry against pan-cytokeratin and microphthalmia-associated transcription factor showed that melanocytes integrated between keratinocytes and remained there throughout the experiments. Keratinocyte- and fibroblast-seeded gels contracted significantly over time, whereas melanocyte-seeded gels did not. Co-culture assays showed that melanocytes mitigate the keratinocyte-dependent contraction (significantly slower and 18-32% less). Fibroblasts augmented the contraction in most assays (approximately 6% more). Non-contact co-cultures showed some influence on the keratinocyte-dependent contraction. Results show that mechanisms attributable to melanocytes, but not fibroblasts, can mitigate keratinocyte contractile behavior. Contact-dependent mechanisms are stronger modulators than non-contact dependent mechanisms, but both modes carry significance to the contraction modulation of keratinocytes. Further investigations are required to determine the mechanisms involved and to determine the utility of melanocytes beyond hypopigmentation in improved clinical regimes of burn wounds and wound healing.

  7. Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

    SciTech Connect

    Chantarawong, Wipa; Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki; Pradermwong, Kantimanee; Shibahara, Shigeki

    2014-11-28

    Highlights: • In human melanocytes, cadmium decreases the expression of MITF-M and tyrosinase and their mRNAs. • In human melanoma cells, cadmium decreases the expression of MITF-M protein and tyrosinase mRNA. • Expression of MITF-H is less sensitive to cadmium toxicity in melanocyte-linage cells. • Cadmium does not decrease the expression of MITF-H in retinal pigment epithelial cells. • MITF-M is the molecular target of cadmium toxicity in melanocytes. - Abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.

  8. In ovo gene manipulation of melanocytes and their adjacent keratinocytes during skin pigmentation of chicken embryos.

    PubMed

    Murai, Hidetaka; Tadokoro, Ryosuke; Sakai, Ken-Ichiro; Takahashi, Yoshiko

    2015-04-01

    During skin pigmentation in avians and mammalians, melanin is synthesized in the melanocytes, and subsequently transferred to adjacently located keratinocytes, leading to a wide coverage of the body surface by melanin-containing cells. The behavior of melanocytes is influenced by keratinocytes shown mostly by in vitro studies. However, it has poorly been investigated how such intercellular cross-talk is regulated in vivo because of a lack of suitable experimental models. Using chicken embryos, we developed a method that enables in vivo gene manipulations of melanocytes and keratinocytes, where these cells are separately labeled by different genes. Two types of gene transfer techniques were combined: one was a retrovirus-mediated gene infection into the skin/keratinocytes, and the other was the in ovo DNA electroporation into neural crest cells, the origin of melanocytes. Since the Replication-Competent Avian sarcoma-leukosis virus long terminal repeat with Splice acceptor (RCAS) infection was available only for the White leghorn strain showing little pigmentation, melanocytes prepared from the Hypeco nera (pigmented) were back-transplanted into embryos of White leghorn. Prior to the transplantation, enhanced green fluorescent protein (EGFP)(+) Neo(r+) -electroporated melanocytes from Hypeco nera were selectively grown in G418-supplemented medium. In the skin of recipient White leghorn embryos infected with RCAS-mOrange, mOrange(+) keratinocytes and transplanted EGFP(+) melanocytes were frequently juxtaposed each other. High-resolution confocal microscopy also revealed that transplanted melanocytes exhibited normal behaviors regarding distribution patterns of melanocytes, dendrite morphology, and melanosome transfer. The method described in this study will serve as a useful tool to understand the mechanisms underlying intercellular regulations during skin pigmentation in vivo.

  9. Acquired Idiopathic Generalized Anhidrosis.

    PubMed

    Gangadharan, Geethu; Criton, Sebastian; Surendran, Divya

    2015-01-01

    Acquired idiopathic generalized anhidrosis is a rare condition, where the exact pathomechanism is unknown. We report a case of acquired idiopathic generalized anhidrosis in a patient who later developed lichen planus. Here an autoimmune-mediated destruction of sweat glands may be the probable pathomechanism.

  10. LABORATORY-ACQUIRED MYCOSES

    DTIC Science & Technology

    laboratory- acquired mycoses . Insofar as possible, the etiological fungus, type of laboratory, classification of personnel, type of work conducted, and other...pertinent data have been listed in this study. More than 288 laboratory- acquired mycoses are described here, including 108 cases of

  11. Dual roles of lineage restricted transcription factors: the case of MITF in melanocytes.

    PubMed

    Levy, Carmit; Fisher, David E

    2011-01-01

    Microphthalmia-associated Transcription Factor, MITF, is a master regulator of melanocyte development, differentiation, migration, and survival.(1) A broad collection of studies have indicated that MITF directly regulates the transcription of genes involved in pigmentation, which are selective to the melanocyte lineage. In addition, MITF controls expression of genes which are expressed in multiple cell lineages, and may also play differential roles in activating vs. maintaining gene expression patterns. In this Point of View article, we discuss lineage restricted transcription factor activation of both tissue-specific and ubiquitously expressed genes using melanocytes and MITF as a model system that may eventually provide insights into such processes in multiple cell lineages.

  12. Melanocytic aggregation in the skin: diagnostic clues from lentigines to melanoma.

    PubMed

    de Giorgi, Vincenzo; Sestini, Serena; Massi, Daniela; Lotti, Torello

    2007-07-01

    Pigmented skin lesions are among the most common skin lesions. Among them, melanocytic proliferations are morphologically diverse and their behavior may be difficult to discern with certainty. Researchers must be able to distinguish melanocytic from nonmelanocytic pigmented skin lesions and, in particular, benign from malignant lesions. The majority of these lesions can be diagnosed with ease; however, a minority of cases is difficult and have potential for error. The authors have systematically analyzed the clinical and dermoscopic features of melanocytic skin lesions, so as to increase in vivo diagnostic accuracy.

  13. Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes

    PubMed Central

    Chen, Tianzhi; Wang, Haidong; Liu, Yu; Zhao, Bingling; Zhao, Yuanyuan; Fan, Ruiwen; Wang, Pengchao; Dong, Changsheng

    2016-01-01

    To investigate whether ocular albinism type 1 (OA1) is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR), immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes’ pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TRP1) and premelanosome protein (PMEL). However, the tyrosinase-related protein 2 (TRP2) level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB) was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may participate in the

  14. Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex".

    PubMed

    Castori, Marco; Scarciolla, Oronzo; Morlino, Silvia; Manente, Liborio; Biscaglia, Assunta; Fragasso, Alberto; Grammatico, Paola

    2012-02-01

    The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded.

  15. Imaging Mass Spectrometry – a new and promising method to differentiate Spitz nevi from Spitzoid malignant melanomas

    PubMed Central

    Lazova, Rossitza; Seeley, Erin H; Keenan, Megan; Gueorguieva, Ralitza; Caprioli, Richard M

    2011-01-01

    Background Differentiating Spitz nevus (SN) from Spitzoid malignant melanoma (SMM) is one the most difficult problems in Dermatopathology. Specific Aim To identify differences on proteomic level between SN and SMM. Methods We performed Imaging Mass Spectrometry (IMS) analysis on formalin-fixed, paraffin embedded tissue samples (FFPE) to identify differences on proteomic level between SN and SMM. The diagnosis of SN and SMM was based on histopathologic criteria, clinical features, and follow up data, which confirmed that none of the lesions diagnosed as SN recurred or metastasized. The melanocytic component (tumor) and tumor microenvironment (dermis) from 114 cases of SN and SMM from the Yale Spitzoid Neoplasm Repository were analyzed. After obtaining mass spectra from each sample, classification models were built using a training set of biopsies from 26 SN and 25 SMM separately for tumor and for dermis. The classification algorithms developed on the training data set were validated on another set of 30 samples from SN and 33 from SMM. Results We found proteomic differences between the melanocytic components of SN and SMM and identified five peptides that were differentially expressed in the two groups. From these data, 29 out of 30 SN and 26 out of 29 SMM were recognized correctly based on tumor analysis in the validation set. This method correctly classified SN with 97% sensitivity and 90% specificity in the validation cohort. Conclusions IMS analysis can reliably differentiate SN from SMM in FFPE tissue based on proteomic differences. PMID:22197864

  16. Cutaneous melanocytic lesions: do not miss the invisible gorilla.

    PubMed

    Prieto, Victor G

    2012-07-01

    Of all pathology fields, the analysis of melanocytic lesions has one of the highest rates of review for legal reasons, particularly regarding the distinction between nevus and melanoma. Among the most frequently involved are desmoplastic melanoma, nevoid melanoma, and Spitz nevus versus spitzoid melanoma. Therefore, it follows that pathologists and dermatopathologists should pay special attention when dealing with such type of lesions. This review article will emphasize a number of clinical, histologic, and immunohistochemical features we believe are essential when evaluating lesions whose differential diagnosis includes melanoma/nevus. Furthermore, we want to stress the importance of examining the entire slide within the context of all available information in order to not miss the invisible gorilla in the slide. Regarding this apparently bizarre choice to illustrate these problems (to not miss an invisible gorilla), we request the reader to continue reading this article to find out why.

  17. CEACAM1: Expression and Role in Melanocyte Transformation

    PubMed Central

    Turcu, Gabriela; Ion, Daniela Adriana; Brînzea, Alice; Cioplea, Mirela Daniela; Jilaveanu, Lucia Beatrice

    2016-01-01

    Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination. PMID:27642217

  18. Acquired inflammatory demyelinating neuropathies.

    PubMed

    Ensrud, E R; Krivickas, L S

    2001-05-01

    The acquired demyelinating neuropathies can be divided into those with an acute onset and course and those with a more chronic course. The acute neuropathies present as Guillain-Barré syndrome and include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute pandysautonomia. The chronic neuropathies are collectively known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and include MADSAM (multifocal acquired demyelinating sensory and motor neuropathy, also know as Lewis-Sumner syndrome) and DADS (distal acquired demyelinating symmetric neuropathy) as variants. The clinical features, pathology, pathogenesis, diagnosis, treatment, rehabilitation, and prognosis of these neuropathies are discussed.

  19. Pleiotrophin inhibits melanogenesis via Erk1/2-MITF signaling in normal human melanocytes.

    PubMed

    Choi, Woo Jong; Kim, Misun; Park, Ji-Youn; Park, Tae Jun; Kang, Hee Young

    2015-01-01

    Pleiotrophin (PTN) is a secreted heparin-binding protein that is involved in various biological functions of cell growth and differentiation. Little is known about the effects of PTN on the melanocyte function and skin pigmentation. In this study, we investigated whether PTN would affect melanogenesis. PTN was expressed in melanocytes and fibroblasts of human skin. Transfection studies revealed that PTN decreased melanogenesis, probably through MITF degradation via Erk1/2 activation in melanocytes. The inhibitory action of PTN in pigmentation was further confirmed in ex vivo cultured skin and in the melanocytes cocultured with fibroblasts. These findings suggest that PTN is a crucial factor for the regulation of melanogenesis in the skin.

  20. Serum Antibodies to Melanocytes in Patients With Vitiligo Are Predictors of Disease Progression.

    PubMed

    Jimenez-Brito, Gustavo; Garza-de-La-Peña, Eduardo; Pérez-Romano, Beatriz; Ruiz-Argüelles, Alejandro

    2016-01-01

    The aim of this study was to investigate whether the amount of serum antibodies to melanocyte antigens could predict clinical activity or disease progression in patients with vitiligo. A solid-phase enzyme immunoassay was developed to semiquantitate serum antibodies to a human melanocyte extract and was used in 127 patients, 93 of whom showed clinical progression of the disease, while the remaining 34 were quiescent. Results showed different values for clinical sensitivity and specificity depending on the cutoff level for decision, but the overall performance of the test was adequate and supported statistical significance to predict clinical activity/progression or quietness of the disease process. The test might prove useful in deciding the indication and aggressiveness of immunosuppressive therapy in patients with vitiligo. Previous findings suggest that melanocyte-specific antibodies might play a pathogenetic role in the depletion of melanocytes, which characterizes this disorder, and that this depletion might be due to apoptosis following antibody internalization.

  1. EdnrB governs regenerative response of melanocyte stem cells by crosstalk with Wnt signaling

    PubMed Central

    Takeo, Makoto; Lee, Wendy; Rabbani, Piul; Sun, Qi; Hu, Hai; Lim, Chae Ho; Manga, Prashiela; Ito, Mayumi

    2017-01-01

    Delineating the crosstalk between distinct signaling pathways is key to understanding the diverse and dynamic responses of adult stem cells during tissue regeneration. Here we demonstrate that the Edn/EdnrB signaling pathway can interact with other signaling pathways to elicit distinct stem cell functions during tissue regeneration. EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells (McSCs), dramatically enhancing the regeneration of hair and epidermal melanocytes. This effect is dependent upon active Wnt signaling that is initiated by Wnt ligand secretion from the hair follicle epithelial niche. Further, this Wnt-dependent EdnrB signaling can rescue the defects in melanocyte regeneration caused by Mc1R loss. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote photoprotective-melanocyte regeneration, which may be useful for those with increased risk of skin cancers due to Mc1R variants. PMID:27134165

  2. ARP101 inhibits α-MSH-stimulated melanogenesis by regulation of autophagy in melanocytes.

    PubMed

    Kim, Eun Sung; Jo, Yoon Kyung; Park, So Jung; Chang, Huikyoung; Shin, Ji Hyun; Choi, Eun Sun; Kim, Jun Bum; Seok, Su Hyeon; Kim, Jae-Sung; Oh, Jeong Su; Kim, Myoung-Hwan; Lee, Eunjoo H; Cho, Dong-Hyung

    2013-12-11

    Autophagy is a cooperative process between autophagosomes and lysosomes that degrades cellular organelles. Although autophagy regulates the turnover of cellular components, its role in melanogenesis is not clearly established. Previously, we reported that ARP101 induces autophagy in various cancer cells. Here, we show that ARP101 inhibits melanogenesis by regulation of autophagy. ARP101 inhibited α-MSH-stimulated melanin synthesis and suppressed the expression of tyrosinase and TRP1 in immortalized mouse melanocytes. ARP101 also induced autophagy in melanocytes. Knockdown of ATG5 reduced both anti-melanogenic activity and autophagy mediated by ARP101 in α-MSH treated melanocytes. Electron microscopy analysis further revealed that autophagosomes engulf melanin or melanosome in α-MSH and ARP101-treated cells. Collectively, our results suggest that ARP101 inhibits α-MSH-stimulated melanogenesis through the activation of autophagy in melanocytes.

  3. Modulation of Melanogenesis and Antioxidant Status of Melanocytes in Response to Phototoxic Action of Doxycycline.

    PubMed

    Rok, Jakub; Buszman, Ewa; Beberok, Artur; Delijewski, Marcin; Otręba, Michał; Wrześniok, Dorota

    2015-11-01

    Doxycycline is a commonly used tetracycline antibiotic showing the broad spectrum of antibacterial action. However, the use of this antibiotic is often connected with the risk of phototoxic reactions that lead to various skin disorders. One of the factors influencing the photosensitivity reactions is the melanin content in melanocytes. In this study, the impact of doxycycline and UVA irradiation on cell viability, melanogenesis and antioxidant defense system in cultured normal human epidermal melanocytes (HEMn-DP) was examined. The exposure of cells to doxycycline and UVA radiation resulted in concentration-dependent loss in melanocytes viability and induced melanin biosynthesis. Significant changes were stated in cellular antioxidant enzymes activity: SOD, CAT and GPx, which indicates alterations of antioxidant defense system. The results obtained in vitro may explain the mechanisms of phototoxic reactions that occur in normal human epidermal melanocytes in vivo after exposure of skin to doxycycline and UVA radiation.

  4. Molecular mechanisms of gravity-dependent signaling in human melanocytic cells involve cyclic GMP

    NASA Astrophysics Data System (ADS)

    Ivanova, Krassimira; Lambers, Britta; Block, Ingrid; Bromeis, Birgit; Das, Pranab K.; Gerzer, Rupert

    2005-08-01

    Gravity alteration (micro- and hypergravity) is known to influence cell functions. As guanosine 3',5'-cyclic monophosphate (cGMP) is an important messenger in melanocyte signaling we have compared the regulation of cGMP levels in human melanocytes and melanoma cells with different metastatic potential under hypergravity conditions. We were able to demonstrate that long-term exposure to hypergravity stimulates cGMP efflux in cultured human melanocytes and non- metastatic melanoma cells, whereas highly metastatic melanoma cells appear to be insensitive to hypergravity, most probably, due to an up-regulated cGMP efflux at 1g. Here we report that these effects are associated with the expression of the multidrug resistance proteins 4 and 5 known to act as selective export pumps for amphiphilic anions like cGMP. Thus, an altered gravity vector may induce cGMP-dependent signaling events in melanocytic cells that could be important for malignant transformation.

  5. Effect of nicotine on melanogenesis and antioxidant status in HEMn-LP melanocytes.

    PubMed

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2014-10-01

    Nicotine is a natural ingredient of tobacco plants and is responsible for the addictive properties of tobacco. Nowadays nicotine is also commonly used as a form of smoking cessation therapy. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn affect biochemical processes in human cells producing melanin. The aim of this study was to examine the effect of nicotine on melanogenesis and antioxidant status in cultured normal human melanocytes HEMn-LP. Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be 7.43 mM. Nicotine inhibited a melanization process in human light pigmented melanocytes and caused alterations of antioxidant defense system. Significant changes in cellular antioxidant enzymes: superoxide dismutase and catalase activities and in hydrogen peroxide content were stated. The obtained results may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long term exposition to nicotine.

  6. NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model.

    PubMed

    Larribere, Lionel; Wu, Huizi; Novak, Daniel; Galach, Marta; Bernhardt, Mathias; Orouji, Elias; Weina, Kasia; Knappe, Nathalie; Sachpekidis, Christos; Umansky, Ludmila; Beckhove, Philipp; Umansky, Viktor; De Schepper, Sofie; Kaufmann, Dieter; Ballotti, Robert; Bertolotto, Corine; Utikal, Jochen

    2015-07-01

    Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) -induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage.

  7. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  8. A survey for spotted fever group rickettsiae and ehrlichiae in Amblyomma variegatum from St. Kitts and Nevis.

    PubMed

    Kelly, Patrick J; Fournier, Pierre-Edouard; Parola, Philippe; Raoult, Didier

    2003-07-01

    Eighty-nine Amblyomma variegatum ticks were collected from the islands of St. Kitts and Nevis in the Caribbean and preserved in 70% ethanol or local rum. After being washed in sterile water, their DNA was extracted and analyzed by a polymerase chain reaction (PCR) for DNA of spotted fever group rickettsiae and ehrlichiae. None of the tested ticks was positive in a PCR assay using the primers 16S EHRD and 16S EHRR for the 16S rRNA gene of Ehrlichia spp.. Forty-one percent of the A. variegatum (36 of 89 of which 34 [47%] of 72 were adult males, 2 (13%) of 16 were adult females, and 0 (0%) of 1 were nymphs) were positive in a PCR assay using the primer pair 190-70 and 190-701 for the outer membrane protein A (ompA) gene of spotted fever group rickettsiae. All PCR amplification products obtained had 100% sequence homology with Rickettsia africae, the agent of African tick-bite fever.

  9. Digital dewaxing of Raman signals: discrimination between nevi and melanoma spectra obtained from paraffin-embedded skin biopsies.

    PubMed

    Tfayli, Ali; Gobinet, Cyril; Vrabie, Valeriu; Huez, Regis; Manfait, Michel; Piot, Olivier

    2009-05-01

    Malignant melanoma (MM) is the most severe tumor affecting the skin and accounts for three quarters of all skin cancer deaths. Raman spectroscopy is a promising nondestructive tool that has been increasingly used for characterization of the molecular features of cancerous tissues. Different multivariate statistical analysis techniques are used in order to extract relevant information that can be considered as functional spectroscopic descriptors of a particular pathology. Paraffin embedding (waxing) is a highly efficient process used to conserve biopsies in tumor banks for several years. However, the use of non-dewaxed formalin-fixed paraffin-embedded tissues for Raman spectroscopic investigations remains very restricted, limiting the development of the technique as a routine analytical tool for biomedical purposes. This is due to the highly intense signal of paraffin, which masks important vibrations of the biological tissues. In addition to being time consuming and chemical intensive, chemical dewaxing methods are not efficient and they leave traces of the paraffin in tissues, which affects the Raman signal. In the present study, we use independent component analysis (ICA) on Raman spectral images collected on melanoma and nevus samples. The sources obtained from these images are then used to eliminate, using non-negativity constrained least squares (NCLS), the paraffin contribution from each individual spectrum of the spectral images of nevi and melanomas. Corrected spectra of both types of lesion are then compared and classified into dendrograms using hierarchical cluster analysis (HCA).

  10. Prostaglandin E{sub 2} regulates melanocyte dendrite formation through activation of PKC{zeta}

    SciTech Connect

    Scott, Glynis Fricke, Alex; Fender, Anne; McClelland, Lindy; Jacobs, Stacey

    2007-11-01

    Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE{sub 2}, a ligand for 4 related G-protein-coupled receptors (EP{sub 1}, EP{sub 2}, EP{sub 3} and EP{sub 4}). Our previous work established that PGE{sub 2} stimulates melanocyte dendrite formation through activation of the EP{sub 1} and EP{sub 3} receptors. The purpose of the present report is to define the signaling intermediates involved in EP{sub 1}- and EP{sub 3}-dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKC{zeta} isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKC{zeta} activation on EP{sub 1}- and EP{sub 3}-dependent dendrite formation in melanocytes. Stimulation of the EP{sub 1} and EP{sub 3} receptors by selective agonists activated PKC{zeta}, and inhibition of PKC{zeta} activation abrogated EP{sub 1}- and EP{sub 3}-receptor-mediated melanocyte dendricity. Because of the importance of Rho-GTP binding proteins in the regulation of melanocyte dendricity, we also examined the effect of EP{sub 1} and EP{sub 3} receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP{sub 1,3}-receptor agonists. We show that melanocytes express only the EP{sub 3A1} isoform, but not the EP{sub 3B} receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP{sub 3} agonists. Our data suggest that PKC{zeta} activation plays a predominant role in regulation of PGE{sub 2}-dependent melanocyte dendricity.

  11. Sensitivity of mouse Skh:HR-2 to ultraviolet radiation: melanocyte inactivation

    SciTech Connect

    Warren, R.; Gardner, P.A.; Reed, J.C.

    1987-03-01

    The hairless mouse, Skh:HR-2, was exposed to doses of ultraviolet (UV) radiation known to induce skin pigmentation. Three parameters associated with perturbations in skin pigmentation were monitored following UV exposure. These include spectroscopy (skin darkness), histology (melanocyte density), and biochemistry (melanin). Within 90 min of UV exposure, the skin became lighter. This was associated with a reduction of quantifiable melanin and the inactivation of epidermal melanocytes.

  12. Regulatory effects of heat on normal human melanocyte growth and melanogenesis: comparative study with UVB.

    PubMed

    Nakazawa, K; Sahuc, F; Damour, O; Collombel, C; Nakazawa, H

    1998-06-01

    Although energy-rich ultraviolet B (UVB) is considered to be primarily responsible for most of the effects associated with solar radiation, small energy recorded as heat appears to contribute to the biologic effects of solar radiation on the skin. We compared the effects of heat and UVB on normal human melanocyte functions. In monolayer culture the following was found. (i) Heat-treated melanocytes showed an increased dendricity and exhibited a larger cell body compared with nontreated melanocytes. (ii) After multiple treatments with UVB (20 mJ per cm2, 312 nm) or heat (42 degrees C for 1 h) for 3 d, melanocytes had a lower survival than nontreated melanocytes, but they resumed proliferation within 6 d in the same manner as seen in control. (iii) The expression levels of cell cycle regulators, p53 and p21 proteins, were increased after multiple treatments with UVB or heat. (iv) The tyrosinase (dopa-oxidase) activity per cell was increased after the multiple treatments with UVB or heat. (v) The number of dopa-positive melanocytes in coculture with keratinocytes in epithelial sheets was greatly increased by UVB or heat treatments. (vi) Similarly, the increased number of tyrosinase-related protein 1 positive melanocytes was seen in skin equivalents after UVB (100 mJ per cm2) or heat (42 degrees C for 1 h) treatments for 7 d. These results suggest that heat shares significant biologic activities with UVB in melanocyte functions. These results could be considered as one of the protective or adaptive responses of the skin pigmentary system to the environment.

  13. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential

    PubMed Central

    Adini, Irit; Adini, Avner; Bazinet, Lauren; Watnick, Randolph S.; Bielenberg, Diane R.; D’Amato, Robert J.

    2015-01-01

    The incidence of certain angiogenesis-dependent diseases is higher in Caucasians than in African Americans. Angiogenesis is amplified in wound healing and cornea models in albino C57 mice compared with black C57 mice. Moreover, mouse and human melanocytes with low pigmentation stimulate endothelial cell (EC) proliferation and migration in vitro more than melanocytes with high pigmentation. This effect is due, in part, to the secretion of an angiogenic protein called fibromodulin (FMOD) from lowly pigmented melanocytes. Herein, we expand upon the mechanism contributing to increased angiogenesis in lighter skin and report that monocyte chemotactic protein-1 (MCP-1) is secreted by nonpigmented mouse melanocytes by 5- to 10-fold more than pigmented melanocytes. MCP-1 protein stimulates EC proliferation and migration in vitro and angiogenesis in vivo. Mechanistic studies determine that FMOD is upstream of MCP-1 and promotes its secretion from both melanocytes and activated ECs via stimulation of NF-κB activity. Mice injected with FMOD-neutralizing antibodies show 2.3-fold decreased levels of circulating MCP-1. Human studies confirmed that, on average, Caucasians have 2-fold higher serum levels of MCP-1 than African Americans. Taken together, this study implicates the FMOD/MCP-1 pathway in the regulation of angiogenesis by local melanocytes and suggests that melanogenic activity may protect against aberrant angiogenic diseases.—Adini, I., Adini, A., Bazinet, L., Watnick, R. S., Bielenberg, D. R., and D’Amato, R. J. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. PMID:25406462

  14. A new, rapid, microwave-stimulated method of staining melanocytic lesions.

    PubMed

    Leong, A S; Gilham, P

    1989-03-01

    A new and sensitive method of staining melanocytic lesions is described. Tissue sections covered by a solution of colloidal silver nitrate are exposed to microwaves for 45 sec in a domestic oven to produce clean, crisp staining of melanocytes and melanoma cells, often showing long delicate dendritic cell processes. The staining technique does not stain other pigments or argyrophilic tissues and is shown to be more sensitive than the standard Masson-Fontana procedure.

  15. NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche.

    PubMed

    Chang, Chiung-Ying; Pasolli, H Amalia; Giannopoulou, Eugenia G; Guasch, Géraldine; Gronostajski, Richard M; Elemento, Olivier; Fuchs, Elaine

    2013-03-07

    Adult stem cells reside in specialized niches where they receive environmental cues to maintain tissue homeostasis. In mammals, the stem cell niche within hair follicles is home to epithelial hair follicle stem cells and melanocyte stem cells, which sustain cyclical bouts of hair regeneration and pigmentation. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment. Dissecting the inter-stem-cell crosstalk governing this intricate coordination has been difficult, because mutations affecting one lineage often affect the other. Here we identify transcription factor NFIB as an unanticipated coordinator of stem cell behaviour. Hair follicle stem-cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair greying typical of melanocyte stem cell differentiation mutants. Furthermore, we pinpoint KIT-ligand as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin-immunoprecipitation with high-throughput-sequencing and transcriptional profiling, we identify endothelin 2 (Edn2) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulates NFIB-deficient phenotypes in wild-type mice. Conversely, endothelin receptor antagonists and/or KIT blocking antibodies prevent precocious melanocyte stem cell differentiation in the NFIB-deficient niche. Our findings reveal how melanocyte and hair follicle stem cell behaviours maintain reliance upon cooperative factors within the niche, and how this can be uncoupled in

  16. Complete regression of a melanocytic nevus after epilation with diode laser therapy

    PubMed Central

    Boleira, Manuela; de Almeida Balassiano, Laila Klotz; Jeunon3, Thiago

    2015-01-01

    The use of lasers and intense pulsed light (IPL) technology has become an established practice in dermatology and aesthetic medicine. The use of laser therapy and IPL in the treatment of pigmented melanocytic lesions is a controversial issue. We report clinical, dermoscopic and histological changes of a completely regressed pigmented melanocytic nevus after hair removal treatment with the LightSheer™ Diode Laser (Lumenis Ltd, Yokneam, Israel). PMID:26114064

  17. Image enhancement of optical images for binary system of melanocytes and keratinocytes

    NASA Astrophysics Data System (ADS)

    Takanezawa, S.; Baba, A.; Sako, Y.; Ozaki, Y.; Date, A.; Toyama, K.; Morita, S.

    2013-05-01

    Automatic determination of the cell shapes of large numbers of melanocytes based on optical images of human skin models have been largely unsuccessful (the complexities introduced by dendrites and the melanin pigmentation over the keratinocytes to give unclear outlines). Here, we present an image enhancement procedure for enhancing the contrast of images with removing the non-uniformity of background. The brightness is normalized also for the non-uniform population density of melanocytes.

  18. Cooperative response of keratinocytes and melanocytes to UV radiation during PUVA therapy

    NASA Astrophysics Data System (ADS)

    Stolnitz, Mikhail M.; Baskakov, Pavel V.; Peshkova, Anna Y.

    1999-03-01

    The mathematical model of processes in UV-irradiated furocoumarin-sensitized epidermis is presented taking into account the mutual influence of keratinocytes and melanocytes populations. The model describes epidermis as a hierarchical structure on tissue (keratinocytes-melanocytes cooperation, melanin screen formation), cellular (proliferation and differentiation, transitions between subpopulations), subcellular (cell movement on mitotic cycle, generation, maturing and migration of melanosomes), and molecular (melanin synthesis, processes of DNA damage and repair, molecular signal transduction) levels.

  19. NFIB is a governor of epithelial–melanocyte stem cell behaviour in a shared niche

    PubMed Central

    Chang, Chiung-Ying; Pasolli, H. Amalia; Giannopoulou, Eugenia G.; Guasch, Géraldine; Gronostajski, Richard M.; Elemento, Olivier; Fuchs, Elaine

    2013-01-01

    Adult stem cells reside in specialized niches where they receive environmental cues to maintain tissue homeostasis. In mammals, the stem cell niche within hair follicles is home to epithelial hair follicle stem cells and melanocyte stem cells, which sustain cyclical bouts of hair regeneration and pigmentation1–4. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment2,5. Dissecting the inter-stem-cell crosstalk governing this intricate coordination has been difficult, because mutations affecting one lineage often affect the other. Here we identify transcription factor NFIB as an unanticipated coordinator of stem cell behaviour. Hair follicle stem-cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair greying typical of melanocyte stem cell differentiation mutants. Furthermore, we pinpoint KIT-ligand as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin-immunoprecipitation with high-throughput-sequencing and transcriptional profiling, we identify endothelin 2 (Edn2) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulates NFIB-deficient phenotypes in wild-type mice. Conversely, endothelin receptor antagonists and/or KIT blocking antibodies prevent precocious melanocyte stem cell differentiation in the NFIB-deficient niche. Our findings reveal how melanocyte and hair follicle stem cell behaviours maintain reliance upon cooperative factors within the niche, and how this can be uncoupled

  20. Nitric oxide enhances the sensitivity of alpaca melanocytes to respond to {alpha}-melanocyte-stimulating hormone by up-regulating melanocortin-1 receptor

    SciTech Connect

    Dong, Yanjun; Cao, Jing; Wang, Haidong; Zhang, Jie; Zhu, Zhiwei; Bai, Rui; Hao, HuanQing; He, Xiaoyan; Fan, Ruiwen; Dong, Changsheng

    2010-06-11

    Nitric oxide (NO) and {alpha}-melanocyte-stimulating hormone ({alpha}-MSH) have been correlated with the synthesis of melanin. The NO-dependent signaling of cellular response to activate the hypothalamopituitary proopiomelanocortin system, thereby enhances the hypophysial secretion of {alpha}-MSH to stimulate {alpha}-MSH-receptor responsive cells. In this study we investigated whether an NO-induced pathway can enhance the ability of the melanocyte to respond to {alpha}-MSH on melanogenesis in alpaca skin melanocytes in vitro. It is important for us to know how to enhance the coat color of alpaca. We set up three groups for experiments using the third passage number of alpaca melanocytes: the control cultures were allowed a total of 5 days growth; the UV group cultures like the control group but the melanocytes were then irradiated everyday (once) with 312 mJ/cm{sup 2} of UVB; the UV + L-NAME group is the same as group UV but has the addition of 300 {mu}M L-NAME (every 6 h). To determine the inhibited effect of NO produce, NO produces were measured. To determine the effect of the NO to the key protein and gene of {alpha}-MSH pathway on melanogenesis, the key gene and protein of the {alpha}-MSH pathway were measured by quantitative real-time PCR and Western immunoblotting. The results provide exciting new evidence that NO can enhance {alpha}-MSH pathway in alpaca skin melanocytes by elevated MC1R. And we suggest that the NO pathway may more rapidly cause the synthesis of melanin in alpaca skin under UV, which at that time elevates the expression of MC1R and stimulates the keratinocytes to secrete {alpha}-MSH to enhance the {alpha}-MSH pathway on melanogenesis. This process will be of considerable interest in future studies.

  1. Nitric oxide enhances the sensitivity of alpaca melanocytes to respond to alpha-melanocyte-stimulating hormone by up-regulating melanocortin-1 receptor.

    PubMed

    Dong, Yanjun; Cao, Jing; Wang, Haidong; Zhang, Jie; Zhu, Zhiwei; Bai, Rui; Hao, HuanQing; He, Xiaoyan; Fan, Ruiwen; Dong, Changsheng

    2010-06-11

    Nitric oxide (NO) and alpha-melanocyte-stimulating hormone (alpha-MSH) have been correlated with the synthesis of melanin. The NO-dependent signaling of cellular response to activate the hypothalamopituitary proopiomelanocortin system, thereby enhances the hypophysial secretion of alpha-MSH to stimulate alpha-MSH-receptor responsive cells. In this study we investigated whether an NO-induced pathway can enhance the ability of the melanocyte to respond to alpha-MSH on melanogenesis in alpaca skin melanocytes in vitro. It is important for us to know how to enhance the coat color of alpaca. We set up three groups for experiments using the third passage number of alpaca melanocytes: the control cultures were allowed a total of 5 days growth; the UV group cultures like the control group but the melanocytes were then irradiated everyday (once) with 312 mJ/cm(2) of UVB; the UV+L-NAME group is the same as group UV but has the addition of 300 microM L-NAME (every 6h). To determine the inhibited effect of NO produce, NO produces were measured. To determine the effect of the NO to the key protein and gene of alpha-MSH pathway on melanogenesis, the key gene and protein of the alpha-MSH pathway were measured by quantitative real-time PCR and Western immunoblotting. The results provide exciting new evidence that NO can enhance alpha-MSH pathway in alpaca skin melanocytes by elevated MC1R. And we suggest that the NO pathway may more rapidly cause the synthesis of melanin in alpaca skin under UV, which at that time elevates the expression of MC1R and stimulates the keratinocytes to secrete alpha-MSH to enhance the alpha-MSH pathway on melanogenesis. This process will be of considerable interest in future studies.

  2. Acquired, Idiopathic, Patterned Facial Pigmentation (AIPFP) Including Periorbital Pigmentation and Pigmentary Demarcation Lines on Face Follows the Lines of Blaschko on Face

    PubMed Central

    Sarma, Nilendu; Chakraborty, Sayantani; Bhattacharya, Sneha Ranjan

    2014-01-01

    Background: Acquired, non-nevoid, apparently idiopathic facial pigmentation are distributed over some specific locations like periorbital area, zygomatic area, malar area, root of nose, perioral and mandibular area. Periorbital pigmentation is the most well known entity in this group. These are bilaterally distributed homogenously diffuse gray to dark gray or slate-gray colored patches showing progressive intensification of pigmentation. These are often considered as physiologic or constitutional pigmentation. Some portions of the margins of these patches were described previously as pigmentary demarcation line (PDL- F, G, H). Aim: To analyze the distributional patterns of acquired, apparently idiopathic facial pigmentations and to evaluate the etiologic aspects of these conditions. Materials and Methods: Spatial patterns, distribution, and orientation were analyzed among 187 individuals with idiopathic non-nevoid, facial pigmentation. Observed patterns were compared with various pigmentary nevi and Blaschko's lines on face. Results: It was found that most of the idiopathic facial pigmentary alterations including periorbital pigmentation and PDL on face had specific patterned distribution that had high similarity to that of the pigmentary nevi and Blaschko's lines on face. Conclusion: It is hypothesized here that phenotypic expression of acquired patterned pigmentation (AIFPFP) is due to genetically determined increased pigmentary functional activity to various known and unknown yet natural factors like UV rays and aging. Mosaicism was a definite possibility. We also consider that the patterns actually reflected the normal patterns of embryological human pigmentation on face. PMID:24470659

  3. Alpha-melanocyte stimulating hormone inhibits monocytes adhesion to vascular endothelium

    PubMed Central

    Yang, Yang; Zhang, Weihua; Meng, Lin; Yu, Haitao; Lu, Na; Fu, Gang

    2015-01-01

    Inflammation and its subsequent endothelial dysfunction have been reported to play a pivotal role in the initiation and progression of chronic vascular diseases. Inhibiting the attachment of monocytes to endothelium is a potential therapeutic strategy for vascular diseases treatment. α-Melanocyte stimulating hormone is generated from a precursor hormone called proopiomelanocortin by post-translational processing. However, whether α-melanocyte stimulating hormone plays a role in regulating endothelial inflammation is still unknown. In this study, the effects of α-melanocyte stimulating hormone on endothelial inflammation in human umbilical vein endothelial cell lines were investigated. And the result indicated that α-melanocyte stimulating hormone inhibits the expression of endothelial adhesion molecules, including vascular adhesion molecule-1 and E-selectin, thereby attenuating the adhesion of THP-1 cells to the surface of endothelial cells. Mechanistically, α-melanocyte stimulating hormone was found to inhibit NF-κB transcriptional activity. Finally, we found that the effect of α-melanocyte stimulating hormone on endothelial inflammation is dependent on its receptor melanocortin receptor 1. PMID:25898835

  4. Effect of nicotine on melanogenesis and antioxidant status in HEMn-LP melanocytes

    SciTech Connect

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2014-10-15

    Nicotine is a natural ingredient of tobacco plants and is responsible for the addictive properties of tobacco. Nowadays nicotine is also commonly used as a form of smoking cessation therapy. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn affect biochemical processes in human cells producing melanin. The aim of this study was to examine the effect of nicotine on melanogenesis and antioxidant status in cultured normal human melanocytes HEMn-LP. Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC{sub 50} was determined to be 7.43 mM. Nicotine inhibited a melanization process in human light pigmented melanocytes and caused alterations of antioxidant defense system. Significant changes in cellular antioxidant enzymes: superoxide dismutase and catalase activities and in hydrogen peroxide content were stated. The obtained results may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long term exposition to nicotine. - Graphical abstract: Nicotine inhibits melanogenesis and induces oxidative stress in HEMn-LP melanocytes. - Highlights: • Nicotine induces concentration-dependent loss in melanocytes viability. • Nicotine in non-cytotoxic concentrations inhibits melanogenesis. • Nicotine in higher concentrations induces oxidative stress.

  5. Recombinant Adeno-Associated Virus Serotype 6 Efficiently Transduces Primary Human Melanocytes

    PubMed Central

    Verdon, Daniel; Chen, Jennifer; Taylor, John A.; Dunbar, P. Rod

    2013-01-01

    The study of melanocyte biology is important to understand their role in health and disease. However, current methods of gene transfer into melanocytes are limited by safety or efficacy. Recombinant adeno-associated virus (rAAV) has been extensively investigated as a gene therapy vector, is safe and is associated with persistent transgene expression without genome integration. There are twelve serotypes and many capsid variants of rAAV. However, a comparative study to determine which rAAV is most efficient at transducing primary human melanocytes has not been conducted. We therefore sought to determine the optimum rAAV variant for use in the in vitro transduction of primary human melanocytes, which could also be informative to future in vivo studies. We have screened eight variants of rAAV for their ability to transduce primary human melanocytes and identified rAAV6 as the optimal serotype, transducing 7–78% of cells. No increase in transduction was seen with rAAV6 tyrosine capsid mutants. The number of cells expressing the transgene peaked at 6–12 days post-infection, and transduced cells were still detectable at day 28. Therefore rAAV6 should be considered as a non-integrating vector for the transduction of primary human melanocytes. PMID:23646140

  6. Pigment-Synthesizing Melanocytic Neoplasm With Protein Kinase C Alpha (PRKCA) Fusion

    PubMed Central

    Bahrami, Armita; Lee, Seungjae; Wu, Gang; Kerstetter, Justin; Rahvar, Maral; Li, Xinmin; Easton, John; Zhang, Jinghui; Barnhill, Raymond L.

    2016-01-01

    IMPORTANCE Melanocytic neoplasms with prominent pigment synthesis mimicking equine melanoma represent a rare variant of biologically indeterminate or low-grade malignant melanocytic tumors in which the molecular profile and exact histologic classification are not established. Tumors with these characteristics rarely occur as congenital lesions. We performed genomic analysis of a congenital pigment synthesizing melanocytic neoplasm with indeterminate biological potential. OBSERVATIONS The patient was a 5-month-old girl presenting with a 6-cm protuberant scalp mass, which had doubled in size since birth. Histologic examination showed heavily pigmented intradermal proliferation of large, epithelioid melanocytes with mild cytologic atypia, low mitotic activity, focal necrosis, and ulceration. RNA sequencing identified a novel ATPase, Ca2+ transporting, plasma membrane 4 (ATP2B4)–protein kinase C-alpha (PRKCA) fusion transcript. The fusion resulted in an in-frame linkage of the PRKCA catalytic domain with the N-terminal of ATP2B4 and high expression of the PRKCA kinase domain. Break-apart fluorescence in situ hybridization showed PRKCA rearrangement, and reverse transcriptase–polymerase chain reaction confirmed the presence of the fusion transcript. The patient was alive and well, with no evidence of recurrence, at the 1-year follow-up. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of PRKCA fusions in melanocytic neoplasms. Future studies need to determine the frequency of PRKCA fusions in pigment-synthesizing melanocytic neoplasms. PMID:26676968

  7. Pax3 and regulation of the melanocyte-specific tyrosinase-related protein-1 promoter.

    PubMed

    Galibert, M D; Yavuzer, U; Dexter, T J; Goding, C R

    1999-09-17

    Previous work has established that the melanocyte-specific tyrosinase-related protein-1 (TRP-1) promoter is regulated positively by the microphthalmia-associated transcription factor Mitf, acting through the conserved M box and negatively by the T-box factor Tbx2, which can bind two "melanocyte-specific elements" termed the MSEu and MSEi. Both the MSEu and MSEi, which share a 6-base pair GTGTGA consensus, are also recognized by a previously unidentified melanocyte-specific factor, MSF. Here we show using a combination of DNA binding assays, proteolytic clipping, and anti-Pax3 antibodies that MSF is indistinguishable from Pax3, a paired homeodomain transcription factor implicated genetically in melanocyte development and the regulation of the Mitf promoter. Consistent with Pax3 being able to bind the TRP-1 promoter, Pax3 is expressed in melanocytes and melanomas, and TRP-1 promoter activity is up-regulated by Pax3. The results identify a novel role for Pax3 in the expression of TRP-1, and the potential role of Pax3 in the melanocyte lineage is discussed.

  8. Melanocyte biology and function with reference to oral melanin hyperpigmentation in HIV-seropositive subjects.

    PubMed

    Feller, Liviu; Chandran, Rakesh; Kramer, Beverley; Khammissa, Razia A G; Altini, Mario; Lemmer, Johan

    2014-09-01

    The color of normal skin and of oral mucosa is not determined by the number of melanocytes in the epithelium but rather by their melanogenic activity. Pigmented biopolymers or melanins are synthesized in melanosomes. Tyrosinase is the critical enzyme in the biosynthesis of both brown/black eumelanin and yellow/red pheomelanin. The number of the melanosomes within the melanocytes, the type of melanin within the melanosomes, and the efficacy of the transfer of melanosomes from the melanocytes to the neighboring keratinocytes all play an important role in tissue pigmentation. Melanin production is regulated by locally produced factors including proopiomelanocortin and its derivative peptides, particularly alpha-melanocyte-stimulating hormone (α-MSH), melanocortin 1 receptor (MC1R), adrenergic and cholinergic agents, growth factors, cytokines, and nitric oxide. Both eumelanin and pheomelanin can be produced by the same melanocytes, and the proportion of the two melanin types is influenced by the degree of functional activity of the α-MSH/MC1R intracellular pathway. The cause of HIV oral melanosis is not fully understood but may be associated with HIV-induced cytokine dysregulation, with the medications commonly prescribed to HIV-seropositive persons, and with adrenocortical dysfunction, which is not uncommon in HIV-seropositive subjects with AIDS. The purpose of this article is to discuss some aspects of melanocyte biology and HIV-associated oral melanin hyperpigmentation.

  9. MELANOCYTIC GALECTIN-3 IS ASSOCIATED WITH TYROSINASE RELATED PROTEIN-1 AND PIGMENT BIOSYNTHESIS

    PubMed Central

    Chalupa, Allison; Koshoffer, Amy; Galan, Emily; Yu, Lan; Liu, Fu-Tong; Boissy, Raymond E.

    2014-01-01

    Galectin-3 is a family member of the carbohydrate binding proteins widely expressed by many cell types and exhibits multiple cellular functions. We demonstrate that melanocytes express galectin-3, which is predominantly localized to the cell body peripherally along the Golgi zone. Downregulation of galectin-3 in human melanocytes using shRNA technology resulted in reduction of both melanin synthesis and expression/activity of Tyrp-1. In the cell body, galectin-3 co-localizes with melanosome destined cargo, specifically tyrosinase and tyrosinase-related protein-1. We studied melanocytes cultured from patients with forms of Hermansky-Pudlak syndrome containing defects in trafficking steps governed by BLOC-2 (HPS5), BLOC-3 (HPS1) and adaptin-3 (HPS2). We found galectin-3 expression mimicked the defective expression of the tyrosinase cargo in dendrites of HPS-5 melanocytes, but was not altered in HPS1 or HPS2 melanocytes. In addition, galectin-3 co-localized predominantly with the HPS-5 component of BLOC-2 in normal human melanocytes. These data indicate that galectin-3 is a regulatory component in melanin synthesis affecting the expression of Tyrp-1. PMID:25054620

  10. Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes.

    PubMed

    Beberok, Artur; Wrześniok, Dorota; Otręba, Michał; Miliński, Maciej; Rok, Jakub; Buszman, Ewa

    2015-03-01

    Fluoroquinolone antibiotics provide broad-spectrum coverage for a number of infectious diseases, including respiratory as well as urinary tract infections. One of the important adverse effects of these drugs is phototoxicity which introduces a serious limitation to their use. To gain insight the molecular mechanisms underlying the fluoroquinolones-induced phototoxic side effects, the impact of two fluoroquinolone derivatives with different phototoxic potential, norfloxacin and moxifloxacin, on melanogenesis and antioxidant enzymes activity in normal human melanocytes HEMa-LP was determined. Both drugs induced concentration-dependent loss in melanocytes viability. The value of EC50 for these drugs was found to be 0.5 mM. Norfloxacin and moxifloxacin suppressed melanin biosynthesis; antibiotics were shown to inhibit cellular tyrosinase activity and to reduce melanin content in melanocytes. When comparing the both analyzed fluoroquinolones, it was observed that norfloxacin possesses greater inhibitory effect on tyrosinase activity in melanocytes than moxifloxacin. The extent of oxidative stress in cells was assessed by measuring the activity of antioxidant enzymes: SOD, CAT, and GPx. It was observed that norfloxacin caused higher depletion of antioxidant status in melanocytes when compared with moxifloxacin. The obtained results give a new insight into the mechanisms of fluoroquinolones toxicity directed to pigmented tissues. Moreover, the presented differences in modulation of biochemical processes in melanocytes may be an explanation for various phototoxic activities of the analyzed fluoroquinolone derivatives in vivo.

  11. Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy.

    PubMed

    Pellegrini, Camilla; Zulian, Alessandra; Gualandi, Francesca; Manzati, Elisa; Merlini, Luciano; Michelini, Maria E; Benassi, Luisa; Marmiroli, Sandra; Ferlini, Alessandra; Sabatelli, Patrizia; Bernardi, Paolo; Maraldi, Nadir M

    2013-06-01

    Dystrophin is a subsarcolemmal protein that, by linking the actin cytoskeleton to the extracellular matrix via dystroglycans, is critical for the integrity of muscle fibers. Here, we report that epidermal melanocytes, obtained from conventional skin biopsy, express dystrophin with a restricted localization to the plasma membrane facing the dermal-epidermal junction. In addition the full-length muscle isoform mDp427 was clearly detectable in melanocyte cultures as assessed by immunohistochemistry, RNA, and Western blot analysis. Melanocytes of Duchenne muscular dystrophy (DMD) patients did not express dystrophin, and the ultrastructural analysis revealed typical mitochondrial alterations similar to those occurring in myoblasts from the same patients. Mitochondria of melanocytes from DMD patients readily accumulated tetramethylrhodamine methyl ester, indicating that they are energized irrespective of the presence of dystrophin but, at variance from mitochondria of control donors, depolarized upon the addition of oligomycin, suggesting that they are affected by a latent dysfunction unmasked by inhibition of the ATP synthase. Pure melanocyte cultures can be readily obtained by conventional skin biopsies and may be a feasible and reliable tool alternative to muscle biopsy for functional studies in dystrophinopathies. The mitochondrial dysfunction occurring in DMD melanocytes could represent a promising cellular biomarker for monitoring dystrophinopathies also in response to pharmacological treatments.

  12. Melanocytic galectin-3 is associated with tyrosinase-related protein-1 and pigment biosynthesis.

    PubMed

    Chalupa, Allison; Koshoffer, Amy; Galan, Emily; Yu, Lan; Liu, Fu-Tong; Boissy, Raymond E

    2015-01-01

    Galectin-3 is a family member of the carbohydrate-binding proteins widely expressed by many cell types and exhibits multiple cellular functions. We demonstrate that melanocytes express galectin-3, which is predominantly localized to the cell body peripherally along the Golgi zone. Downregulation of galectin-3 in human melanocytes using short hairpin RNA technology resulted in the reduction of both melanin synthesis and expression/activity of tyrosinase-related protein-1 (Tyrp-1). In the cell body, galectin-3 colocalizes with melanosome-destined cargo, specifically tyrosinase and Tyrp-1. We studied melanocytes cultured from patients with forms of Hermansky-Pudlak syndrome (HPS) containing defects in trafficking steps governed by biogenesis of lysosome-related organelle complex-2 (BLOC-2) (HPS-5), BLOC-3 (HPS-1), and adaptin-3 (HPS-2). We found that galectin-3 expression mimicked the defective expression of the tyrosinase cargo in dendrites of HPS-5 melanocytes, but it was not altered in HPS-1 or HPS-2 melanocytes. In addition, galectin-3 colocalized predominantly with the HPS-5 component of BLOC-2 in normal human melanocytes. These data indicate that galectin-3 is a regulatory component in melanin synthesis affecting the expression of Tyrp-1.

  13. The effects of IGF1 on the melanogenesis in alpaca melanocytes in vitro.

    PubMed

    Hu, Shuaipeng; Liu, Yu; Yang, Shanshan; Ji, Kaiyuan; Liu, Xuexian; Zhang, Junzhen; Fan, Ruiwen; Dong, Changsheng

    2016-09-01

    In order to investigate the effects of the insulin-like growth factor 1(IGF-1) on alpaca melanocyte in vitro, different dosees of IGF1 (0, 10, 20, 40 ng/ml) were added in the medium of alpaca melanocyte. The RTCA machine was used to monitor the proliferation, quantitative real-time PCR, and western blot to test the relative gene expression, ELISA to test cAMP production, and spectrum method to test the melanin production. The results showed that compared to the normal melanocyte, the proliferation of melanocytes was increased within 60 h following adding IGF1. It also showed that cAMP content produced by melanocytes was increased, microphthalmia-associtated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein 2 (TYRP2) expression was increased, and melanin production with most obvious change in 10 ng/ml supplementary group, when compared with the control group. The results suggested that IGF1 with the dose of 10 ng/ml had the important effects on the melanogenesis in alpaca melanocyte by the cAMP pathway.

  14. Correspondence between dermoscopic features and epidermal structures revealed by scanning electron microscope.

    PubMed

    Nagashima, Yoko; Tsuchida, Tetsuya

    2011-01-01

    It is already known that some typical dermoscopic patterns seen in melanocytic nevi on the sole have their own favorite site. In the weight-bearing area, melanocytic nevi with a parallel furrow pattern were preferentially observed. Those with a lattice-like pattern were observed in the arch area, whereas those with a crista reticulated pattern were seen in the border area. To investigate the relationship between the distribution of the dermoscopic patterns seen in plantar melanocytic nevi and the 3-D structures of the epidermis, the basal surfaces of the plantar epidermis from 14 skin lesions were observed by scanning electron microscopy (SEM). Our SEM observations revealed that transverse ridges formed a couple of parallel lamellae on the crista profunda limitans (limiting ridges). Between the limiting ridges and the crista profunda intermedia (intermediate ridges), the transverse ridges had different shapes according to the anatomical location of the sole. From these results, it was suggested that the characteristic dermoscopic patterns seen in acquired and junctional melanocytic nevi on the sole simulate the arrangement of transverse ridges.

  15. Acquired hypofibrinogenemia: current perspectives

    PubMed Central

    Besser, Martin W; MacDonald, Stephen G

    2016-01-01

    Acquired hypofibrinogenemia is most frequently caused by hemodilution and consumption of clotting factors. The aggressive replacement of fibrinogen has become one of the core principles of modern management of massive hemorrhage. The best method for determining the patient’s fibrinogen level remains controversial, and particularly in acquired dysfibrinogenemia, could have major therapeutic implications depending on which quantification method is chosen. This review introduces the available laboratory and point-of-care methods and discusses the relative advantages and limitations. It also discusses current strategies for the correction of hypofibrinogenemia. PMID:27713652

  16. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach.

  17. Functional melanocytes are readily reprogrammable from multilineage-differentiating stress-enduring (muse) cells, distinct stem cells in human fibroblasts.

    PubMed

    Tsuchiyama, Kenichiro; Wakao, Shohei; Kuroda, Yasumasa; Ogura, Fumitaka; Nojima, Makoto; Sawaya, Natsue; Yamasaki, Kenshi; Aiba, Setsuya; Dezawa, Mari

    2013-10-01

    The induction of melanocytes from easily accessible stem cells has attracted attention for the treatment of melanocyte dysfunctions. We found that multilineage-differentiating stress-enduring (Muse) cells, a distinct stem cell type among human dermal fibroblasts, can be readily reprogrammed into functional melanocytes, whereas the remainder of the fibroblasts do not contribute to melanocyte differentiation. Muse cells can be isolated as cells positive for stage-specific embryonic antigen-3, a marker for undifferentiated human embryonic stem cells, and differentiate into cells representative of all three germ layers from a single cell, while also being nontumorigenic. The use of certain combinations of factors induces Muse cells to express melanocyte markers such as tyrosinase and microphthalmia-associated transcription factor and to show positivity for the 3,4-dihydroxy-L-phenylalanine reaction. When Muse cell-derived melanocytes were incorporated into three-dimensional (3D) cultured skin models, they localized themselves in the basal layer of the epidermis and produced melanin in the same manner as authentic melanocytes. They also maintained their melanin production even after the 3D cultured skin was transplanted to immunodeficient mice. This technique may be applicable to the efficient production of melanocytes from accessible human fibroblasts by using Muse cells, thereby contributing to autologous transplantation for melanocyte dysfunctions, such as vitiligo.

  18. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern

    PubMed Central

    Hafner, Christian; López-Knowles, Elena; Luis, Nuno M.; Toll, Agustí; Baselga, Eulàlia; Fernández-Casado, Alex; Hernández, Silvia; Ribé, Adriana; Mentzel, Thomas; Stoehr, Robert; Hofstaedter, Ferdinand; Landthaler, Michael; Vogt, Thomas; Pujol, Ramòn M.; Hartmann, Arndt; Real, Francisco X.

    2007-01-01

    Activating mutations of the p110 α subunit of PI3K (PIK3CA) oncogene have been identified in a broad spectrum of malignant tumors. However, their role in benign or preneoplastic conditions is unknown. Activating FGF receptor 3 (FGFR3) mutations are common in benign skin lesions, either as embryonic mutations in epidermal nevi (EN) or as somatic mutations in seborrheic keratoses (SK). FGFR3 mutations are also common in low-grade malignant bladder tumors, where they often occur in association with PIK3CA mutations. Therefore, we examined exons 9 and 20 of PIK3CA and FGFR3 hotspot mutations in EN (n = 33) and SK (n = 62), two proliferative skin lesions lacking malignant potential. Nine of 33 (27%) EN harbored PIK3CA mutations; all cases showed the E545G substitution, which is uncommon in cancers. In EN, R248C was the only FGFR3 mutation identified. By contrast, 10 of 62 (16%) SK revealed the typical cancer-associated PIK3CA mutations E542K, E545K, and H1047R. The same lesions displayed a wide range of FGFR3 mutations. Corresponding unaffected tissue was available for four EN and two mutant SK: all control samples displayed a WT sequence, confirming the somatic nature of the mutations found in lesional tissue. Forty of 95 (42%) lesions showed at least one mutation in either gene. PIK3CA and FGFR3 mutations displayed an independent distribution; 5/95 lesions harbored mutations in both genes. Our findings suggest that, in addition to their role in cancer, oncogenic PIK3CA mutations contribute to the pathogenesis of skin tumors lacking malignant potential. The remarkable genotype–phenotype correlation as observed in this study points to a distinct etiopathogenesis of the mutations in keratinocytes occuring either during fetal development or in adult life. PMID:17673550

  19. Initial experiments with the Nevis Cyclotron, the Brookhaven Cosmotron, the Brookhaven AGS and their effects on high energy physics

    SciTech Connect

    Lindenbaum, S.J.

    1988-01-01

    The first experiment at the Nevis Cyclotron by Bernardini, Booth and Lindenbaum demonstrated that nuclear stars are produced by a nucleon-nucleon cascade within the nucleon. This solved a long standing problem in Cosmic rays and made it clear that where they overlap cosmic ray investigation would not be competitive with accelerator investigations. The initial experiments at the Brookhaven Cosmotron by Lindenbaum and Yuan demonstrated that low energy pion nucleon scattering and pion production were unexpectedly mostly due to excitation of the isotopic spin = angular momentum = 3/2 isobaric state of the nucleon. This contradicted the Fermi statistical theory and led to the Isobar model proposed by the author and a collaborator. The initial experiments at the AGS by the author and collaborators demonstrated that the Pomeronchuck Theorem would not come true till at least several hundred GeV. These scattering experiments led to the development of the ''On-line Computer Technique'' by the author and collaborators which is now the almost universal technique in high energy physics. The first accomplishment which flowed from this technique led to contradiction of the Regge pole theory as a dynamical asymptotic theory, by the author and collaborators. The first critical experimental proof of the forward dispersion relation in strong interactions was accomplished by the author and collaborators. They were then used as a crystal ball to predict that ''Asymptopia''---the theoretically promised land where all asymptotic theorems come true---would not be reached till at least 25,000 BeV and probably not before 1,000,000 BeV. 26 refs., 11 figs., 2 tabs.

  20. Acquired Brain Injury Program.

    ERIC Educational Resources Information Center

    Schwartz, Stacey Hunter

    This paper reviews the Acquired Brain Injury (ABI) Program at Coastline Community College (California). The ABI Program is a two-year, for-credit educational curriculum designed to provide structured cognitive retraining for adults who have sustained an ABI due to traumatic (such as motor vehicle accident or fall) or non-traumatic(such as…

  1. The Transcription Factors Ets1 and Sox10 Interact During Murine Melanocyte Development

    PubMed Central

    Saldana-Caboverde, Amy; Perera, Erasmo M.; Watkins-Chow, Dawn; Hansen, Nancy F.; Vemulapalli, Meghana; Mullikin, James C; Pavan, William J.; Kos, Lidia

    2015-01-01

    Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was

  2. Cytosolic dsDNA triggers apoptosis and pro-inflammatory cytokine production in normal human melanocytes.

    PubMed

    Wang, Suiquan; Liu, Dongyin; Ning, Weixuan; Xu, Aie

    2015-04-01

    Considerable evidence implicates that viral infection might be a participant factor in the pathogenesis of vitiligo. However, it is still unclear how viral infection leads to the melanocyte destruction. To elucidate the effects of viral dsDNA on the viability and cytokine synthesis of normal human melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were transfected with poly(dA:dT). The results demonstrated that poly(dA:dT) triggered apoptosis instead of pyroptosis in melanocytes. Knocking down AIM2 or RIG-I by RNA interference partially reduced the poly(dA:dT)-induced LDH release, suggesting the involvement of both nucleic acid sensors in the process of melanocyte death. Poly(dA:dT) induced the expression of pro-inflammatory cytokine genes including IFN-β, TNF-α, IL-6 and IL-8 as well, whereas the pro-inflammatory cytokine production was suppressed by RIG-I siRNA, but not by AIM2 siRNA. Poly(dA:dT) treatment increased the phosphorylation of p38 and JNK and NFκB. Accordingly, NFκB inhibitor Bay 11-7082 and JNK inhibitor SP600125 blocked the induction of the cytokine genes except IFN-β. The production of IL6 and IL8 was also suppressed by p38 inhibitor SB203580. On the contrary, the Poly(dA:dT)-induced melanocyte death was only decreased by SP600125. This study provides the possible mechanism of melanocyte destruction and immuno-stimulation in vitiligo by innate immune response following viral infection.

  3. Differentiating the stem cell pool of human hair follicle outer root sheath into functional melanocytes.

    PubMed

    Schneider, Marie; Dieckmann, Christina; Rabe, Katrin; Simon, Jan-Christoph; Savkovic, Vuk

    2014-01-01

    Bench-to-Bedside concepts for regenerative therapy place significant weight on noninvasive approaches, with harvesting of the starting material as a header. This is particularly important in autologous treatments, which use one's bodily constituents for therapy. Precisely the stretch between obtaining therapeutic elements invasively and noninvasively places non-intrusive "sampling" rather than "biopsy" in the center of the road map of developing an autologous regenerative therapy. We focus on such a noninvasively available source of adult stem cells that we carry with us throughout our life, available at our fingertips-or shall we say hair roots, by a simple plucking of hair: the human hair follicle. This chapter describes an explant procedure for cultivating melanocytes differentiated from the stem cell pool of the hair follicle Outer Root Sheath (ORS). In vivo, the most abundant derivatives of the heterogeneous ORS stem cell pool are epidermal cells-melanocytes and keratinocytes which complete their differentiation-either spontaneously or upon picking up regenerative cues from damaged skin-and migrate from the ORS towards the adjacent regenerating area of the epidermis. We have taken advantage of the ORS developmental potential by optimizing explant primary culture, expansion and melanogenic differentiation of resident ORS stem cells towards end-stage melanocytes in order to obtain functional melanocytes noninvasively for the purposes of transplantation and use them for the treatment of depigmentation disorders. Our protocol specifies sampling of hair with their ORS, follicle medium-air interface primary culture, stimulation of cell outgrowth, adherent culture and differentiation of ORS stem cells and precursors towards fully functional melanocytes. Along with cultivation, we describe selection techniques for establishing and maintaining a pure melanocyte population and methods suitable for determining melanocyte identity.

  4. Differential responses of choroidal melanocytes and uveal melanoma cells to low oxygen conditions

    PubMed Central

    Weidmann, Cindy; Pomerleau, Jade; Trudel-Vandal, Laurence

    2017-01-01

    Purpose Tissue culture is traditionally performed at atmospheric oxygen concentration (21%), which induces hyperoxic stress, as endogenous physiologic oxygen tension found in tissues varies between 2% and 9%. This discrepancy may lead to misinterpretation of results and may explain why effects observed in vitro cannot always be reproduced in vivo and vice versa. Only a few studies have been conducted in low physiologic oxygen conditions to understand the development and differentiation of cells from the eye. Methods The aim of this study was to investigate the growth and gene expression profile of melanocytes from the choroid permanently exposed to 21% (hyperoxic) or 3% (physiologic) oxygen with proliferation assays and DNA microarray. The cellular behavior of the melanocytes was then compared to that of cancer cells. Results The gross morphology and melanin content of choroidal melanocytes changed slightly when they were exposed to 3% O2, and the doubling time was statistically significantly faster. There was an increase in the percentage of choroidal melanocytes in the active phases of the cell cycle as observed by using the proliferation marker Ki67. The caveolin-1 senescence marker was not increased in choroidal melanocytes or uveal melanoma cells grown in hyperoxia. In comparison, the morphology of the uveal melanoma cells was similar between the two oxygen levels, and the doubling time was slower at 3% O2. Surprisingly, gene expression profiling of the choroidal melanocytes did not reveal a large list of transcripts considerably dysregulated between the two oxygen concentrations; only the lactate transporter monocarboxylate transporter (MCT4) was statistically significantly upregulated at 3% O2. Conclusions This study showed that the oxygen concentration must be tightly controlled in experimental settings, because it influences the subsequent cellular behavior of human choroidal melanocytes. PMID:28356703

  5. Lack of prognostic significance of angiogenesis in canine melanocytic tumours.

    PubMed

    Cuitiño, M C; Massone, A R; Idiart, J R

    2012-01-01

    The prognostic significance of angiogenesis in some canine tumours has been investigated, but little is known about its relevance in canine melanocytic tumours (MTs). The aim of this study was to evaluate the prognostic significance of angiogenesis in canine MTs. A total of 36 cutaneous melanocytomas (benign MTs), 40 cutaneous melanomas (malignant MTs) and 43 oral melanomas were studied. Survival data were available for a subset of 59 cases. Microvessel density (MVD) and endothelial area (EA) were determined by immunolabelling using an antibody specific for von Willebrand factor (vWF). Mean MVD (expressed as the number of microvessels per mm(2)) was 129 ± 14 in melanocytomas, 191 ± 16 in cutaneous melanomas and 208 ± 16 in oral melanomas. Mean EA (expressed as the percentage of the total area) was 1.5 ± 0.14 in melanocytomas, 2.6 ± 0.2 in cutaneous melanomas and 2.4 ± 0.3 in oral melanomas. The differences in MVD and EA between melanocytomas and melanomas were significant (P = 0.001 and P = 0.003, respectively). MVD and EA were significantly correlated between cutaneous and oral MTs (r = 0.54; P <0.001 and r = 0.63; P <0.001, respectively). MVD and EA were not related to survival in cutaneous and oral MTs. In conclusion, tumour vascularization was higher in melanomas than in melanocytomas, but it seemed to have no prognostic significance in these tumours.

  6. Central nervous system imaging and congenital melanocytic naevi

    PubMed Central

    Kinsler, V; Aylett, S; Coley, S; Chong, W; Atherton, D

    2001-01-01

    AIM—To establish the prevalence of central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) in a population of children with congenital melanocytic naevi (CMN) over the head and/or spine, and to compare this with clinical findings.
METHODS—Forty three patients identified from outpatient clinics underwent MRI of the brain and/or spine. These were reported by a paediatric radiologist and findings compared with the clinical picture.
RESULTS—Nine patients had abnormal clinical neurology, seven had abnormal findings on MRI, and six had both abnormal clinical and radiological findings. Only three of the abnormal MRIs showed features of intracranial melanosis. Three others showed structural brain abnormalities: one choroid plexus papilloma, one cerebellar astrocytoma, and one posterior fossa arachnoid cyst; the first two of these have not previously been described in association with CMN. The last abnormal MRI showed equivocal changes requiring reimaging.
CONCLUSIONS—The prevalence of radiological CNS abnormality in this group of children was 7/43. Six of these developed abnormal clinical neurological signs within the first 18 months of life, but two did not do so until after the MRI. Two of the CNS lesions were operable; for this reason we support the routine use of early MRI in this group.

 PMID:11159293

  7. Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo.

    PubMed

    Shi, Q; Zhang, W; Guo, S; Jian, Z; Li, S; Li, K; Ge, R; Dai, W; Wang, G; Gao, T; Li, C

    2016-03-01

    Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H2O2-induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo.

  8. Hyperoside protects human primary melanocytes against H2O2-induced oxidative damage

    PubMed Central

    YANG, BIN; YANG, QIN; YANG, XIN; YAN, HONG-BO; LU, QI-PING

    2016-01-01

    Cuscutae semen has been shown to have beneficial effects in the treatment of vitiligo, recorded in the Chinese Pharmacopoeia, whereas the effects of its constituent compounds remains to be elucidated. Using a tetrazolium bromide assay, the present study found that hyperoside (0.5–200 µg/ml) significantly increased the viability of human melanocytes in a time- and dose-dependent manner. The present study used a cell model of hydrogen peroxide (H2O2)-induced oxidative damage to examine the effect of hyperoside on human primary melanocytes. The results demonstrated that hyperoside pretreatment for 2 h decreased cell apoptosis from 54.03±9.11 to 17.46±3.10% in the H2O2-injured melanocytes. The levels of oxidative stress in the mitochondrial membrane potential of the melanocytes increased following hyperoside pretreatment. The mRNA and protein levels of B-cell lymphoma-2/Bcl-2-associated X protein and caspase 3 were regulated by hyperoside, and phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling were also mediated by hyperoside. In conclusion, the results of the present study demonstrated that hyperoside protected the human primary melanocytes against oxidative damage. PMID:27082158

  9. UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes.

    PubMed

    Bellono, Nicholas W; Kammel, Laura G; Zimmerman, Anita L; Oancea, Elena

    2013-02-05

    Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.

  10. Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

    PubMed Central

    Levin, Mark D.; Lu, Min Min; Petrenko, Nataliya B.; Hawkins, Brian J.; Gupta, Tara H.; Lang, Deborah; Buckley, Peter T.; Jochems, Jeanine; Liu, Fang; Spurney, Christopher F.; Yuan, Li J.; Jacobson, Jason T.; Brown, Christopher B.; Huang, Li; Beermann, Friedrich; Margulies, Kenneth B.; Madesh, Muniswamy; Eberwine, James H.; Epstein, Jonathan A.; Patel, Vickas V.

    2009-01-01

    Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias. PMID:19855129

  11. Amides from Piper nigrum L. with dissimilar effects on melanocyte proliferation in-vitro.

    PubMed

    Lin, Zhixiu; Liao, Yonghong; Venkatasamy, Radhakrishnan; Hider, Robert C; Soumyanath, Amala

    2007-04-01

    Melanocyte proliferation stimulants are of interest as potential treatments for the depigmentary skin disorder, vitiligo. Piper nigrum L. (Piperaceae) fruit (black pepper) water extract and its main alkaloid, piperine (1), promote melanocyte proliferation in-vitro. A crude chloroform extract of P. nigrum containing piperine was more stimulatory than an equivalent concentration of the pure compound, suggesting the presence of other active components. Piperine (1), guineensine (2), pipericide (3), N-feruloyltyramine (4) and N-isobutyl-2E, 4E-dodecadienamide (5) were isolated from the chloroform extract. Their activity was compared with piperine and with commercial piperlongumine (6) and safrole (7), and synthetically prepared piperettine (8), piperlonguminine (9) and 1-(3, 4-methylenedioxyphenyl)-decane (10). Compounds 6-10 either occur in P. nigrum or are structurally related. Compounds 1, 2, 3, 8 and 9 stimulated melanocyte proliferation, whereas 4, 5, 6, 7 and 10 did not. Comparison of structures suggests that the methylenedioxyphenyl function is essential for melanocyte stimulatory activity. Only those compounds also possessing an amide group were active, although the amino component of the amide group and chain linking it to the methylenedioxyphenyl group can vary. P. nigrum, therefore, contains several amides with the ability to stimulate melanocyte proliferation. This finding supports the traditional use of P. nigrum extracts in vitiligo and provides new lead compounds for drug development for this disease.

  12. Agreement Between Cytology and Histopathology for Regional Lymph Node Metastasis in Dogs With Melanocytic Neoplasms.

    PubMed

    Grimes, Janet A; Matz, Brad M; Christopherson, Pete W; Koehler, Jey W; Cappelle, Kelsey K; Hlusko, Katelyn C; Smith, Annette

    2017-01-01

    Melanocytic neoplasms are common in dogs and frequently occur within the oral cavity or in haired skin. The behavior of melanocytic neoplasms is variable and depends on tumor location, size, and histopathologic features. This study compared cytopathology and histopathology of 32 lymph nodes from 27 dogs diagnosed with melanocytic neoplasms. Agreement between the original cytology report, cytology slide review, original histopathology report, and histopathology slide review was determined for each lymph node. A subset of lymph nodes was subjected to immunohistochemistry (Melan-A) and additional histochemical stains/techniques (Prussian blue, bleach) to assist in differentiation of melanocytes and melanophages. Agreement ranged from slight to fair for each of the variables evaluated with weighted kappa (κw) or kappa (κ) analysis (original cytology vs cytology review κw = 0.24; original cytology vs original histopathology κw = 0.007; original cytology vs histopathology review κw = 0.23; cytology review vs original histopathology κw = 0.008; cytology review vs histopathology review κw = 0.006; and original histopathology vs histopathology review κ = 0.18). The diagnoses (metastatic, equivocal, or negative for metastasis) of the original report and slide review for both cytology and histopathology were not significantly correlated with survival in this population of patients. Overall, agreement between cytology and histopathology was poor even with a single clinical or anatomic pathologist performing slide review. Consensus between routine cytology and histopathology for staging of lymph nodes in patients with melanocytic neoplasms is poor and does not correlate with survival.

  13. Differential PAX3 functions in normal skin melanocytes and melanoma cells.

    PubMed

    Medic, Sandra; Rizos, Helen; Ziman, Mel

    2011-08-12

    The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as "stem" cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated "stem" cell like phenotype, PAX3 may contribute to melanoma development and progression.

  14. UVB represses melanocyte cell migration and acts through β-catenin.

    PubMed

    Bertrand, Juliette U; Petit, Valérie; Hacker, Elke; Berlin, Irina; Hayward, Nicholas K; Pouteaux, Marie; Sage, Evelyne; Whiteman, David C; Larue, Lionel

    2017-02-13

    The exposure of skin to ultraviolet (UV) radiation can have both beneficial and deleterious effects: it can lead, for instance, to increased pigmentation and vitamin D synthesis but also to inflammation and skin cancer. UVB may induce genetic and epigenetic alterations, and have reversible effects associated with post-translational and gene regulation modifications. β-catenin is a main driver in melanocyte development; although infrequently mutated in melanoma, its cellular localization and activity is frequently altered. Here, we evaluate the consequence of UVB on β-catenin in the melanocyte lineage. We report that in vivo, UVB induces cytoplasmic/nuclear relocalization of β-catenin in melanocytes of newborn mice and adult human skin. In mouse melanocyte and human melanoma cell lines in vitro, UVB increases β-catenin stability, accumulation in the nucleus, and co-transcriptional activity, leading to the repression of cell motility and velocity. The activation of the β-catenin signaling pathway and its effect on migration by UVB are increased by an inhibitor of GSK3β, and decreased by an inhibitor of β-catenin. In conclusion, UVB represses melanocyte migration and does so by acting through the GSK3-β-catenin axis. This article is protected by copyright. All rights reserved.

  15. The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes.

    PubMed

    Zhao, Wei; Mazar, Joseph; Lee, Bongyong; Sawada, Junko; Li, Jian-Liang; Shelley, John; Govindarajan, Subramaniam; Towler, Dwight; Mattick, John S; Komatsu, Masanobu; Dinger, Marcel E; Perera, Ranjan J

    2016-04-01

    The long noncoding RNA SPRIGHTLY (formerly SPRY4-IT1), which lies within the intronic region of the SPRY4 gene, is up-regulated in human melanoma cells compared to melanocytes. SPRIGHTLY regulates a number of cancer hallmarks, including proliferation, motility, and apoptosis. To better understand its oncogenic role, SPRIGHTLY was stably transfected into human melanocytes, which resulted in increased cellular proliferation, colony formation, invasion, and development of a multinucleated dendritic-like phenotype. RNA sequencing and mass spectrometric analysis of SPRIGHTLY-expressing cells revealed changes in the expression of genes involved in cell proliferation, apoptosis, chromosome organization, regulation of DNA damage responses, and cell cycle. The proliferation marker Ki67, minichromosome maintenance genes 2-5, antiapoptotic gene X-linked inhibitor of apoptosis, and baculoviral IAP repeat-containing 7 were all up-regulated in SPRIGHTLY-expressing melanocytes, whereas the proapoptotic tumor suppressor gene DPPIV/CD26 was down-regulated, followed by an increase in extracellular signal-regulated kinase 1/2 phosphorylation, suggesting an increase in mitogen-activated protein kinase activity. Because down-regulation of DPPIV is known to be associated with malignant transformation in melanocytes, SPRIGHTLY-mediated DPPIV down-regulation may play an important role in melanoma pathobiology. Together, these findings provide important insights into how SPRIGHTLY regulates cell proliferation and anchorage-independent colony formation in primary human melanocytes.

  16. Hypergravity modulates cyclic GMP efflux in nitric oxide-stimulated human melanocytic cells

    NASA Astrophysics Data System (ADS)

    Stieber, Christiane; Ivannova, Krassimira; Block, Ingrid; Gerzer, Rupert

    2005-08-01

    Gravity alteration is known to influence cell functions. We recently found that hypergravity may stimulate cGMP efflux in human melanocytic cells when cGMP hydrolysis is inhibited. Here we examined whether hypergravity modulates cGMP efflux in nitric oxide (NO)-stimulated melanocytes and melanoma cells (MCs) using NONOates as direct NO donors. In the presence of 0.1 mM DETA-NO and long-term application of hypergravity (up to 5g for 24 h) an elevated cGMP efflux in cultured melanocytes and non-metastatic MCs compared to 1g was observed, whereas short-term exposure was not effective. The hypergravity-stimulated cGMP efflux was inhibited by 1 μM trequinsin, a selective inhibitor of the multidrug resistance proteins 4 and 5 (MRP4/5). The results of the present study indicate that hypergravity may stimulate cGMP efflux in NO- stimulated human melanocytes and non-metastatic MCs most probably by an enhanced expression of MRP4/5. Thus, an altered acceleration vector may induce signaling events in human melanocytic cells.

  17. Nicotine impact on melanogenesis and antioxidant defense system in HEMn-DP melanocytes.

    PubMed

    Delijewski, Marcin; Wrześniok, Dorota; Otręba, Michał; Beberok, Artur; Rok, Jakub; Buszman, Ewa

    2014-10-01

    Nicotine is a compound of tobacco plants and is responsible for addictive properties of tobacco which is used by about one billion of smokers all over the world. Recently, nicotine has drawn even more attention due to its presumed neuroprotective and antioxidant features as far as common use in various forms of smoking cessation therapies. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn influence biochemical processes in human cells producing melanin. The aim of this study was to examine the impact of nicotine on melanogenesis and antioxidant defense system in cultured normal human melanocytes (HEMn-DP). Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be 2.52 mM. Nicotine modulated melanin biosynthesis in normal human melanocytes. Significant changes in hydrogen peroxide content and cellular antioxidant enzymes: SOD, CAT, and GPx activities were stated in melanocytes exposed to nicotine, which indicates alterations of antioxidant defense system. The results obtained in vitro may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long-term exposition to nicotine.

  18. Melanocytes and keratinocytes have distinct and shared responses to ultraviolet radiation and arsenic.

    PubMed

    Cooper, K L; Yager, J W; Hudson, L G

    2014-01-30

    The rise of melanoma incidence in the United States is a growing public health concern. A limited number of epidemiology studies suggest an association between arsenic levels and melanoma risk. Arsenic acts as a co-carcinogen with ultraviolet radiation (UVR) for the development of squamous cell carcinoma and proposed mechanisms include generation of oxidative stress by arsenic and UVR and inhibition of UVR-induced DNA repair by arsenic. In this study, we investigate similarities and differences in response to arsenic and UVR in keratinocytes and melanocytes. Normal melanocytes are markedly more resistant to UVR-induced cytotoxicity than normal keratinocytes, but both cell types are equally sensitive to arsenite. Melanocytes were more resistant to arsenite and UVR stimulation of superoxide production than keratinocytes, but the concentration of arsenite necessary to inhibit the activity of the DNA repair protein poly(ADP-ribose)polymerase and enhance retention of UVR-induced DNA damage was essentially equivalent in both cell types. These findings suggest that although melanocytes are less sensitive than keratinocytes to initial UVR-mediated DNA damage, both of these important target cells in the skin share a mechanism related to arsenic inhibition of DNA repair. These findings suggest that concurrent chronic arsenic exposure could promote retention of unrepaired DNA damage in melanocytes and act as a co-carcinogen in melanoma.

  19. Impact of kanamycin on melanogenesis and antioxidant enzymes activity in melanocytes--an in vitro study.

    PubMed

    Wrześniok, Dorota; Otręba, Michał; Beberok, Artur; Buszman, Ewa

    2013-12-01

    Aminoglycosides, broad spectrum aminoglycoside antibiotics, are used in various infections therapy due to their good antimicrobial characteristics. However, their adverse effects such as nephrotoxicity and auditory ototoxicity, as well as some toxic effects directed to pigmented tissues, complicate the use of these agents. This study was undertaken to investigate the effect of aminoglycoside antibiotic-kanamycin on viability, melanogenesis and antioxidant enzymes activity in cultured human normal melanocytes (HEMa-LP). It has been demonstrated that kanamycin induces concentration-dependent loss in melanocytes viability. The value of EC50 was found to be ~6.0 mM. Kanamycin suppressed melanin biosynthesis: antibiotic was shown to inhibit cellular tyrosinase activity and to reduce melanin content in normal human melanocytes. Significant changes in the cellular antioxidant enzymes: SOD, CAT and GPx were stated in melanocytes exposed to kanamycin. Moreover, it was observed that kanamycin caused depletion of antioxidant defense sytem. It is concluded that the inhibitory effect of kanamycin on melanogenesis and not sufficient antioxidant defense mechanism in melanocytes in vitro may explain the potential mechanisms of undesirable side effects of this drug directed to pigmented tissues in vivo.

  20. Manassantin B inhibits melanosome transport in melanocytes by disrupting the melanophilin-myosin Va interaction.

    PubMed

    Chang, Huikyoung; Choi, Hyunjung; Joo, Kyung-Mi; Kim, Daegun; Lee, Tae Ryong

    2012-11-01

    Human skin hyperpigmentation disorders occur when the synthesis and/or distribution of melanin increases. The distribution of melanin in the skin is achieved by melanosome transport and transfer. The transport of melanosomes, the organelles where melanin is made, in a melanocyte precedes the transfer of the melanosomes to a keratinocyte. Therefore, hyperpigmentation can be regulated by decreasing melanosome transport. In this study, we found that an extract of Saururus chinensis Baill (ESCB) and one of its components, manassantin B, inhibited melanosome transport in Melan-a melanocytes and normal human melanocytes (NHMs). Manassantin B disturbed melanosome transport by disrupting the interaction between melanophilin and myosin Va. Manassantin B is neither a direct nor an indirect inhibitor of tyrosinase. The total melanin content was not reduced when melanosome transport was inhibited in a Melan-a melanocyte monoculture by manassantin B. Manassantin B decreased melanin content only when Melan-a melanocytes were co-cultured with SP-1 keratinocytes or stimulated by α-MSH. Therefore, we propose that specific inhibitors of melanosome transport, such as manassantin B, are potential candidate or lead compounds for the development of agents to treat undesirable hyperpigmentation of the skin.

  1. Hospital-acquired thrombocytopenia.

    PubMed

    McMahon, Christine M; Cuker, Adam

    2014-10-01

    The development of thrombocytopenia is common in hospitalized patients and is associated with increased mortality. Frequent and important causes of thrombocytopenia in hospitalized patients include etiologies related to the underlying illness for which the patient is admitted, such as infection and disseminated intravascular coagulation, and iatrogenic etiologies such as drug-induced immune thrombocytopenia, heparin-induced thrombocytopenia, posttransfusion purpura, hemodilution, major surgery, and extracorporeal circuitry. This review presents a brief discussion of the pathophysiology, distinguishing clinical features, and management of these etiologies, and provides a diagnostic approach to hospital-acquired thrombocytopenia that considers the timing and severity of the platelet count fall, the presence of hemorrhage or thrombosis, the clinical context, and the peripheral blood smear. This approach may offer guidance to clinicians in distinguishing among the various causes of hospital-acquired thrombocytopenia and providing management appropriate to the etiology.

  2. Desmosomes in acquired disease

    PubMed Central

    Stahley, Sara N.; Kowalczyk, Andrew P.

    2015-01-01

    Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement functions to integrate adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, that occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on how human diseases inform our understanding of basic desmosome biology, and in turn, how fundamental advances in the cell biology of desmosomes may lead to new treatments for acquired diseases of the desmosome. PMID:25795143

  3. Desmosomes in acquired disease.

    PubMed

    Stahley, Sara N; Kowalczyk, Andrew P

    2015-06-01

    Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome.

  4. Melanocyte migration is influenced by E-cadherin-dependent adhesion of keratinocytes in both two- and three-dimensional in vitro wound models.

    PubMed

    Keswell, Dheshnie; Kidson, Susan H; Davids, Lester M

    2015-02-01

    During wound healing, melanocytes are required to migrate into the wounded area that is still in the process of re-construction. The role and behaviour of melanocytes during this process is poorly understood, that is, whether melanocyte migration into the wound is keratinocyte-dependent or not. This paper attempts, through the use of both two- and three-dimensional in vitro models, to understand the role and behaviour of melanocytes during the process of wound healing. In addition, it sheds light on whether keratinocytes influence/contribute toward melanocyte migration and ultimately wound healing. Scratch assays were performed to analyse migration and Western blot analyses measured cellular E-cadherin expression. Immunohistochemistry was used to analyse the in vivo 3D wound healing effect. Scratch assays performed on co-cultures of melanocytes and keratinocytes demonstrated that melanocytes actively migrated, with the use of their dendrites, into the scratch ahead of the proliferating keratinocyte sheet. Migration of the melanocyte into the wound bed was accompanied by loss of attachment to keratinocytes at the wound front with concomitant downregulation of E-cadherin expression as observed through immunocytochemistry. This result suggests that, in vitro, melanocyte migration occurs independently of keratinocytes but that the migration is influenced by keratinocyte E-cadherin expression. We now demonstrate that melanocyte migration during re-pigmentation is an active process, and suggest that targeting of mechanisms involved in active melanocyte migration (e.g. the melanocyte dendrite) may enhance the re-pigmentation process.

  5. The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology.

    PubMed

    Kawakami, Akinori; Fisher, David E

    2017-03-06

    Certain transcription factors have vital roles in lineage development, including specification of cell types and control of differentiation. Microphthalmia-associated transcription factor (MITF) is a key transcription factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis, including genes encoding proteins involved in apoptosis (eg, BCL2) and the cell cycle (eg, CDK2). Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas. In this article, we review basic features of MITF biological function and highlight key unresolved questions regarding this remarkable transcription factor.Laboratory Investigation advance online publication, 6 March 2017; doi:10.1038/labinvest.2017.9.

  6. Topology of feather melanocyte progenitor niche allows complex pigment patterns to emerge.

    PubMed

    Lin, S J; Foley, J; Jiang, T X; Yeh, C Y; Wu, P; Foley, A; Yen, C M; Huang, Y C; Cheng, H C; Chen, C F; Reeder, B; Jee, S H; Widelitz, R B; Chuong, C M

    2013-06-21

    Color patterns of bird plumage affect animal behavior and speciation. Diverse patterns are present in different species and within the individual. Here, we study the cellular and molecular basis of feather pigment pattern formation. Melanocyte progenitors are distributed as a horizontal ring in the proximal follicle, sending melanocytes vertically up into the epithelial cylinder, which gradually emerges as feathers grow. Different pigment patterns form by modulating the presence, arrangement, or differentiation of melanocytes. A layer of peripheral pulp further regulates pigmentation via patterned agouti expression. Lifetime feather cyclic regeneration resets pigment patterns for physiological needs. Thus, the evolution of stem cell niche topology allows complex pigment patterning through combinatorial co-option of simple regulatory mechanisms.

  7. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients.

    PubMed

    Ruggieri, Martino; Milone, Pietro; Pavone, Piero; Falsaperla, Raffaele; Polizzi, Agata; Caltabiano, Rosario; Fichera, Marco; Gabriele, Anna Lia; Distefano, Angela; De Pasquale, Rocco; Salpietro, Vincenzo; Micali, Giuseppe; Pavone, Lorenzo

    2012-11-01

    The term twin spotting refers to phenotypes characterized by the spatial and temporal co-occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra-cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so-called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28-year-old man and a 15-year-old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke-Davidoff-Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large hepatic cavernous vascular malformation, and left Legg-Calvé-Perthes disease (LCPD) [LCPD-like presentation]. Array-CGH analysis and mutation analysis of the RASA1 gene were normal in both patients.

  8. siRNA-mediated knock-down of COX-2 in melanocytes suppresses melanogenesis.

    PubMed

    Kim, Ji Y; Shin, Jae Y; Kim, Miri R; Hann, Seung-Kyung; Oh, Sang H

    2012-06-01

    Cyclooxygenase-2 (COX-2) is an enzyme induced in response to multiple mitogenic and inflammatory stimuli, including UV light. UV-induced COX-2 expression induces production of prostaglandin E2 (PGE2) in keratinocytes, which mediates inflammation and cell proliferation. Until recently, studies regarding COX-2 and PGE2 in the skin have focused on keratinocytes and skin cancer and the effect of PGs produced by keratinocytes on melanocytes. However, the effects of COX-2 itself or COX-2 inhibitors on melanogenesis are not well known. Therefore, to establish the role of COX-2 in melanogenesis, we investigated the effects of knock-down of COX-2 in melanocytes on melanin production and the expression of melanogenic molecules through silencing of COX-2 expression with COX-2 short interfering RNA (siRNA). COX-2 knock-down in melanocytes decreased the expressions of tyrosinase, TRP-1, TRP-2, gp100 and MITF and also reduced tyrosinase enzyme activity. Furthermore, COX-2 siRNA-transfected melanocytes showed markedly reduced alpha-melanocyte stimulating hormone (α-MSH)-induced melanin production. In addition, α-MSH-induced COX-2 expression in both scrambled siRNA-transfected and COX-2 siRNA-transfected melanocytes was greater than α-MSH-untreated cells. Our results suggest that COX-2 might be a candidate target for the development of anti-melanogenic agents and α-MSH-induced pigmentation could be closely associated with COX-2 expression. COX-2 inhibitors might therefore be of particular use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo.

  9. Melanocytes and melanin represent a first line of innate immunity against Candida albicans.

    PubMed

    Tapia, Cecilia V; Falconer, Maryanne; Tempio, Fabián; Falcón, Felipe; López, Mercedes; Fuentes, Marisol; Alburquenque, Claudio; Amaro, José; Bucarey, Sergio A; Di Nardo, Anna

    2014-07-01

    Melanocytes are dendritic cells located in the skin and mucosae that synthesize melanin. Some infections induce hypo- or hyperpigmentation, which is associated with the activation of Toll-like receptors (TLRs), especially TLR4. Candida albicans is an opportunist pathogen that can switch between blastoconidia and hyphae forms; the latter is associated with invasion. Our objectives in this study were to ascertain whether C. albicans induces pigmentation in melanocytes and whether this process is dependent on TLR activation, as well as relating this with the antifungal activity of melanin as a first line of innate immunity against fungal infections. Normal human melanocytes were stimulated with C. albicans supernatants or with crude extracts of the blastoconidia or hyphae forms, and pigmentation and TLR2/TLR4 expression were measured. Expression of the melanosomal antigens Melan-A and gp100 was examined for any correlation with increased melanin levels or antifungal activity in melanocyte lysates. Melanosomal antigens were induced earlier than cell pigmentation, and hyphae induced stronger melanization than blastoconidia. Notably, when melanocytes were stimulated with crude extracts of C. albicans, the cell surface expression of TLR2/TLR4 began at 48 h post-stimulation and peaked at 72 h. At this time, blastoconidia induced both TLR2 and TLR4 expression, whereas hyphae only induced TLR4 expression. Taken together, these results suggest that melanocytes play a key role in innate immune responses against C. albicans infections by recognizing pathogenic forms of C. albicans via TLR4, resulting in increased melanin content and inhibition of infection.

  10. Differential responses of normal human melanocytes to intra- and extracellular dsRNA.

    PubMed

    Wang, Suiquan; Liu, Dongyin; Jin, Rong; Zhu, Yiping; Xu, Aie

    2015-06-01

    Viral factor has been implicated in the etiopathogenesis of vitiligo. To elucidate the effects of viral double-stranded RNA (dsRNA) on melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were treated with synthetic viral dsRNA analog poly(I:C). The results demonstrated that poly(I:C)-triggered apoptosis when transfected into melanocytes, while extracellular poly(I:C) did not have that effect. Intracellular poly(I:C)-induced melanocyte death was decreased by RIG-I or MDA5 siRNA, but not by TLR3 siRNA. Both intracellular and extracellular poly(I:C) induced the expression of IFNB, TNF, IL6, and IL8. However, extracellular poly(I:C) demonstrated a much weaker induction capacity of cytokine genes than intracellular poly(I:C). Further analysis revealed that phosphorylation of TBK1, IRF3, IRF7, and TAK1 was differentially induced by intra- or extracellular poly(I:C). NFκB inhibitor Bay 11-7082 decreased the induction of all the cytokines by poly(I:C), suggesting the ubiquitous role of NFκB in the process. Poly(I:C) treatment also induced the phosphorylation of p38 and JNK in melanocytes. Both JNK and p38 inhibitors showed suppression on the cytokine induction by intra- or extracellular poly(I:C). However, only the JNK inhibitor decreased the intracellular poly(I:C)-induced melanocyte death. Taken together, this study provides the possible mechanism of viral factor in the pathogenesis of vitiligo.

  11. Porcine melanotic cutaneous lesions and lymph nodes: immunohistochemical differentiation of melanocytes and melanophages.

    PubMed

    Grossi, A B; Hyttel, P; Jensen, H E; Leifsson, P S

    2015-01-01

    Porcine melanomas have proven interesting in a wider biological perspective due to a common phenomenon of spontaneous regression, which is characterized by infiltration of macrophages, among others. Separation of neoplastic melanocytes from pigment-laden macrophages may, however, be challenging as the morphology of melanocytes varies considerably and sometimes resembles macrophages. The aim of this study was correspondingly to characterize and differentiate the cells in 20 porcine melanocytomas and regional lymph nodes by histologic examination and immunohistochemistry for melan A, PNL2, S100, lysozyme, alpha-1-antitrypsin, and ionized calcium binding adaptor molecule 1 (Iba1). Grossly, the melanocytomas were divided into 2 distinct types: pigmented maculae (n = 7) and raised tumors (n = 13). In the maculae, the pigmented cells were mainly melanocytes reactive for melan A, PNL2 and S100. In contrast, the majority of the cells in the raised tumors were melanophages, which expressed Iba1, alpha-1-antitrypsin, and lysozyme. Yet, cells histomorphologically indistinguishable from the melanophages expressed melan A and PNL2. These cells were Iba1 and S100 negative, and ultrastructurally, they were devoid of lysosomal bodies and filled with stage III and IV melanosomes. In the regional lymph nodes, melanocytes were present in the trabecular sinuses. In focally or diffusely black lymph nodes, pigmentation was, however, mainly due to aggregates of melanophages, which were confined to the trabeculae, deep cortex, and peripheral lymphoreticular tissue. Normal and neoplastic porcine melanocytes express melan A and PNL2, and immunohistochemical staining for melan A, PNL2, and Iba1 was found useful to identify and distinguish melanocytes and melanophages in porcine melanotic lesions.

  12. Acquired Factor V Inhibitor

    PubMed Central

    Hirai, Daisuke; Yamashita, Yugo; Masunaga, Nobutoyo; Katsura, Toshiaki; Akao, Masaharu; Okuno, Yoshiaki; Koyama, Hiroshi

    2016-01-01

    Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important. PMID:27746446

  13. Mechanisms contributing to differential regulation of PAX3 downstream target genes in normal human epidermal melanocytes versus melanoma cells.

    PubMed

    Bartlett, Danielle; Boyle, Glen M; Ziman, Mel; Medic, Sandra

    2015-01-01

    Melanoma is a highly aggressive and drug resistant form of skin cancer. It arises from melanocytes, the pigment producing cells of the skin. The formation of these melanocytes is driven by the transcription factor PAX3 early during embryonic development. As a result of alternative splicing, the PAX3 gene gives rise to eight different transcripts which encode isoforms that have different structures and activate different downstream target genes involved in pathways of cell proliferation, migration, differentiation and survival. Furthermore, post-translational modifications have also been shown to alter the functions of PAX3. We previously identified PAX3 downstream target genes in melanocytes and melanoma cells. Here we assessed the effects of PAX3 down-regulation on this panel of target genes in primary melanocytes versus melanoma cells. We show that PAX3 differentially regulates various downstream target genes involved in cell proliferation in melanoma cells compared to melanocytes. To determine mechanisms behind this differential downstream target gene regulation, we performed immunoprecipitation to assess post-translational modifications of the PAX3 protein as well as RNAseq to determine PAX3 transcript expression profiles in melanocytes compared to melanoma cells. Although PAX3 was found to be post-translationally modified, there was no qualitative difference in phosphorylation and ubiquitination between melanocytes and melanoma cells, while acetylation of PAX3 was reduced in melanoma cells. Additionally, there were differences in PAX3 transcript expression profiles between melanocytes and melanoma cells. In particular the PAX3E transcript, responsible for reducing melanocyte proliferation and increasing apoptosis, was found to be down-regulated in melanoma cells compared to melanocytes. These results suggest that alternate transcript expression profiles activate different downstream target genes leading to the melanoma phenotype.

  14. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  15. Acquired epidermodysplasia verruciformis.

    PubMed

    Rogers, Heather D; Macgregor, Jennifer L; Nord, Kristin M; Tyring, Stephen; Rady, Peter; Engler, Danielle E; Grossman, Marc E

    2009-02-01

    Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis with an increased susceptibility to specific human papillomavirus (HPV) genotypes. Classically, this viral infection leads to the development of tinea versicolor-like macules on the trunk, neck, arms, and face during childhood, and over time, these lesions can progress to squamous cell carcinoma. More recently, an EV-like syndrome has been described in patients with impaired cell-mediated immunity. We describe two cases of EV-like syndrome in HIV-positive patients, review all previously reported cases of EV in patients with impaired cell-mediated immunity, introduce the term "acquired epidermodysplasia verruciformis" to describe EV developing in the immunocompromised host and examine the limited treatment options for these patients.

  16. AIDS: acquired immunodeficiency syndrome.

    PubMed Central

    Gilmore, N. J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1983-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of utmost importance. PMID:6342737

  17. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  18. Situation Reports--Afghanistan, Bahrein, Brazil, Ecuador, Indonesia, Iraq, Morocco, Paraguay, People's Democratic Republic of Yemen, Peru, Qatar, Saudi Arabia, Sri Lanka, St. Christopher/Nevis, Sudan, United Arab Emirates, Yemen Arab Republic.

    ERIC Educational Resources Information Center

    International Planned Parenthood Federation, London (England).

    Data relating to population and family planning in 17 foreign countries are presented in these situation reports. Countries included are Afghanistan, Bahrein, Brazil, Ecuador, Indonesia, Iraq, Morocco, Paraguay, People's Democratic Republic of Yemen, Peru, Qatar, Saudi Arabia, Sri Lanka, St. Christopher/Nevis, Sudan, United Arab Emirates, and…

  19. Improving the Quality of Basic Education, Volume 6. Country Papers: Antigua, Bermuda, India, St. Kitts, Nevis, Turks & Caicos Islands. Conference of Commonwealth Education Ministers (11th, Barbados, October 29-November 2, 1990).

    ERIC Educational Resources Information Center

    Commonwealth Inst., London (England).

    Commonwealth Ministries of Education were asked to report on how they are undertaking the improvement of the quality of basic education in their respective countries. The papers in this volume focus on: (1) Antigua; (2) Bermuda; (3) India; (4) St. Kitts and Nevis; and (5) Turks and Caicos Islands. Charts and statistical data support each country's…

  20. Selective proliferation of normal human melanocytes in vitro in the presence of phorbol ester and cholera toxin by Eisinger and Marko.

    PubMed

    Scott, Glynis

    2014-01-01

    Melanocytes are pigment producing cells that arise from the neural crest and migrate to the skin early in fetal development. The pigment that melanocytes synthesize, melanin, plays a critical role in protecting the skin from mutagenic ultraviolet irradiation. Melanocytes are also precursor cells for melanoma, a deadly form of skin cancer. Because melanocytes make up a minority population of cells in the epidermis they have been difficult to propagate in culture. The landmark paper by Eisinger and Marko, described below, was the first successful report of large scale propagation of pure cultures of melanocytes. This paper set the stage for an explosive growth in knowledge in the biology of human melanocytes and allowed scientists to begin dissecting the different oncogenic events involved in the transition of melanocytes to melanoma.

  1. Effects of PGF{sub 2{alpha}} on human melanocytes and regulation of the FP receptor by ultraviolet radiation

    SciTech Connect

    Scott, Glynis . E-mail: Glynis_Scott@urmc.rochester.edu; Jacobs, Stacey; Leopardi, Sonya; Anthony, Frank A.; Learn, Doug; Malaviya, Rama; Pentland, Alice

    2005-04-01

    Prostaglandins are potent lipid hormones that activate multiple signaling pathways resulting in regulation of cellular growth, differentiation, and apoptosis. In the skin, prostaglandins are rapidly released by keratinocytes following ultraviolet radiation and are chronically present in inflammatory skin lesions. We have shown previously that melanocytes, which provide photoprotection to keratinocytes through the production of melanin, express several receptors for prostaglandins, including the PGE{sub 2} receptors EP{sub 1} and EP{sub 3} and the PGF{sub 2{alpha}} receptor FP, and that PGF{sub 2{alpha}} stimulates melanocyte dendricity. We now show that PGF{sub 2{alpha}} stimulates the activity and expression of tyrosinase, the rate-limiting enzyme in melanin synthesis. Analysis of FP receptor regulation showed that the FP receptor is regulated by ultraviolet radiation in melanocytes in vitro and in human skin in vivo. We also show that ultraviolet irradiation stimulates production of PGF{sub 2{alpha}} by melanocytes. These results show that PGF{sub 2{alpha}} binding to the FP receptor activates signals that stimulate a differentiated phenotype (dendricity and pigmentation) in melanocytes. The regulation of the FP receptor and the stimulation of production of PGF{sub 2{alpha}} in melanocytes in response to ultraviolet radiation suggest that PGF{sub 2{alpha}} could act as an autocrine factor for melanocyte differentiation.

  2. 4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo.

    PubMed

    Kroll, Tara M; Bommiasamy, Hemamalini; Boissy, Raymond E; Hernandez, Claudia; Nickoloff, Brian J; Mestril, Ruben; Caroline Le Poole, I

    2005-04-01

    The trigger initiating an autoimmune response against melanocytes in vitiligo remains unclear. Patients frequently experience stress to the skin prior to depigmentation. 4-tertiary butyl phenol (4-TBP) was used as a model compound to study the effects of stress on melanocytes. Heat shock protein (HSP)70 generated and secreted in response to 4-TBP was quantified. The protective potential of stress proteins generated following 4-TBP exposure was examined. It was studied whether HSP70 favors dendritic cell (DC) effector functions as well. Melanocytes were more sensitive to 4-TBP than fibroblasts, and HSP70 generated in response to 4-TBP exposure was partially released into the medium by immortalized vitiligo melanocyte cell line PIG3V. Stress protein HSP70 in turn induced membrane tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and activation of DC effector functions towards stressed melanocytes. Melanocytes exposed to 4-TBP demonstrated elevated TRAIL death receptor expression. DC effector functions were partially inhibited by blocking antibodies to TRAIL. TRAIL expression and infiltration by CD11c+ cells was abundant in perilesional vitiligo skin. Stressed melanocytes may mediate DC activation through release of HSP70, and DC effector functions appear to play a previously unappreciated role in progressive vitiligo.

  3. Enhanced bleaching treatment: opportunities for immune-assisted melanocyte suicide in vitiligo.

    PubMed

    Webb, Kirsten C; Eby, Jonathan M; Hariharan, Vidhya; Hernandez, Claudia; Luiten, Rosalie M; Le Poole, I Caroline

    2014-08-01

    Depigmentation in vitiligo occurs by progressive loss of melanocytes from the basal layer of the skin, and can be psychologically devastating to patients. T cell-mediated autoimmunity explains the progressive nature of this disease. Rather than being confronted with periods of rapid depigmentation and bouts of repigmentation, patients with long-standing, treatment-resistant vitiligo can undergo depigmentation treatment. The objective is to remove residual pigmentation to achieve a cosmetically acceptable result--that of skin with a uniform appearance. In the United States, only the use of mono-benzyl ether of hydroquinone (MBEH) is approved for this purpose. However, satisfactory results can take time to appear, and there is a risk of repigmentation. MBEH induces necrotic melanocyte death followed by a cytotoxic T-cell response to remaining, distant melanocytes. As cytotoxic T-cell responses are instrumental to depigmentation, we propose that combining MBEH with immune adjuvant therapies will accelerate immune-mediated melanocyte destruction to achieve faster, more definitive depigmentation than with MBEH alone. As Toll-like Receptor (TLR) agonists--imiquimod, CpG, and Heat Shock Protein 70 (HSP 70)--all support powerful Th1 responses, we propose that using MBEH in combination with these agents can achieve superior depigmentation results for vitiligo patients.

  4. Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes.

    PubMed

    Ferrucio, Bianca; Tiago, Manoela; Fannin, Richard D; Liu, Liwen; Gerrish, Kevin; Maria-Engler, Silvya Stuchi; Paules, Richard S; Barros, Silvia Berlanga de Moraes

    2017-02-01

    Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100μM) and solar radiation (375mJ/cm(2)). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKN1A, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation.

  5. Investigation by in vivo reflectance confocal microscopy: melanocytes at the edges of solar lentigines.

    PubMed

    Nakajima, Akiko; Funasaka, Yoko; Kawana, Seiji

    2012-07-01

    In vivo reflectance confocal microscopy (RCM) provides high-resolution, real-time optical sections of the skin in a non-invasive manner, allowing visualization of the skin in its native state. Highly reflective skin components including melanin, collagen and keratin appear bright (white) in RCM images. RCM examination of solar lentigines is known to show features that correlate well with histologic findings such as supranuclear melanin caps, but there are a limited number of reports on melanocyte dendrites. In this study, we utilized RCM to investigate the melanocyte dendricity and distribution within solar lentigines. Seventeen healthy Japanese females who had fairly large solar lentigines on their faces were recruited to join our clinical study, and we examined them by using RCM on their non-lesional areas, and the inside and the outer rim of the lesional areas. As a result, we discovered that dendritic melanocytes were rarely seen in the center of a solar lentigo (SL), but were seen at a very high frequency in the outer rim of a SL. The results suggest that the melanocytes are more active at the edge of a SL, produce more melanin, and often spread their dendrites widely in a horizontal direction. The findings in this report might shed light on the dynamic pathomechanisms of solar lentigines in vivo.

  6. Disruption of melanosome transport in melanocytes treated with theophylline causes their degradation by autophagy.

    PubMed

    Katsuyama, Yushi; Taira, Norihisa; Yoshioka, Masato; Okano, Yuri; Masaki, Hitoshi

    2017-02-07

    Melanosomes containing melanin are transported from the perinuclear area to the tips of dendrites in epidermal melanocytes, and are then transferred to keratinocytes. Thus, skin color is determined by the amount of melanin synthesized in melanocytes and the subsequent dispersion of melanosomes in the epidermis. Therefore, disrupting intracellular melanosome transport in melanocytes is considered an effective approach to regulate skin color. However, the fate of melanosomes that accumulate in melanocytes due to disrupted intracellular transport is unclear. In this study, we disrupted melanosome transport by knockdown of the motor protein MyosinVa. Knock-down of MyosinVa (M-KD) in cells treated with theophylline significantly down-regulated the mRNA and protein expression levels of tyrosinase. Interestingly, intracellular melanin contents in M-KD cells were decreased. Furthermore, M-KD cells showed activation of autophagy through increased expression of Microtubule-associated protein 1 light chain 3 (LC3) -II and decreased expression of p62. The sum of these results indicate that disruption of melanosome transport causes their degradation by autophagy.

  7. The human melanocyte as a particular target for UVA radiation and an endpoint for photoprotection assessment.

    PubMed

    Marrot, L; Belaidi, J P; Meunier, J R; Perez, P; Agapakis-Causse, C

    1999-06-01

    The induction of DNA breaks by UVA (320-400 nm) in the nucleus of normal human melanocytes in culture was investigated using single cell gel electrophoresis, also called the comet assay. Endogenous pigment and/or melanin-related molecules were found to enhance DNA breakage: comets were more intense in melanocytes than in fibroblasts, in cells with high melanin content or after stimulation of melanogenesis by supplying tyrosine in the culture medium. After UVA doses where strong comets were observed, neither cytotoxicity nor stimulation of tyrosinase activity were detected. However, the accumulation of p53 protein suggested that cells reacted to genotoxic stress under these experimental conditions. The same approach was used to compare two sunscreens with identical sun protection factors but different UVA protection factors. The results presented in this paper suggest that human melanocytes may be used as a target cell to evidence broadspectrum photoprotection. Moreover, these data appear to be helpful in getting a better understanding of the role of sunlight in the initiating steps of melanocyte transformation.

  8. Ultraviolet radiation acts as an independent mitogen for normal human melanocytes in culture

    SciTech Connect

    Libow, L.F.; Scheide, S.; DeLeo, V.A.

    1988-01-01

    Identification of growth factors for normal human melanocytes has been significantly aided by the recent development of in vitro culture systems for this cell. Utilizing such a system, we studied the effect of ultraviolet radiation (UVR) on both melanocyte growth and melanization by incorporation of 3H-thymidine and 3H-L-dihydroxyphenylalanine (3H-DOPA), respectively. 3H-thymidine incorporation was found to be significantly stimulated during the first 24 h following a single irradiation. 3H-DOPA incorporation was stimulated after a delay of 2 days postirradiation. Whereas UVR has long been known to induce melanocyte proliferation in vivo, these studies show that UVR can act as a mitogenic stimulus for this cell independent of the cutaneous environment. UVR can thus be added to a growing list of growth factors for epidermal pigment cells and is the only physical agent conclusively shown to act as a mitogen. Included in this list are substances that act via stimulation of the CAMP-kinase or protein kinase systems such as cholera toxin and phorbol esters. UVR is postulated to induce melanocyte proliferation by modulation of these second messenger pathways. With recent evidence linking growth factors, oncogenes and malignant transformation, this study supports the association between UVR exposure and the development of malignant melanoma, and suggests mechanisms whereby UVR may contribute to malignant transformation of this cell.

  9. CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.

    PubMed

    Slominski, Andrzej; Zbytek, Blazej; Szczesniewski, Andrzej; Semak, Igor; Kaminski, Jan; Sweatman, Trevor; Wortsman, Jacobo

    2005-04-01

    The response to systemic stress is organized along the hypothalamic-pituitary-adrenal axis (HPA), whereas the response to a peripheral stress (solar radiation) is mediated by epidermal melanocytes (cells of neural crest origin) responsible for the pigmentary reaction. Melanocytes express proopiomelanocortin (POMC), corticotropin-releasing hormone (CRH), and CRH receptor-1 (CRH-R1) and can produce corticosterone. In the present study, incubation of normal epidermal melanocytes with CRH was found to trigger a functional cascade structured hierarchically and arranged along the same algorithm as in the HPA axis: CRH activation of CRH-R1 stimulated cAMP accumulation and increased POMC gene expression and production of ACTH. CRH and ACTH also enhanced production of cortisol and corticosterone, and cortisol production was also stimulated by progesterone. The chemical identity of the cortisol was confirmed by liquid chromatography-mass spectrometry (LC/MS2) with [corrected] mass spectrometry-mass spectrometry analyses. POMC gene silencing abolished the stimulatory effect of CRH on corticosteroid synthesis, indicating that this is indirect and mediated via production of ACTH. Thus the melanocyte response to CRH is highly organized along the same functional hierarchy as the HPA axis. This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels.

  10. Proliferation, DNA ploidy, p53 overexpression and nuclear DNA fragmentation in six equine melanocytic tumours.

    PubMed

    Roels, S; Tilmant, K; Van Daele, A; Van Marck, E; Ducatelle, R

    2000-09-01

    Melanocytic tumours are a well-known clinical and pathological entity in horses, but further phenotypic characterization of these tumours is lacking. Six melanocytic tumours from five horses (two metastatic and four benign) were examined by Ki67, PCNA and p53 immunostaining, DNA nick end labelling (Tunel) and Feulgen staining. The stainings were evaluated using quantitative image analysis. The resulting parameters of growth fraction (Ki67), S-phase index (PCNA), p53 index, apoptotic index, DNA index, nuclear diameter, ploidy balance, proliferation index (Feulgen) and hyperploidy were analysed. The metastatic melanomas showed overexpression of p53 in a large portion of the cells. Apoptosis was also found in the metastatic melanomas. No differences were found in growth fraction, S-phase index (PCNA) nor in DNA configuration between the metastatic and the benign tumours. No immunohistochemical evidence of mutant p53 could be found in the tumours. In conclusion, melanocytic tumours in horses seem to have different phenotypic characteristics in comparison with melanocytic tumours in dogs, cats and humans, especially with respect to proliferative activity of the benign tumours. Therefore, markers put forward in these other species for predicting the clinical behaviour of the melanomas seem to be of no value in the horse. Moreover, quantitative DNA changes or p53 mutations do not seem to be involved in tumourogenesis in these cases.

  11. Postnatal lineage mapping of follicular melanocytes with the Tyr::CreER(T) (2) transgene.

    PubMed

    Harris, Melissa L; Pavan, William J

    2013-03-01

    One of the main advantages of using inducible and conditional transgenes to study pigment cell biology is that they allow for genetic manipulation within melanocytes after roles in general neural crest or melanoblast development have been fulfilled. Specifically, we focus here on the ability of the Tyr::CreER(T) (2) transgenic line to alter genes within follicular melanocytes postnatally. Using the Gt(ROSA)26Sor(tm1sor) reporter allele, we present in detail the expression and activity of Tyr::CreER(T) (2) when induced during hair morphogenesis and adult hair cycling. We find that despite similarities in expression pattern to endogenous TYR, Tyr::CreER(T) (2) is effective at targeting both undifferentiated and differentiated melanocytes within the hair follicle. We also find that Tyr::CreER(T) (2) provides the highest levels of recombination when induced during the early phases of hair growth. In conclusion, the descriptions provided here will guide future analyses of gene function within the melanocyte system of the hair follicle when using this Tyr::CreER(T) (2) transgene.

  12. TRPM1 Forms Ion Channels Associated with Melanin Content in Melanocytes

    PubMed Central

    Oancea, Elena; Vriens, Joris; Brauchi, Sebastian; Jun, Janice; Splawski, Igor; Clapham, David E.

    2014-01-01

    TRPM1(melastatin), which encodes the founding member of the TRPM family of transient receptor potential (TRP) ion channels, was first identified by its reduced expression in a highly metastatic mouse melanoma cell line. Clinically, TRPM1 is used as a predictor of melanoma progression in humans because of its reduced abundance in more aggressive forms of melanoma. Although TRPM1 is found primarily in melanin-producing cells and has the molecular architecture of an ion channel, its function is unknown. Here we describe an endogenous current in primary human neonatal epidermal melanocytes and mouse melanoma cells that was abrogated by expression of microRNA directed against TRPM1. Messenger RNA analysis showed that at least five human ion channel–forming isoforms of TRPM1 could be present in melanocytes, melanoma, brain, and retina. Two of these isoforms are encoded by highly conserved splice variants that are generated by previously uncharacterized exons. Expression of these two splice variants in human melanoma cells generated an ionic current similar to endogenous TRPM1 current. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures. Plasma membrane TRPM1 currents are small, raising the possibility that their primary function is intracellular, or restricted to specific regions of the plasma membrane. In neonatal human epidermal melanocytes, TRPM1 expression correlates with melanin content. We propose that TRPM1 is an ion channel whose function is critical to normal melanocyte pigmentation and is thus a potential target for pigmentation disorders. PMID:19436059

  13. The immunology and inflammatory responses of human melanocytes in infectious diseases.

    PubMed

    Gasque, Philippe; Jaffar-Bandjee, Marie Christine

    2015-10-01

    Melanin is a canonical and major defense molecule in invertebrates but its role in mammalian immunity remains unexplored. In contrast, several recent studies have highlighted the emerging innate immune activities of human melanin-producing cells which can sense and respond to bacterial and viral infections. Indeed, the skin is a major portal of entry for pathogens such as arboviruses (Chikungunya, Dengue) and bacteria (mycobacterium leprae, Leptospira spirochetes). Melanocytes of the epidermis could contribute to the phagocytosis of these invading pathogens and to present antigens to competent immune cells. Melanocytes are known to produce key cytokines such as IL-1β, IL6 and TNF-α as well as chemokines. These molecules will subsequently alert macrophages, neutrophils, fibroblasts and keratinocytes through unique crosstalk mechanisms. The infection and the inflammatory responses will control melanocyte's immune and metabolic functions and could contribute to skin manifestations (rash, hyper or de-pigmentation, epidermolysis and psoriasis-like lesions). This review will address the potential role of melanocytes in immunity, inflammation and infection of the skin in health and diseases.

  14. Helium-neon laser irradiation stimulates migration and proliferation in melanocytes and induces repigmentation in segmental-type vitiligo.

    PubMed

    Yu, Hsin-Su; Wu, Chieh-Shan; Yu, Chia-Li; Kao, Ying-Hsien; Chiou, Min-Hsi

    2003-01-01

    Low-energy helium-neon lasers (632.8 nm) have been employed in a variety of clinical treatments including vitiligo management. Light-mediated reaction to low-energy laser irradiation is referred to as biostimulation rather than a thermal effect. This study sought to determine the theoretical basis and clinical evidence for the effectiveness of helium-neon lasers in treating vitiligo. Cultured keratinocytes and fibroblasts were irradiated with 0.5-1.5 J per cm2 helium-neon laser radiation. The effects of the helium-neon laser on melanocyte growth and proliferation were investigated. The results of this in vitro study revealed a significant increase in basic fibroblast growth factor release from both keratinocytes and fibroblasts and a significant increase in nerve growth factor release from keratinocytes. Medium from helium-neon laser irradiated keratinocytes stimulated [3H]thymidine uptake and proliferation of cultured melanocytes. Furthermore, melanocyte migration was enhanced either directly by helium-neon laser irradiation or indirectly by the medium derived from helium-neon laser treated keratinocytes. Thirty patients with segmental-type vitiligo on the head and/or neck were enrolled in this study. Helium-neon laser light was administered locally at 3.0 J per cm2 with point stimulation once or twice weekly. The percentage of repigmented area was used for clinical evaluation of effectiveness. After an average of 16 treatment sessions, initial repigmentation was noticed. Marked repigmentation (>50%) was observed in 60% of patients with successive treatments. Basic fibroblast growth factor is a putative melanocyte growth factor, whereas nerve growth factor is a paracrine factor for melanocyte survival in the skin. Both nerve growth factor and basic fibroblast growth factor stimulate melanocyte migration. It is reasonable to propose that helium-neon laser irradiation clearly stimulates melanocyte migration and proliferation and mitogen release for melanocyte growth

  15. Biological characterization of human fibroblast-derived mitogenic factors for human melanocytes.

    PubMed Central

    Imokawa, G; Yada, Y; Morisaki, N; Kimura, M

    1998-01-01

    To clarify the paracrine linkage between human fibroblasts and melanocytes in cutaneous pigmentation, we studied the effects of human fibroblast-derived factors on the proliferation of human melanocytes. In medium conditioned for 4 days with human fibroblast culture, factors were produced that markedly stimulated DNA synthesis of human melanocytes. The stimulatory effect was higher in medium conditioned with fibroblasts from aged skin than in medium conditioned with fibroblasts from young skin, and was interrupted by inhibitors of tyrosine kinase, such as tyrphostin, genistein and herbimycin, but not by inhibitors of protein kinases C and A, such as H-7 and phloretin. The conditioned medium was also capable of activating mitogen-activated protein kinase of human melanocytes, with old fibroblasts being more effective than young ones. Analysis of factors released into the conditioned medium revealed that levels of hepatocyte growth factor (HGF) and stem cell factor (SCF) were increased in old-fibroblast-conditioned medium compared with young-fibroblast-conditioned medium. In contrast, levels of basic fibroblast growth factor (bFGF) were similar in both media. When the conditioned medium was treated with HGF antibody with or without SCF antibody, the increase in DNA synthesis by human melanocytes was decreased to 20% of the elevated level, whereas antibodies to bFGF had no effect. Analysis of the medium conditioned for 4 days after cytokine application demonstrated that, of the cytokines tested, interleukin 1alpha and tumour necrosis factor alpha are highly effective in stimulating HGF secretion by old fibroblasts. HGF and SCF, but not bFGF, were markedly increased in culture medium in the presence of IL-1alpha, and this stimulatory effect was confined to young human fibroblasts. These findings suggest that SCF and HGF derived from human fibroblasts may play a part in regulating cutaneous pigmentation during inflammation and aging. PMID:9494091

  16. Effects of hypergravity on the expression of multidrug resistance proteins in human melanocytic cells

    NASA Astrophysics Data System (ADS)

    Lambers, B.; Stieber, C.; Grigorieva, O.; Block, I.; Bromeis, B.; Buravkova, L.; Gerzer, R.; Ivanova, K.

    In humans the skin serves as a barrier against potentially harmful effects of the environment Human melanocytes constitute the principal cells for skin pigmentation by synthesizing the pigment melanin Melanin acts as a scavenger for free radicals that may arise during metabolic stress The melanocytes are also able to secrete a wide range of signal molecules In previous studies we found that normal human melanocytes NHMs and non-metastatic melanoma cells respond to long-time exposure to hypergravity up to 5 g for 24 h with elevated efflux of guanosine 3 5 -cyclic monophosphate cGMP in the presence of phosphodiesterase PDE inhibitors e g 3-isobutyl-1-methylxanthine Cyclic GMP is known to play a signaling role in human melanocyte physiology It controls the signaling activities of nitric oxide NO in relation to melanogenesis as well as in melanocyte-extracellular matrix interactions that may be important for some pathological processes including metastasis The present study investigated the effects of hypergravity on the expression of the multidrug resistance proteins MRP 4 and 5 as highly selective cGMP exporters in non-stimulated and NO-stimulated NHMs and melanoma cells MCs on mRNA levels using semi-quantitative RT-PCR analysis Hypergravity up to 5 g for 24 h was produced by horizontal centrifugal acceleration The NONOate DETA-NO 0 1 mM was used as a direct NO donor for cell stimulation For 5-g experiments the mRNA levels for the highly specific cGMP transporter MRP5 appeared to be

  17. Acquired aplastic anemia.

    PubMed

    Keohane, Elaine M

    2004-01-01

    Acquired aplastic anemia (AA) is a disorder characterized by a profound deficit of hematopoietic stem and progenitor cells, bone marrow hypocellularity, and peripheral blood pancytopenia. It primarily affects children, young adults, and those over 60 years of age. The majority of cases are idiopathic; however, idiosyncratic reactions to some drugs, chemicals, and viruses have been implicated in its etiology. An autoimmune T-cell reaction likely causes the stem cell depletion, but the precise mechanism, as well as the eliciting and target antigens, is unknown. Symptoms vary from severe life-threatening cytopenias to moderate or non-severe disease that does not require transfusion support. The peripheral blood typically exhibits pancytopenia, reticulocytopenia, and normocytic or macrocytic erythrocytes. The bone marrow is hypocellular and may exhibit dysplasia of the erythrocyte precursors. First line treatment for severe AA consists of hematopoietic stem cell transplantation in young patients with HLA identical siblings, while immunosuppression therapy is used for older patients and for those of any age who lack a HLA matched donor. Patients with AA have an increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute leukemia. Further elucidation of the pathophysiology of this disease will result in a better understanding of the interrelationship among AA, PNH, and MDS, and may lead to novel targeted therapies.

  18. Acquired spatial dyslexia.

    PubMed

    Siéroff, E

    2015-08-10

    Acquired spatial dyslexia is a reading disorder frequently occurring after left or right posterior brain lesions. This article describes several types of spatial dyslexia with an attentional approach. After right posterior lesions, patients show left neglect dyslexia with errors on the left side of text, words, and non-words. The deficit is frequently associated with left unilateral spatial neglect. Severe left neglect dyslexia can be detected with unlimited exposure duration of words or non-words. Minor neglect dyslexia is detected with brief presentation of bilateral words, one in the left and one in the right visual field (phenomenon of contralesional extinction). Neglect dyslexia can be explained as a difficulty in orienting attention to the left side of verbal stimuli. With left posterior lesions, spatial dyslexia is also frequent but multiform. Right neglect dyslexia is frequent, but right unilateral spatial neglect is rare. Attentional dyslexia represents difficulty in selecting a stimulus, letter or word among other similar stimuli; it is a deficit of attentional selection, and the left hemisphere plays a crucial role in selection. Two other types of spatial dyslexia can be found after left posterior lesions: paradoxical ipsilesional extinction and stimulus-centred neglect dyslexia. Disconnections between left or right parietal attentional areas and the left temporal visual word form area could explain these deficits. Overall, a model of attention dissociating modulation, selection control, and selection positioning can help in understanding these reading disorders.

  19. Acquired reactive perforating collagenosis

    PubMed Central

    Fei, Chengwen; Wang, Yao; Gong, Yu; Xu, Hui; Yu, Qian; Shi, Yuling

    2016-01-01

    Abstract Background: Reactive perforating collagenosis (RPC) is a rare form of transepithelial elimination, in which altered collagen is extruded through the epidermis. There are 2 types of RPC, acquired RPC (ARPC) and inherited RPC, while the latter is extremely rare. Here we report on 1 case of ARPC. Methods: A 73-year-old female was presented with strongly itchy papules over her back and lower limbs for 3 months. She denied the history of oozing or vesiculation. A cutaneous examination showed diffusely distributed multiple well-defined keratotic papules, 4 to 10 mm in diameter, on the bilateral lower limbs and back as well as a few papules on her chest and forearm. Scratching scars were over the resolved lesions while Koebner phenomenon was negative. The patient had a history of type 2 diabetes for 15 years. Laboratory examinations showed elevated blood glucose level. Skin lesion biopsy showed a well-circumscribed area of necrosis filled with a keratotic plug. Parakeratotic cells and lymphocytic infiltration could be seen in the necrosed area. In dermis, sparse fiber bundles were seen perforating the epidermis. These degenerated fiber bundles were notarized as collagen fiber by elastic fiber stain, suggesting a diagnosis of RPC. Results: Then a diagnosis of ARPC was made according to the onset age and the history of diabetes mellitus. She was treated with topical application of corticosteroids twice a day and oral antihistamine once a day along with compound glycyrrhizin tablets 3 times a day. And the blood glucose was controlled in a satisfying range. Two months later, a significant improvement was seen in this patient. Conclusion: Since there is no efficient therapy to RPC, moreover, ARPC is considered to be associated with some systemic diseases, the management of the coexisting disease is quite crucial. The patient in this case received a substantial improvement due to the control of blood glucose and application of compound glycyrrhizin tablets. PMID

  20. Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression.

    PubMed Central

    de Vries, T. J.; Quax, P. H.; Denijn, M.; Verrijp, K. N.; Verheijen, J. H.; Verspaget, H. W.; Weidle, U. H.; Ruiter, D. J.; van Muijen, G. N.

    1994-01-01

    Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis. Recently, we reported that highly metastatic behavior of human melanoma cells in nude mice correlates with urokinase-type PA (u-PA) expression and activity and with PA inhibitor type 1 and 2 (PAI-1, PAI-2) expression. Here we report on the occurrence of components of the PA system in the various stages of human melanoma tumor progression in situ. We studied the protein distribution on freshly frozen lesions of common nevocellular nevi (n = 25), dysplastic (= atypical) nevi (n = 16), early primary melanomas (n = 8), advanced primary melanomas (n = 11), and melanoma metastases (n = 17). Tissue-type PA was present in endothelial cells in all lesions, whereas in metastases it could be detected in tumor cells in a minority of the lesions. u-PA, its receptor, PAI-1, and PAI-2 could not be detected in benign and in early stages but appeared frequently in advanced primary melanoma and melanoma metastasis lesions. u-PA was detected in stromal cells and in tumor cells at the invasive front, the u-PA receptor and PAI-2 in tumor cells, and PAI-1 in the extracellular matrix surrounding tumor cells. Localization of the corresponding messenger RNAs and enzyme activities revealed a similar distribution. We conclude that plasminogen activation is a late event in melanoma tumor progression. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:8291613

  1. Pigmented oral compound nevus of retromolar area - A rare case report.

    PubMed

    Gombra, Virender; Kaur, Mandeep; Sircar, Keya; Popli, Deepika Bablani

    2016-12-01

    Solitary pigmented melanocytic intraoral lesions of the oral cavity are rare. Oral nevus is a congenital or acquired benign neoplasm. Oral compound nevus constitutes 5.9%-16.5% of all oral melanocytic nevi. The oral compound nevus is commonly seen on hard palate and buccal mucosa and rarely on other intraoral sites. The objective of this article is to present a rare case report of oral compound nevus in the retromolar pad region along with a review of literature. A 22 year old female reported with a solitary black pigmented papule at retromolar pad region which was surgically removed and microscopic investigation confirmed the diagnosis of oral compound nevus.

  2. Role of nitric oxide and cyclic GMP signaling in melanocyte response to hypergravity

    NASA Astrophysics Data System (ADS)

    Ivanova, Krassimira; Lambers, Britta; Tsiockas, Wasiliki; Block, Ingrid; Gerzer, Rupert

    Nitric oxide (NO) has a prominent role in many (patho)physiological processes in the skin including erythema, inflammation, and cancerogenesis. The soluble guanylyl cyclase (sGC), a key transducer in NO signaling, catalyzes the formation of the second messenger guanosine 3´,5´-cyclic monophosphate (cyclic cGMP or cGMP). For human melanocytes, which are responsible for skin pigmentation by synthesizing the pigment melanin, it has been reported that the NO/sGC/cGMP pathway is involved in UVB-induced melanogenesis. Melanin acts as a scavenger for free radicals that may arise during metabolic stress. It may also act as a photosensitizer that generates active oxygen species upon UV irradiation, which may initiate hypopigmentary disorders (e.g., vitiligo) as well as UV-induced oncogene cell transformation. In addition, melanoma, a deadly skin cancer, which arises from transformed melanocytes, is characterized by a resistance to chemotherapy. In our studies we have shown that NO can induce perturbation of melanocyte-extracellular matrix component interactions, which may contribute to loss of melanocytes or melanoma metastasis. Such NO effects appear to be modulated partly via cGMP. Moreover, we found that different guanylyl cyclase isoforms are responsible for cGMP synthesis in melanocytic cells. Normal human melanocytes and nonmetastatic melanoma cells predominantly express sGC, which appears to be associated with melanogenesis, whereas absence of NO-sensitive GC, but up-regulated activities of the natriuretic peptide-sensitive membrane guanylyl cyclase isoforms were found in highly metastatic phenotypes. Due to the growing interest in the regulation of signaling activities in normal and transformed cells under altered gravity conditions, we have further investigated whether the NO/cGMP signaling is involved in melanocyte response to gravitational stress. We found that normal human melanocytes and non-metastatic melanoma cell lines, but not highly metastatic cells

  3. Pigmentation PAX-ways: The role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease

    PubMed Central

    Kubic, Jennifer D.; Young, Kacey P.; Plummer, Rebecca S.; Ludvik, Anton E.; Lang, Deborah

    2010-01-01

    Transcription factors initiate a program of gene expression and are catalysts in downstream molecular cascades that modulate a variety of cellular processes. Pax3 is a transcription factor that is important in the melanocyte and influences melanocytic proliferation, resistance to apoptosis, migration, lineage specificity and differentiation. In this review, we focus on Pax3 and the molecular pathways that Pax3 is a part of during melanogenesis and in the melanocyte stem cell. These roles of Pax3 are emphasized during the development of diseases and syndromes resulting from either too much or too little Pax3 function. Due to its key task in melanocyte stem cells and tumors, the Pax3 pathway may provide an ideal target for either stem cell or cancer therapies. PMID:18983540

  4. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  5. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  6. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  7. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  8. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Acquiring and acquired persons. 801.2 Section 801.2 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976 COVERAGE RULES § 801.2...

  9. Reversal of developmental restrictions in neural crest lineages: Transition from Schwann cells to glial-melanocytic precursors in vitro

    PubMed Central

    Dupin, Elisabeth; Real, Carla; Glavieux-Pardanaud, Corinne; Vaigot, Pierre; Le Douarin, Nicole M.

    2003-01-01

    In vertebrate embryos, diversification of the lineages arising from the neural crest (NC) is controlled to a large extent by environmental factors. In previous work, we showed that endothelin 3 (ET3) peptide favors the development of glial and melanocytic NC precursors in vitro. This factor is also capable of inducing proliferation of cultured epidermal pigment cells and their conversion to glia. ET3 therefore strongly promotes the emergence of melanocytic and glial phenotypes from precursors and acts on the maintenance of these phenotypes. In the present work, we explored the capacity of ET3 to reprogram glial cells into melanocytes. Schwann cells expressing glial-specific markers [such as the Schwann cell myelin protein (SMP)] were isolated from sciatic nerves of quail embryos and cultured in vitro. We found that ET3 promotes cell growth and sequential expression of melanocyte differentiation markers in cultures of purified SMP-expressing cells, whereas it had no significant effect on SMP-negative cells from the same nerves. Moreover, we provide evidence for the transition of differentiated Schwann cells to melanocytes in clonal cultures. This transition involves the production of a mixed progeny of melanoblasts/melanocytes, glia, and cells bearing differentiation markers of both phenotypes. Therefore, Schwann cells exposed to ET3 transdifferentiate to melanocytes through reversion to the stage of bipotent glial-melanocytic NC precursors. These findings show that NC-derived pigment and glial cells are phenotypically unstable in vitro and may undergo reversal of precursor hierarchy to function as bipotent stem cells. PMID:12702775

  10. Oral compound nevus.

    PubMed

    Cardoso, Lyzete Berriel; Consalaro, Alberto; da Silva Santos, Paulo Sérgio; da Silva Sampieri, Marcelo Bonifácio; Tinoco-Araújo, José Endrigo

    2014-02-18

    The melanocytic nevus is a benign and focal proliferation of nevus cells that can be congenital or acquired. Intraoral lesions are uncommon, and the etiology and pathogenesis are poorly understood. The occurrence rate of oral compound nevus is about 5.9% to 16.5% of all oral melanocytic nevi. A 22-year-old male patient presented with a dark brown macule on the buccal mucosa of the maxilla in the region of tooth 26. The lesion was elliptical, 0.7 x 0.5 cm, well circumscribed, asymptomatic, and the evolution time was unknown. An excisional biopsy was performed and microscopic analysis revealed nests of nevus cells in the epithelium and underlying connective tissue that were compatible with melanocytic compound nevus. Owing to the clinical similarity between oral melanocytic nevus and oral melanoma, a histopathological analysis is mandatory for definitive diagnosis.

  11. Substantial Effect of Melanin Influencing Factors on In vitro Melanogenesis in Muzzle Melanocytes of Differently Colored Hanwoo

    PubMed Central

    Amna, Touseef; Park, Kyoung Mi; Cho, In-Kyung; Choi, Tae Jeong; Lee, Seung Soo; Seo, Kang-Seok; Hwang, Inho

    2012-01-01

    The present study was designed to investigate the effect of α-melanocyte-stimulating hormone (α-MSH), nitric oxide (NO) and L-cysteine on melanin production and expression of related genes MC1R, Tyr, Tyrp-1 and Tyrp-2 in muzzle melanocytes of differently colored three native Hanwoo cattle. Muzzle samples were taken from black, brindle and brown Hanwoo and purified melanocytes were cultured with α-MSH, nitric oxide and L-cysteine at 100 nM, 50 µM and 0.07 mg/ml of media respectively. The amounts of total melanin, eumelanin and mRNA expression at Tyr, Tyrp-1, Tyrp-2 and MC1R levels were quantified. α-MSH and nitric oxide significantly increased (p<0.05) the amount of total melanin in black and brindle whereas eumelanin production in brown Hanwoo muzzle melanocytes. On the contrary, L-cysteine greatly (p<0.05) depressed the eumelanin production in black color but increased in brown. Simultaneously, up regulation of Tyr by nitric oxide and α-MSH and down regulation of Tyr, Tyrp-2 and MC1R genes by L-cysteine were observed in muzzle melanocytes of all three phenotypes. The results of this study revealed nitric oxide and α-MSH contribute hyper-pigmentation by enhancing eumelanogenesis whereas L-cysteine contributes to pheomelanin production in different colored Hanwoo muzzle melanocytes. PMID:25049660

  12. Nests with numerous SOX10 and MiTF-positive cells in lichenoid inflammation: pseudomelanocytic nests or authentic melanocytic proliferation?

    PubMed

    Silva, Claudine Yap; Goldberg, Lynne J; Mahalingam, Meera; Bhawan, Jag; Wolpowitz, Deon

    2011-10-01

    Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Both melanocytic and cytokeratin immunohistochemical stains may be utilized to differentiate these entities. Unlike true melanocytic nests, pseudomelanocytic nests contain Melanoma Antigen Recognized by T-cells 1 (MART-1)/ Melan-A-positive cells and cells positive for pan-cytokeratins, CD3 and/or CD68. Recently, rare (1-2 cells/nest) microphthalmia- associated transcription factor (MiTF)-positive cells were also reported in pseudomelanocytic nests. We present a 48-year-old man with a 2 × 3 cm violaceous to hyperpigmented, non-blanching, polygonal patch on the neck. Histopathology showed focal epidermal atrophy, irregularly distributed junctional nests and a lichenoid infiltrate with colloid bodies. Immunoperoxidase studies revealed occasional pan-cytokeratin and MART-1/Melan-A-positive staining in nests as well as focal S-100 protein-positive cells. Importantly, the majority of nests showed numerous cells positive for MiTF and SOX10 (>2 cells/nest and some the majority of cells). This combined staining pattern confounds the above-described immunohistochemical distinction between pseudo and true melanocytic nests. Clinically felt to represent unilateral lichen planus pigmentosus/erythema dyschromicum perstans and not malignant melanoma in situ, this lesion highlights the importance of clinicopathologic correlation and suggests either a new melanocytic entity or a novel pattern of benign melanocytic reorganization in a subset of lichenoid dermatitides.

  13. Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes.

    PubMed

    Devi, Sulochana; Markandeya, Yogananda; Maddodi, Nityanand; Dhingra, Anuradha; Vardi, Noga; Balijepalli, Ravi C; Setaluri, Vijayasaradhi

    2013-05-01

    Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Gαo and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6, and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca(2+) uptake. Knockdown of TRPM1 or mGluR6 by shRNA abolished L-AP4-induced Ca(2+) influx and TRPM1 currents, showing that TRPM1 activity in melanocytes is positively coupled to mGluR6 signaling. Gαo protein is absent in melanocytes. However, forced expression of Gαo restored negative coupling of TRPM1 to mGluR6 signaling, but treatment with pertussis toxin, an inhibitor of Gi /Go proteins, did not affect basal or mGluR6-induced Ca(2+) uptake. Additionally, chronic stimulation of mGluR6 altered melanocyte morphology and increased melanin content. These data suggest differences in coupling of TRPM1 function to mGluR6 signaling explain different cellular responses to glutamate in the retina and the skin.

  14. Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes

    PubMed Central

    Devi, Sulochana; Markandeya, Yogananda; Maddodi, Nityanand; Dhingra, Anuradha; Vardi, Noga; Balijepalli, Ravi C; Setaluri, Vijayasaradhi

    2013-01-01

    SUMMARY Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Gαo and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6 and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca2+ uptake. Knockdown of TRPM1 or mGluR6 by shRNA abolished L-AP4-induced Ca2+ influx and TRPM1 currents showing that TRPM1 activity in melanocytes is positively coupled to mGluR6 signaling. Gαo protein is absent in melanocytes. However, forced expression of Gαo restored negative coupling of TRPM1 to mGluR6 signaling, but treatment with and pertussis toxin, an inhibitor of Gi/Go proteins, did not affect basal or mGluR6-induced Ca2+ uptake. Additionally, chronic stimulation of mGluR6 altered melanocyte morphology and increased melanin content. These data suggest differences in coupling of TRPM1 function to mGluR6 signaling explain different cellular responses to glutamate in the retina and the skin. PMID:23452348

  15. Pseudomelanocytic nests mimicking atypical melanocytic proliferations: first reported cases in the oral cavity.

    PubMed

    Boros, Audrey L; Handlers, Janice P; Melrose, Raymond J

    2014-10-01

    The concept of pseudomelanocytic nests has been recently described in the dermatology literature. To our knowledge, this entity has yet to be published in the oral pathology literature. We report 2 cases with features of pseudomelanocytic nests. In both instances, nests of cells suspicious for melanocytes were observed. Interpretation of melan-A was negative. Both cases showed strong and diffuse immunoreactivity of the nested cells to CD68. This immunohistochemical staining pattern is most consistent with a melanophage identity. Pseudomelanocytic nests are a recently described entity that represents a potential diagnostic pitfall. Distinguishing pseudomelanocytic nests from an authentic atypical melanocytic proliferation can be challenging and is important for appropriate patient management. Clinicopathologic correlation with cautious interpretation of immunohistochemistry may be necessary to arrive at the correct diagnosis. These cases represent the first reports of pseudomelanocytic nests in the oral pathology literature.

  16. "Sky Full of Stars" Pattern: Dermoscopic Findings in a Desmoplastic Giant Congenital Melanocytic Nevus.

    PubMed

    Martín-Carrasco, Pablo; Bernabeu-Wittel, José; Dominguez-Cruz, Javier; Zulueta Dorado, Teresa; Conejo-Mir Sanchez, Julian

    2017-02-27

    Desmoplastic giant congenital melanocytic nevus (DGCN) is an uncommon variant of congenital nevus, presenting as a progressive induration and hypopigmentation of the lesion that occasionally causes hair loss and even total or partial disappearance of the nevus. A 6-month-old girl with a giant congenital melanocytic nevus that involved the entire posterior side of the right thigh was seen in our department. Nine months later, the peripheral area of the nevus presented as a marked induration with hypopigmentation. Dermoscopy demonstrated a reticular pattern exclusively located in the perifollicular areas, with a radial distribution from the follicular ostium that mimicked a "sky full of stars." We report a case of DGCN, including a dermoscopic description of the findings noted in the indurated and hypopigmented areas that appear as a "sky full of stars" image.

  17. Melanocyte response to gravitational stress: an overview with a focus on the role of cyclic nucleotides

    NASA Astrophysics Data System (ADS)

    Ivanova, Krassimira; Tsiockas, Wasiliki; Eiermann, Peter; Hauslage, Jens; Hemmersbach, Ruth; Block, Ingrid; Gerzer, Rupert

    Human melanocytes are responsible for skin pigmentation by synthesizing the pigment melanin. A well known modulator of melanogenesis is the second messenger adenosine 3',5'-cyclic monophos-phate (cAMP). It has also been reported that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/guanosine 3',5'-cyclic monophosphate (cGMP) pathway is involved in UVB-induced melanogenesis. Melanin acts as a scavenger for free radicals during oxidative stress, but it may additionally act as a photosensitizer that generates active oxygen species upon UV radiation, which may initiate hypopigmentary disorders (e.g., vitiligo) as well as UV-induced oncogene cell transformation. Melanoma, a deadly skin cancer which arises from transformed melanocytes, is characterized by a resistance to chemotherapy. In our studies we were able to show that hu-man melanocytic cells differentially respond to gravitational stress. Hypergravity (up to 5 g for 24 h) stimulated cGMP efflux in cultured human melanocytes and non-metastatic melanoma cells, but not in metastatic phenotypes under the conditions of limited degradation [e.g., in the presence of phosphodiesterase (PDE) inhibitors] or stimulated synthesis of cGMP [e.g., by NO donors, but not natriuretic peptides], whereas cellular proliferation and morphology were not altered. Interestingly, long-term exposure to hypergravity stimulated an increase in both intra-cellular as well as extracellular cAMP levels as well as melanogenesis in pigmented melanocytes and non-metastatic melanoma cells. As some cAMP-PDEs are regulated by cGMP, it seems that the hypergravity-induced alteration of melanocyte pigmentation could be a result of a cross-talk between these two cyclic nucleotides. Hypergravity induced further an increase in the mRNA and protein levels of the selective cGMP and cAMP exporters, the multidrug resistance proteins (MRP) 4 and 5 -but not 8 -, whereas simulated microgravity (up to 1.21x10-2 g for 24 h) -provided by a fast-rotating clinostat

  18. Resolution of vitiligo following excision of halo congenital melanocytic nevus: a rare case report.

    PubMed

    Wang, Kai; Wang, Zhi; Huang, Weiqing

    2016-05-01

    Halo congenital melanocytic nevus (CMN) associated with vitiligo is rare, especially with regard to CMN excision. Only two reports of excision of halo CMN following repigmentation of vitiligo are found in the literature. We present a case of a girl with halo CMN and periorbital vitiligo. The halo CMN was excised and followed by spontaneous improvement of vitiligo. The result suggests excision of the inciting lesion may be a promising way to control vitiligo.

  19. Uncovering the Role of BMP Signaling in Melanocyte Development and Melanoma Tumorigenesis

    DTIC Science & Technology

    2014-07-01

    Signaling in Melanocyte Development and Melanoma Tumorigenesis PRINCIPAL INVESTIGATOR: Craig J. Ceol, Ph.D. CONTRACTING ORGANIZATION...Development 5a. CONTRACT NUMBER And Melanoma Tumorigenesis 5b. GRANT NUMBER W81XWH-13-1-0107 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dr. Craig...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Melanoma is the most

  20. Characterization and expression of soluble guanylate cyclase in skins and melanocytes of sheep.

    PubMed

    Yang, Shanshan; Zhang, Junzhen; Ji, Kaiyuan; Jiao, Dingxing; Fan, Ruiwen; Dong, Changsheng

    2016-04-01

    The study reported the characterization of soluble guanylate cyclase (sGC) with the size of CDS of 1860bp, encoding a protein of 620 amino acids and containing several conserved functional domains including HNOB, HNOBA, and CHD. Quantitative real time PCR analysis of sGC showed that the expression of sGC mRNA is higher (∼5 fold) in white sheep skin relative to black sheep skin with significant difference (P<0.01). Using a rabbit polyclonal anti-sGC antibody, an immune reactive band corresponding to sheep sGC protein was detected in the skin samples by Western blotting analysis, and the expression of sGC protein was significantly higher in white sheep skin compared to black sheep skin (P<0.01). Immunohistochemical analysis revealed that sGC protein was localized in cytoplasm and intercellular substance of upper hair papilla in hair follicles of white sheep skin, but the protein was localized in cytoplasm and intercellular substance of lower hair bulb and outer root sheath cells in hair follicles of black sheep skin. The immunocytochemical analysis revealed that sGC was expressed in melanocytes in vitro of sheep skin. Over expression of sGC in melanocytes resulted in decreased expression of key melanogenic genes including microphthalmia transcription factor (MITF), tyrosinase (TYR), tyrosinase related protein 1(TYRTP1), and tyrosinase related protein 2(TYRP2) both at mRNA and protein level. Moreover, the melanocytes was capable of producing cGMP and cAMP. The observed differential expression and localization of sGC in sheep skins and melanocytes and the capability of producing cGMP and cAMP, which suggested a potential role for this gene in hair color regulation.

  1. Limbal melanocytes support limbal epithelial stem cells in 2D and 3D microenvironments.

    PubMed

    Dziasko, Marc A; Tuft, Stephen J; Daniels, Julie T

    2015-09-01

    Human limbal epithelial stem cells (LESCs) are essential for the maintenance of the corneal epithelium of the ocular surface. LESCs are located within limbal crypts between the palisades of Vogt in the limbus; the interface between the peripheral cornea and conjunctiva. The limbal crypts have been proposed as a LESC niche owing to their support of epithelial cells, which can form holoclone colonies in vitro. Closely associated with the limbal crypts is a concentrated population of melanocytes. The anatomical location and close proximity to putative LESC suggests that melanocytes might play a role in maintenance of these stem cells in the niche. The aim of this study was to assess the ability of human limbal melanocytes (hLM) to support the expansion of human limbal epithelial cells (LECs) in vitro as an indicator of functional cell-cell interaction. After observing that hLM co-localize with clusters of compact epithelial cells in the native limbal crypts, hLM were isolated from crypt-rich cadaveric limbal biopsies and used as feeders for the culture of LECs. Interestingly, LECs grown on mitotically active hLM were able to generate large epithelial colonies that contained small and compact cells with morphological stem cell characteristics. Immunocytochemistry revealed that LECs expanded on hLM were positive for the expression of the putative stem cell markers CK15, Bmi-1 and p63α and negative for the marker of terminal cell differentiation CK3. LECs and hLM were finally co-cultured on RAFT (real architecture for 3D tissue) collagen tissue equivalents. In 3D co-cultures, hLM promoted multi-layering of the epithelial sheet in which basal cells were maintained in an undifferentiated state. Taken together, these observations suggest melanocytes could play an important role in the maintenance of LESCs in the native human limbal stem cell niche.

  2. Detection of serum anti-melanocyte antibodies and identification of related antigens in patients with vitiligo.

    PubMed

    Zhu, M C; Liu, C G; Wang, D X; Zhan, Z

    2015-12-07

    We detected autoantibodies against melanocytes in serum samples obtained from 50 patients, including 4 with HBV, with vitiligo and identified the associated membrane antigens. Heat shock protein 70 (HSP70) and anti-tyrosinase-related protein 1 (TRP-1) antibody levels were analyzed. The associated antigens in normal human melanocyte were identified by immunofluorescence. Autoantibodies against melanocyte membrane and cytoplasmic proteins were detected by western blot. Membrane antigens with higher frequencies were identified by protein mass spectrometry. The HSP70 and anti-TRP-1 antibody levels (N = 70; 10 with HBV) were detected by ELISA. The specific antigens were detected in melanocyte cytoplasm and membrane (40/50; 80% incidence; western blot). The autoantibodies reacted with several membrane antigens with approximate molecular weights (Mr) of 86,000, 75,000, 60,000, 52,000, and 44,000 (strip positive rates: 36, 58, 22, 2, and 2%, respectively). Thirty percent of the patients showed the presence of cytoplasmic antigens (Mr: 110,000, 90,000, 75,000, 50,000, and 400,000; strip positive rates: 12, 4, 12, 10, and 2%, respectively). Fifteen and 5% of the healthy subjects showed positive expression of membrane and cytoplasmic antigens, respectively. Protein mass spectrometry predicted membrane proteins with Mr of 86,000 and 75,000 and 60,000 to be Lamin A /C and Vimentin X1, respective. High titers of anti-TRP-1 antibody were detected and showed positive correlation with HSP70 (r = 0. 927, P < 0. 01). This study identified a novel membrane antigen associated with vitiligo, which might assist future investigations into autoimmune pathogenesis of vitiligo and formation of autoantibodies. HBV infection was correlated to vitiligo.

  3. Uncovering the Role of BMP Signaling in Melanocyte Development and Melanoma Tumorigenesis

    DTIC Science & Technology

    2015-06-01

    involved. Using genomic studies and cross-species comparisons, we identified the BMP factor GDF6 as a gene that may cooperate with mutant BRAF to...promote melanoma. The aims of this grant are to determine if GDF6 does in fact cooperate with mutant BRAF and uncover the mechanisms by which GDF6 acts...in melanomas and normal melanocytes. Toward these aims, we have used our zebrafish model to demonstrate cooperativity between GDF6 and mutant BRAF

  4. UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6

    SciTech Connect

    Miyata, Maiko; Ichihara, Masatoshi; Tajima, Orie; Sobue, Sayaka; Kambe, Mariko; Sugiura, Kazumitsu; Furukawa, Koichi; Furukawa, Keiko

    2014-03-07

    Highlights: • Melanocytes showed low ST8SIA1 and high B3GALT4 levels in contrast with melanomas. • Direct UVB irradiation of melanocytes did not induce ganglioside synthase genes. • Culture supernatants of UVB-irradiated keratinocytes induced ST8SIA1 in melanocytes. • TNFα and IL-6 secreted from keratinocytes enhanced ST8SIA1 expression in melanocytes. • Inflammatory cytokines induced melanoma-related ST8SIA1 in melanocytes. - Abstract: Although expression of gangliosides and their synthetic enzyme genes in malignant melanomas has been well studied, that in normal melanocytes has been scarcely analyzed. In particular, changes in expression levels of glycosyltransferase genes responsible for ganglioside synthesis during evolution of melanomas from melanocytes are very important to understand roles of gangliosides in melanomas. Here, expression of glycosyltransferase genes related to the ganglioside synthesis was analyzed using RNAs from cultured melanocytes and melanoma cell lines. Quantitative RT-PCR revealed that melanomas expressed high levels of mRNA of GD3 synthase and GM2/GD2 synthase genes and low levels of GM1/GD1b synthase genes compared with melanocytes. As a representative exogenous stimulation, effects of ultraviolet B (UVB) on the expression levels of 3 major ganglioside synthase genes in melanocytes were analyzed. Although direct UVB irradiation of melanocytes caused no marked changes, culture supernatants of UVB-irradiated keratinocytes (HaCaT cells) induced definite up-regulation of GD3 synthase and GM2/GD2 synthase genes. Detailed examination of the supernatants revealed that inflammatory cytokines such as TNFα and IL-6 enhanced GD3 synthase gene expression. These results suggest that inflammatory cytokines secreted from UVB-irradiated keratinocytes induced melanoma-associated ganglioside synthase genes, proposing roles of skin microenvironment in the promotion of melanoma-like ganglioside profiles in melanocytes.

  5. The epidermal melanocyte population in the skin of ultraviolet-irradiated crested newt

    SciTech Connect

    Losa, M.; Zavanella, T.; Milani, S.

    1982-02-01

    The response of the epidermal melanocyte population to repeated ultraviolet (UV) exposure (wavelength spectrum 275-350 nm) has been investigated in the crested newt, Triturus cristatus carnifex. The effects of different doses of UV light were studied. The animals were killed 7 months after the first UV exposure. Only a slight decrease in the number of pigment cells was found after 85 sequential irradiations with a total dose of 1.3 x 10(5) J/m2, whereas striking decreases were observed when the same total dose was fractionated into 14 exposures or when a double dose was given in 57 exposures. The relationship between the square roots of the epidermal melanocyte densities and single doses appeared to be roughly linear, at least over the range of doses administered. The main factor in melanocyte damage seemed to be the single dose of irradiation rather than the cumulative dose administered. Decreased melanin content of the keratinocytes was observed in most irradiated animals.

  6. Rhododendrol, a depigmentation-inducing phenolic compound, exerts melanocyte cytotoxicity via a tyrosinase-dependent mechanism.

    PubMed

    Sasaki, Minoru; Kondo, Masatoshi; Sato, Kohji; Umeda, Mai; Kawabata, Keigo; Takahashi, Yoshito; Suzuki, Tamio; Matsunaga, Kayoko; Inoue, Shintaro

    2014-09-01

    Rhododendrol, an inhibitor of melanin synthesis developed for lightening/whitening cosmetics, was recently reported to induce a depigmentary disorder principally at the sites of repeated chemical contact. Rhododendrol competitively inhibited mushroom tyrosinase and served as a good substrate, while it also showed cytotoxicity against cultured human melanocytes at high concentrations sufficient for inhibiting tyrosinase. The cytotoxicity was abolished by phenylthiourea, a chelator of the copper ions at the active site, and by specific knockdown of tyrosinase with siRNA. Hence, the cytotoxicity appeared to be triggered by the enzymatic conversion of rhododendrol to active product(s). No reactive oxygen species were detected in the treated melanocytes, but up-regulation of the CCAAT-enhancer-binding protein homologous protein gene responsible for apoptosis and/or autophagy and caspase-3 activation were found to be tyrosinase dependent. These results suggest that a tyrosinase-dependent accumulation of ER stress and/or activation of the apoptotic pathway may contribute to the melanocyte cytotoxicity.

  7. A melanocyte--melanoma precursor niche in sweat glands of volar skin.

    PubMed

    Okamoto, Natsuko; Aoto, Takahiro; Uhara, Hisashi; Yamazaki, Satoshi; Akutsu, Hidenori; Umezawa, Akihiro; Nakauchi, Hiromitsu; Miyachi, Yoshiki; Saida, Toshiaki; Nishimura, Emi K

    2014-11-01

    Determination of the niche for early-stage cancer remains a challenging issue. Melanoma is an aggressive cancer of the melanocyte lineage. Early melanoma cells are often found in the epidermis around sweat ducts of human volar skin, and the skin pigmentation pattern is an early diagnostic sign of acral melanoma. However, the niche for melanoma precursors has not been determined yet. Here, we report that the secretory portion (SP) of eccrine sweat glands provide an anatomical niche for melanocyte-melanoma precursor cells. Using lineage-tagged H2B-GFP reporter mice, we found that melanoblasts that colonize sweat glands during development are maintained in an immature, slow-cycling state but renew themselves in response to genomic stress and provide their differentiating progeny to the epidermis. FISH analysis of human acral melanoma expanding in the epidermis revealed that unpigmented melanoblasts with significant cyclin D1 gene amplification reside deep in the SP of particular sweat gland(s). These findings indicate that sweat glands maintain melanocyte-melanoma precursors in an immature state in the niche and explain the preferential distribution of early melanoma cells around sweat glands in human volar skin.

  8. α-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes

    PubMed Central

    Dalziel, Martin; Kolesnichenko, Marina; das Neves, Ricardo Pires; Iborra, Francisco; Goding, Colin; Furger, André

    2011-01-01

    Alternative splicing enables higher eukaryotes to increase their repertoire of proteins derived from a restricted number of genes. However, the possibility that functional diversity may also be augmented by splicing between adjacent genes has been largely neglected. Here, we show that the human melanocortin 1 receptor (MC1R) gene, a critical component of the facultative skin pigmentation system, has a highly complex and inefficient poly(A) site which is instrumental in allowing intergenic splicing between this locus and its immediate downstream neighbour tubulin-β-III (TUBB3). These transcripts, which produce two distinct protein isoforms localizing to the plasma membrane and the endoplasmic reticulum, seem to be restricted to humans as no detectable chimeric mRNA could be found in MC1R expressing mouse melanocytes. Significantly, treatment with the MC1R agonist α-MSH or activation of the stress response kinase p38-MAPK, both key molecules associated with ultraviolet radiation dermal insult and subsequent skin tanning, result in a shift in expression from MC1R in favour of chimeric MC1R-TUBB3 isoforms in cultured melanocytes. We propose that these chimeric proteins serve to equip melanocytes with novel cellular phenotypes required as part of the pigmentation response. PMID:21071418

  9. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model

    PubMed Central

    Kim, Eun Sung; Park, So Jung; Bae, Il-Hong; Jo, Yoon Kyung; Jeong, In Young; Kim, Hyoung-June; Lee, Youngjin; Park, Hea Chul; Jeon, Hong Bae; Kim, Ki Woo; Lee, Tae Ryong; Cho, Dong-Hyung

    2016-01-01

    The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling. PMID:27941997

  10. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus

    NASA Astrophysics Data System (ADS)

    Lobo, Daniel; Lobikin, Maria; Levin, Michael

    2017-01-01

    Progress in regenerative medicine requires reverse-engineering cellular control networks to infer perturbations with desired systems-level outcomes. Such dynamic models allow phenotypic predictions for novel perturbations to be rapidly assessed in silico. Here, we analyzed a Xenopus model of conversion of melanocytes to a metastatic-like phenotype only previously observed in an all-or-none manner. Prior in vivo genetic and pharmacological experiments showed that individual animals either fully convert or remain normal, at some characteristic frequency after a given perturbation. We developed a Machine Learning method which inferred a model explaining this complex, stochastic all-or-none dataset. We then used this model to ask how a new phenotype could be generated: animals in which only some of the melanocytes converted. Systematically performing in silico perturbations, the model predicted that a combination of altanserin (5HTR2 inhibitor), reserpine (VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB) would break the all-or-none concordance. Remarkably, applying the predicted combination of three reagents in vivo revealed precisely the expected novel outcome, resulting in partial conversion of melanocytes within individuals. This work demonstrates the capability of automated analysis of dynamic models of signaling networks to discover novel phenotypes and predictively identify specific manipulations that can reach them.

  11. Effective intra-S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines.

    PubMed

    Cordeiro-Stone, Marila; McNulty, John J; Sproul, Christopher D; Chastain, Paul D; Gibbs-Flournoy, Eugene; Zhou, Yingchun; Carson, Craig; Rao, Shangbang; Mitchell, David L; Simpson, Dennis A; Thomas, Nancy E; Ibrahim, Joseph G; Kaufmann, William K

    2016-01-01

    The objective of this study was to assess potential functional attenuation or inactivation of the intra-S checkpoint during melanoma development. Proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines were exposed to increasing fluences of UVC and intra-S checkpoint responses were quantified. Melanocytes displayed stereotypic intra-S checkpoint responses to UVC qualitatively and quantitatively equivalent to those previously demonstrated in skin fibroblasts. In comparison with fibroblasts, primary melanocytes displayed reduced UVC-induced inhibition of DNA strand growth and enhanced degradation of p21Waf1 after UVC, suggestive of enhanced bypass of UVC-induced DNA photoproducts. All nine melanoma cell lines examined, including those with activating mutations in BRAF or NRAS oncogenes, also displayed proficiency in activation of the intra-S checkpoint in response to UVC irradiation. The results indicate that bypass of oncogene-induced senescence during melanoma development was not associated with inactivation of the intra-S checkpoint response to UVC-induced DNA replication stress.

  12. Effect of thioridazine on antioxidant status of HEMn-DP melanocytes.

    PubMed

    Otręba, Michał; Beberok, Artur; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2015-10-01

    Thioridazine as an antipsychotic agent was extensively used to treat various psychotic disorders, e.g. schizophrenia. However, the therapy with this drug can induce serious side effects such as extrapyramidal symptoms or ocular and skin disorders, which mechanisms are still not fully established. To gain inside the molecular mechanisms underlying thioridazine toxicity, we examined the effect of this drug on cell viability, antioxidant defence system as well as melanogenesis in normal human melanocytes. It was demonstrated that thioridazine induces concentration-dependent loss in cell viability. The value of EC50 was calculated to be 2.24 μM. To study the effect of thioridazine on antioxidant defence system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were determined. The drug in concentrations of 0.1, 0.25, 1.0 and 2.5 μM caused changes in cellular antioxidant defence system indicating the induction of oxidative stress. It was also shown that the analysed neuroleptic in concentrations of 1.0 and 2.5 μM significantly inhibited melanogenesis. The observed changes in cell viability, antioxidant defence system and melanization in normal human melanocytes after thioridazine treatment may explain an important role of reactive oxygen species as well as melanin in mechanisms involved in this drug side effects directed on pigmented tissues.

  13. NMR metabolic fingerprints of murine melanocyte and melanoma cell lines: application to biomarker discovery.

    PubMed

    Santana-Filho, Arquimedes Paixão de; Jacomasso, Thiago; Riter, Daniel Suss; Barison, Andersson; Iacomini, Marcello; Winnischofer, Sheila Maria Brochado; Sassaki, Guilherme Lanzi

    2017-02-15

    Melanoma is the most aggressive type of skin cancer and efforts to improve the diagnosis of this neoplasia are largely based on the use of cell lines. Metabolomics is currently undergoing great advancements towards its use to screening for disease biomarkers. Although NMR metabolomics includes both 1D and 2D methodologies, there is a lack of data in the literature regarding heteronuclear 2D NMR assignments of the metabolome from eukaryotic cell lines. The present study applied NMR-based metabolomics strategies to characterize aqueous and lipid extracts from murine melanocytes and melanoma cell lines with distinct tumorigenic potential, successfully obtaining fingerprints of the metabolites from the extracts of the cell lines by means of 2D NMR HSQC correlation maps. Relative amounts of the identified metabolites were compared between the 4 cell lines. Multivariate analysis of (1)H NMR data was able not only to differentiate the melanocyte cell line from the tumorigenic ones but also distinguish among the 3 tumorigenic cell lines. We also investigated the effects of mitogenic agents, and found that they can markedly influence the metabolome of the melanocyte cell line, resembling the pattern of most proliferative cell lines.

  14. NMR metabolic fingerprints of murine melanocyte and melanoma cell lines: application to biomarker discovery

    PubMed Central

    Santana-Filho, Arquimedes Paixão de; Jacomasso, Thiago; Riter, Daniel Suss; Barison, Andersson; Iacomini, Marcello; Winnischofer, Sheila Maria Brochado; Sassaki, Guilherme Lanzi

    2017-01-01

    Melanoma is the most aggressive type of skin cancer and efforts to improve the diagnosis of this neoplasia are largely based on the use of cell lines. Metabolomics is currently undergoing great advancements towards its use to screening for disease biomarkers. Although NMR metabolomics includes both 1D and 2D methodologies, there is a lack of data in the literature regarding heteronuclear 2D NMR assignments of the metabolome from eukaryotic cell lines. The present study applied NMR-based metabolomics strategies to characterize aqueous and lipid extracts from murine melanocytes and melanoma cell lines with distinct tumorigenic potential, successfully obtaining fingerprints of the metabolites from the extracts of the cell lines by means of 2D NMR HSQC correlation maps. Relative amounts of the identified metabolites were compared between the 4 cell lines. Multivariate analysis of 1H NMR data was able not only to differentiate the melanocyte cell line from the tumorigenic ones but also distinguish among the 3 tumorigenic cell lines. We also investigated the effects of mitogenic agents, and found that they can markedly influence the metabolome of the melanocyte cell line, resembling the pattern of most proliferative cell lines. PMID:28198377

  15. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus

    PubMed Central

    Lobo, Daniel; Lobikin, Maria; Levin, Michael

    2017-01-01

    Progress in regenerative medicine requires reverse-engineering cellular control networks to infer perturbations with desired systems-level outcomes. Such dynamic models allow phenotypic predictions for novel perturbations to be rapidly assessed in silico. Here, we analyzed a Xenopus model of conversion of melanocytes to a metastatic-like phenotype only previously observed in an all-or-none manner. Prior in vivo genetic and pharmacological experiments showed that individual animals either fully convert or remain normal, at some characteristic frequency after a given perturbation. We developed a Machine Learning method which inferred a model explaining this complex, stochastic all-or-none dataset. We then used this model to ask how a new phenotype could be generated: animals in which only some of the melanocytes converted. Systematically performing in silico perturbations, the model predicted that a combination of altanserin (5HTR2 inhibitor), reserpine (VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB) would break the all-or-none concordance. Remarkably, applying the predicted combination of three reagents in vivo revealed precisely the expected novel outcome, resulting in partial conversion of melanocytes within individuals. This work demonstrates the capability of automated analysis of dynamic models of signaling networks to discover novel phenotypes and predictively identify specific manipulations that can reach them. PMID:28128301

  16. Multimode optical dermoscopy (SkinSpect) analysis for skin with melanocytic nevus

    NASA Astrophysics Data System (ADS)

    Vasefi, Fartash; MacKinnon, Nicholas; Saager, Rolf; Kelly, Kristen M.; Maly, Tyler; Chave, Robert; Booth, Nicholas; Durkin, Anthony J.; Farkas, Daniel L.

    2016-04-01

    We have developed a multimode dermoscope (SkinSpect™) capable of illuminating human skin samples in-vivo with spectrally-programmable linearly-polarized light at 33 wavelengths between 468nm and 857 nm. Diffusely reflected photons are separated into collinear and cross-polarized image paths and images captured for each illumination wavelength. In vivo human skin nevi (N = 20) were evaluated with the multimode dermoscope and melanin and hemoglobin concentrations were compared with Spatially Modulated Quantitative Spectroscopy (SMoQS) measurements. Both systems show low correlation between their melanin and hemoglobin concentrations, demonstrating the ability of the SkinSpect™ to separate these molecular signatures and thus act as a biologically plausible device capable of early onset melanoma detection.

  17. MC1R and the response of melanocytes to ultraviolet radiation.

    PubMed

    Rouzaud, Francois; Kadekaro, Ana Luisa; Abdel-Malek, Zalfa A; Hearing, Vincent J

    2005-04-01

    The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists alpha-melanocyte-stimulating hormone (alphaMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of alphaMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is

  18. Interleukin-18 augments growth ability of primary human melanocytes by PTEN inactivation through the AKT/NF-κB pathway.

    PubMed

    Zhou, Jia; Shang, Jing; Song, Jing; Ping, Fengfeng

    2013-02-01

    Normal human skin relies on melanocytes to provide photoprotection and thermoregulation by producing melanin. The growth and behavior of melanocytes are controlled by many factors. Interleukin-18 (IL-18) is expressed in both immune and non-immune cells and participates in the adjustment of multitude cellular functions. Nonetheless, the regulative roles of IL-18 in melanogenesis and growth of melanocytes have not been explored. The present study was conducted to investigate the effects of IL-18 on melanocytes and elucidate the underlying mechanisms. We proved that IL-18 increased the tyrosinase activity and melanin content in normal human foreskin-derived epidermal melanocytes (NHEM). Treatment with IL-18 (20 ng/ml) enhanced the expression of c-Kit, microphtalmia-associated transcription factor (MITF) and its downstream tyrosinase-related protein 1 (TRP-1), and TRP-2. In addition, IL-18 induced NHEM migration at concentration of 20 ng/ml. These results indicated a promotive action of IL-18 on melanogenesis in NHEM. Our data revealed that IL-18 stimulated ERK1/2 and NF-κB activation, improved p-Akt, p70 S6K and anti-apoptotic Bcl-2 levels, and deactivated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in NHEM. Besides, IL-18 increased level of PTEN phosphorylation to protect NHEM from damage induced by H(2)O(2). These results in vitro showed the accommodation of IL-18 in melanocytes growth. Therefore, we suggested an important regulating action of IL-18 to melanogenesis and cell growth ability of skin melanocytes.

  19. Acquired Bilateral Nevus of ota-like Macules with Mucosal Involvement: A New Variant of Hori's Nevus

    PubMed Central

    Bhat, Ramesh M; Pinto, Hyacinth Peter; Dandekeri, Sukumar; Ambil, Srinath Madapally

    2014-01-01

    Acquired bilateral nevus of Ota-like macules (ABNOM) or Hori's nevus, a rare form of acquired dermal melanocytoses, presents as bilateral facial blue-gray macules without ocular or mucosal involvement. This condition is mostly found in women of Asian descent and usually appears in the fourth or fifth decade of life. Pathogenesis is unknown, though few theories have been proposed. Effective treatment has been found to be achieved with pigment-specific lasers. Herein, we report a case of Hori's nevus with mucosal involvement. A 42-year-old male patient, presented to us with blue-gray discoloration on either side of his face, both eyes, and in the mouth since the age of one year. Histopathological examination showed clusters and singly dispersed pigmented melanocytes within the upper and mid-dermis regions. Special staining of melanocytes using Masson-Fontana stain was positive. Diagnosis of Hori's nevus was made by correlating clinical and histopathological findings. Patient was informed of his treatment options, but refused treatment. A similar case of Hori's nevus with mucosal involvement has not been reported so far. PMID:24891664

  20. Adolescent Onset of Localized Papillomatosis, Lymphedema, and Multiple Beta-Papillomavirus Infection: Epidermal Nevus, Segmental Lymphedema Praecox, or Verrucosis? A Case Report and Case Series of Epidermal Nevi

    PubMed Central

    Kadam, Pooja; Rand, Janne; Rady, Peter; Tyring, Stephen; Stehlik, Jan; Sedivcova, Monica; Kazakov, Dmitry V.; Ray, Kathy; Hill, Jerome; Agag, Richard; Carlson, J. Andrew

    2014-01-01

    Herein, we report the case of a 12-year-old female who noted the recent onset of an oval, circumscribed, 10-cm papillomatous plaque affecting the thigh and vulva that showed histologic signs of lymphedema without evidence of secondary lymphedema. The sequencing of genes associated with a delayed onset of lymphedema or epidermal nevi (EN) – GATA2 and GJC2, and HRAS and KRAS, respectively – showed wild-type alleles. Polymerase chain reaction for human papillomavirus (HPV) DNA demonstrated infections with 15 HPV genotypes. Evidence of productive HPV infection, HPV capsid expression, and cytopathic changes was detected. At the 6-month follow-up, no evidence of recurrence was found after complete excision. The analysis of a consecutive series of 91 EN excision specimens revealed that 76% exhibited histologic evidence of lymphostasis. Notably, multiple acrochordon-like EN, which most closely resembled this case, showed similar signs of localized lymphedema. The late onset and evidence of lymphedema favors the diagnosis of congenital unisegmental lymphedema. However, the clinical findings and epidermal changes point to the diagnosis of EN. Moreover, localized verrucosis also accurately describes this patient's cutaneous findings. Based on the above evidence, we postulate that an abnormal development of lymphatics may play a primary role in the pathogenesis of some types of EN and facilitate productive HPV infection. PMID:27047923

  1. Gene expression analysis of zebrafish melanocytes, iridophores, and retinal pigmented epithelium reveals indicators of biological function and developmental origin.

    PubMed

    Higdon, Charles W; Mitra, Robi D; Johnson, Stephen L

    2013-01-01

    In order to facilitate understanding of pigment cell biology, we developed a method to concomitantly purify melanocytes, iridophores, and retinal pigmented epithelium from zebrafish, and analyzed their transcriptomes. Comparing expression data from these cell types and whole embryos allowed us to reveal gene expression co-enrichment in melanocytes and retinal pigmented epithelium, as well as in melanocytes and iridophores. We found 214 genes co-enriched in melanocytes and retinal pigmented epithelium, indicating the shared functions of melanin-producing cells. We found 62 genes significantly co-enriched in melanocytes and iridophores, illustrative of their shared developmental origins from the neural crest. This is also the first analysis of the iridophore transcriptome. Gene expression analysis for iridophores revealed extensive enrichment of specific enzymes to coordinate production of their guanine-based reflective pigment. We speculate the coordinated upregulation of specific enzymes from several metabolic pathways recycles the rate-limiting substrate for purine synthesis, phosphoribosyl pyrophosphate, thus constituting a guanine cycle. The purification procedure and expression analysis described here, along with the accompanying transcriptome-wide expression data, provide the first mRNA sequencing data for multiple purified zebrafish pigment cell types, and will be a useful resource for further studies of pigment cell biology.

  2. Study on the effects of nylon-chitosan-blended membranes on the spheroid-forming activity of human melanocytes.

    PubMed

    Lin, Sung-Jan; Hsiao, Wen-Chu; Jee, Shiou-Hwa; Yu, Hsin-Su; Tsai, Tsen-Fang; Lai, Juin-Yih; Young, Tai-Horng

    2006-10-01

    Though reported limitedly in tissue engineering, modification of cellular functions can be achieved by culturing them into multicellular spheroids. We have shown melanocytes form spheroids on chitosan surface. However, how biomaterials promote spheroid formation has never been systemically investigated. In this work, nylon, which inhibits melanocyte spheroid formation, and chitosan, which promotes melanocyte spheroid formation, are used to prepare nylon/chitosan-blended membranes. Membranes composed of pure nylon, pure chitosan and various ratios of nylon and chitosan are employed to examine their effects on spheroid formation. Melanocytes show better adhesion to nylon membranes than that to chitosan membranes. In blended membranes, as more nylon is incorporated, cell adhesion increases and the trend for spheroid formation decreases. Melanocytes can only form spheroids on membranes with poorer cell adhesion. Examining the surface of the blended membranes shows phase separation of nylon and chitosan. As nylon content increases, the nylon phase on the membrane surface increases and thereby enhances cell adhesion. The opposite trend for cell adhesion and spheroid formation substantiates our hypothesis of spheroid formation on biomaterials: a balance between cell-substrate interaction and cell-cell interaction. The decrease in cell-substrate interaction tilts the balance to a state more favorable for spheroid formation. Our work can serve as a model to investigate the relative strengths of cell-cell and cell-substrate interactions and also pave way to design blended membranes with desired physical properties while preserving the spheroid-forming activity.

  3. [Phenotypic plasticity of neural crest-derived melanocytes and Schwann cells].

    PubMed

    Dupin, Elisabeth

    2011-01-01

    Melanocytes, the pigmented cells of the skin, and the glial Schwann cells lining peripheral nerves are developmentally derived from an early and transient ectodermal structure of the vertebrate embryo, the neural crest, which is also at the origin of multiple neural and non-neural cell types. Besides melanocytes and neural cells of the peripheral nervous system, the neural crest cells give rise to mesenchymal cell types in the head, which form most of the craniofacial skeleton, dermis, fat tissue and vascular musculo-connective components. How such a wide diversity of differentiation fates is established during embryogenesis and is later maintained in adult tissues are among key questions in developmental and stem cell biology. The analysis of the developmental potentials of single neural crest cells cultured in vitro led to characterizing multipotent stem/progenitor cells as well as more restricted precursors in the early neural crest of avian and mammalian embryos. Data support a hierarchical model of the diversification of neural crest lineages through progressive restrictions of multipotent stem cell potentials driven by local environmental factors. In particular, melanocytes and glial Schwann cells were shown to arise from a common bipotent progenitor, which depends upon the peptide endothelin-3 for proliferation and self-renewal ability. In vivo, signaling by endothelin-3 and its receptor is also required for the early development of melanocytes and proper pigmentation of the vertebrate body. It is generally assumed that, after lineage specification and terminal differentiation, specialized cell types, like the melanocytes and Schwann cells, do not change their identity. However, this classic notion that somatic cell differentiation is a stable and irreversible process has been challenged by emerging evidence that dedifferentiation can occur in different biological systems through nuclear transfer, cell fusion, epigenetic modifications and ectopic gene

  4. Melanocytes expressing MC1R polymorphisms associated with red hair color have altered MSH-ligand activated pigmentary responses in coculture with keratinocytes.

    PubMed

    Roberts, Donald W; Newton, Richard A; Leonard, J Helen; Sturm, Richard A

    2008-05-01

    The occurrence of red hair and pale skin in individuals, which is associated with UV-radiation sensitivity and increased skin cancer risk, is mainly due to polymorphisms in the melanocortin-1 receptor (MC1R) expressed in melanocytes. We have established a serum free human melanocyte-keratinocyte coculture system to study the behavior and functional abilities of melanocytes expressing MC1R red hair color (RHC) variants in order to identify differences from their wild type (WT) counterparts. This model revealed the importance of elevated calcium levels in promoting strong melanocyte interaction with the surrounding keratinocytes and resulted in a dendritic melanocyte morphology similar to that in skin. However, the dendricity response following agonist activation of the MC1R receptor by NDP-MSH peptide, was markedly enhanced in WT melanocytes in comparison to RHC strains. Analysis of mRNA expression and protein levels of the major pigmentation markers following NDP-MSH treatment distinguished the enzyme dopachrome tautomerase as preferentially upregulated in cocultures of WT strains, with negligible or a much reduced response in melanocytes with RHC variant alleles. These results highlight the use of the coculture system in determining fundamental differences in the physiology of melanocytes expressing RHC MC1R receptors and those of WT genotype, which are likely to contribute to the increased skin cancer risk for individuals that carry these variants.

  5. Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth

    PubMed Central

    Soong, Joanne; Chen, Yulin; Shustef, Elina; Scott, Glynis

    2011-01-01

    Semaphorins are secreted and membrane bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilins receptors. We recently reported that Plexin B1, the Semaphorin 4D receptor, is a tumor suppressor protein for melanoma, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to ultraviolet irradiation, that it stimulates proliferation, and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, in part through down-regulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Semaphorin 4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly down-regulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF dependent effects on melanocytes, including melanocyte migration. PMID:22189792

  6. Prognostic markers for canine melanocytic neoplasms: a comparative review of the literature and goals for future investigation.

    PubMed

    Smedley, R C; Spangler, W L; Esplin, D G; Kitchell, B E; Bergman, P J; Ho, H-Y; Bergin, I L; Kiupel, M

    2011-01-01

    Many studies have evaluated various prognostic markers for canine melanocytic neoplasms either as primary or secondary goals; however, design, methodology, and statistical validation vary widely across these studies. The goal of this article was to evaluate and compare published canine melanocytic neoplasm studies in relation to the principals established in the Recommended Guidelines for the Conduct and Evaluation of Prognostic Studies in Veterinary Oncology. Based on this evaluation, we determined which parameters currently have the most statistically supported validity for prognostic use in canine melanocytic neoplasia. This information can also be used as part of evidence-based prospective evaluations of treatment regimens. Additionally, we highlight areas in which the current data are incomplete and that warrant further evaluation. This article represents an initiative of the American College of Veterinary Pathologists' Oncology Committee and has been reviewed and endorsed by the World Small Animal Veterinary Association.

  7. Risk Factors and Relationship of Cutaneous and Uveal Melanocytic Lesions in Monozygotic and Dizygotic Twin Pairs

    PubMed Central

    Varga, Anita; Szabó, Hajnalka; Orvos, Hajnalka; Kemény, Lajos; Oláh, Judit

    2016-01-01

    Background The similar genetic background of a pair of twins, and the similar environmental impacts to which they are exposed allow an exact and objective investigation of various constitutional and environmental factors in naevus development. As far as we are aware, this is the first published survey that simultaneously examines cutaneous and ocular pigmented lesions in an appreciable sample of identical and non-identical twins. Methods 172 pairs of twins of Caucasian origin were included in this study. A whole-body skin examination and a detailed ophthalmological examination were performed to determine the density of melanocytic lesions. A standardized questionnaire was used to assess the data relating to constitutional, sun exposure and other variables. Results A notably high proportion of the subjects (36.78%) manifested one or more clinically atypical melanocytic naevi (CAMNs), and approximately one-third (31.4%) of them at least one benign uveal pigmented lesion (BUPL). The incidence of iris freckles (IFs), iris naevi (INs) and choroidal naevi (CHNs) proved to be 25.35%, 5.98% and 3.52%, respectively. The interclass correlation coefficients for common melanocytic naevi (CMNs), CAMNs, and INs were 0.77, 0.76 and 0.86 in monozygotic twins, as compared with 0.5, 0.27 and 0.25 in dizygotic twin pairs, respectively. A statistically significant correlation was found between the prevalence of CAMNs and that of INs. Conclusions This significant correlation suggests the existence of a subgroup of Caucasian people with an increased susceptibility to both cutaneous and ocular naevus formation. There is accumulating evidence that, besides the presence of cutaneous atypical naevi, INs can serve as a marker of a predisposed phenotype at risk of uveal melanoma. The correlation between cutaneous and ocular pigmented lesions underlines the need for the adequate ophthalmological screening of subjects with CAMNs and INs. PMID:27486750

  8. Risk factors for growth and metastasis of small choroidal melanocytic lesions.

    PubMed Central

    Shields, C L; Shields, J A; Kiratli, H; De Potter, P; Cater, J R

    1995-01-01

    PURPOSE: To investigate the clinical features that predict growth and metastasis of an unselected group of small melanocytic choroidal tumors. METHODS: A retrospective review was performed on 1329 patients with small melanocytic choroidal tumors measuring 3 mm in thickness or less. Clinical parameters of the patient and tumor were extracted and analyzed for their relationship to eventual tumor growth and metastasis using a Cox proportional hazards regression model. RESULTS: Tumor growth was documented in 18% of patients. The factors predictive of tumor growth (multivariate analysis) included greater tumor thickness, posterior tumor margin touching optic disc, symptoms of flashes, floaters, and blurred vision, orange pigment on the tumor surface, and the presence of subretinal fluid. The relative risk (rr) was greatest for initial tumor thickness > 2.0 mm (rr 5.2) and posterior margin touching the optic disc (rr 2.6). After adjusting for significant tumor variables, the effect of interventional tumor treatment showed a decreasing risk for tumor growth as compared to continued observation without treatment. Of 1329 patients, 35 (3%) developed metastases. The factors predictive of metastases (multivariate analysis) included: posterior tumor margin touching the optic disc, documented growth, and greater tumor thickness. The relative risk for metastases was greatest for tumor thickness 1.1-3.0 mm (rr 8.8) and growth (rr 3.2). CONCLUSION: Of small choroidal melanocytic tumors measuring 3 mm or less in thickness at the time of initial examination, 18% demonstrate growth and 3% metastasize during the period of followup. Based on this analysis, the clinical features of these tumors can be used to estimate the risk for tumor growth and metastases and assist the clinician with patient management. PMID:8719682

  9. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    PubMed

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans.

  10. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    PubMed Central

    Swope, Viki B.; Abdel-Malek, Zalfa A.

    2016-01-01

    The membrane bound melanocortin 1 receptor (MC1R), and the endothelin B receptor (ENDBR) are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR), the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH) and adrenocorticotropic hormone (ACTH). The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET)-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies. PMID:27582758

  11. MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a.

    PubMed

    Zhao, Yuanyuan; Wang, Pengchao; Meng, Jinzhu; Ji, Yuankai; Xu, Dongmei; Chen, Tianzhi; Fan, Ruiwen; Yu, Xiuju; Yao, Jianbo; Dong, Changsheng

    2015-05-14

    MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a-3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post-transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced β-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression.

  12. Modulation of the pro-inflammatory cytokines and matrix metalloproteinases production in co-cultivated human keratinocytes and melanocytes.

    PubMed

    Decean, H; Perde-Schrepler, M; Tatomir, C; Fischer-Fodor, E; Brie, I; Virag, P

    2013-10-01

    The human epidermis exerts immunoregulatory functions through the variety of cytokines and other molecules elaborated by keratinocytes and melanocytes. Their constitutive production is very low; however, considerably increased upon stimulation. In vivo, keratinocytes and melanocytes have a typical exposure in the skin, referred as melanocyte epidermal unit. In the present study we co-cultivated these cells in vitro proposing to elucidate some communication links in close cell-to-cell association. We assessed the amounts of IL-6, IL-8, and matrix metalloproteinases (MMP-2 and MMP-9) in individually and co-cultured cells, exposed or not to UVB radiation. Normal human epidermal keratinocytes and melanocytes were grown in specific media and supplements. Cells were exposed to UVB radiation (100 mJ/cm(2)) to create comparable stress to the environmental one. Cytokines were determined with ELISA and confirmed with Western blot and metalloproteinases with gel zimography. Pure cultures of keratinocytes and melanocytes released low amounts of cytokines and metalloproteinases, these secretions being enhanced by UVB irradiation. In co-cultures, the cell-to-cell proximity triggered signals which markedly augmented the cytokines' secretions, whereas metalloproteinases were down-regulated. UVB irradiation did not influence either of these secretions in co-cultures. Concurrently with the highest levels of the pro-inflammatory cytokines, MMP-9 was up-regulated creating pro-inflammatory conditions and premises for changes in cellular survival, differentiation and phenotype. A complex network of interactions occurred between keratinocytes and melanocytes in co-cultures, resulting in modulated pro-inflammatory cytokines and metalloproteinases productions. Therefore, any disturbances in the microenvironmental signaling system and its molecular constituents may result in inflammation or even tumorigenesis in the epidermis.

  13. Basal cell carcinoma arising in a congenital melanocytic naevus in an adult.

    PubMed

    Cooper, Lillian; Srinivasan, Karthik; Nugent, Nora

    2017-02-13

    Congenital melanocytic naevi (CMN) are common skin lesions. They harbour a risk of malignant transformation, and various lesions have been described as developing within them. A basal cell cancer occurring within a CMN has never previously been described. A case is described of a woman aged 52 years presenting with a slow-growing, symptomatic 3 cm lesion in the centre of a 10×5 cm CMN on her right upper back. Diagnostic core biopsy revealed an ulcerated, infiltrative basal cell carcinoma which was then further excised. The scar has healed with no evidence of local recurrence at 1-year follow-up.

  14. Nuclear hormone receptor functions in keratinocyte and melanocyte homeostasis, epidermal carcinogenesis and melanomagenesis

    PubMed Central

    Hyter, Stephen; Indra, Arup K

    2013-01-01

    Skin homeostasis is maintained, in part, through regulation of gene expression orchestrated by type II nuclear hormone receptors in a cell and context specific manner. This group of transcriptional regulators is implicated in various cellular processes including epidermal proliferation, differentiation, permeability barrier formation, follicular cycling and inflammatory responses. Endogenous ligands for the receptors regulate actions during skin development and maintenance of tissue homeostasis. Type II nuclear receptor signaling is also important for cellular crosstalk between multiple cell types in the skin. Overall, these nuclear receptors are critical players in keratinocyte and melanocyte biology and present targets for cutaneous disease management. PMID:23395795

  15. rhCSF3 accelerates the proliferation of human melanocytes in culture through binding CSF3R and the expression of CSF3R transcripts.

    PubMed

    Lu, Yan; Guo, Ze; Zhou, Mei-Hua; Li, Xue; Sun, Jie; Gong, Qing-Li; Zhu, Wen-Yuan

    2015-05-01

    Melanogenic paracrine and autocrine cytokine networks have recently been discovered in vitro between melanocytes and other types of skin cells. Granulocyte colony-stimulating factor receptor (CSF3R) controls the survival, proliferation and differentiation of many kinds of cells, including neutrophils. To understand the function of CSF3R and recombinant human granulocyte colony-stimulating factor (rhCSF3) on melanocyte proliferation, this study compared the expression of CSF3R and the effects of rhCSF3 in primary human melanocytes, neutrophils and HEL 92.1.7 cells. The results show that CSF3R is localized in the cytoplasm and on cell membranes of melanocytes and neutrophils. The percentage of CSF3R(+) melanocytes was higher than CSF3R(+) HEL 92.1.7 cells, but was lower than CSF3R(+) neutrophils. Both CSF3R mRNA and CSF3R protein levels in melanocytes were higher than in HEL 92.1.7 cells, but were lower than in neutrophils. Treatment with rhCSF3 increased the proliferation of human melanocytes, but not their tyrosinase activity. Transcripts of CSF3R in human melanocytes, M14, A375 melanoma and A431 squamous cell carcinoma cells were also detected. Expression of the CSF3R V3 transcript was lower in melanocytes than in M14, A375 melanoma and A431 squamous cell carcinoma cells. In conclusion, rhCSF3 can promote melanocyte proliferation through CSF3R without affecting tyrosinase activity.

  16. Molecular responses to stress induced in normal human caucasian melanocytes in culture by exposure to simulated solar UV.

    PubMed

    Marrot, Laurent; Belaïdi, Jean-Philippe; Jones, Christophe; Perez, Philippe; Meunier, Jean-Roch

    2005-01-01

    Melanocytes play a central role in the response of skin to sunlight exposure. They are directly involved in UV-induced pigmentation as a defense mechanism. However, their alteration can lead to melanoma, a process where the role of sun overexposure is highly probable. The transformation process whereby UV damage may result in melanoma initiation is poorly understood, especially in terms of UV-induced genotoxicity in pigmented cells, where melanin can act either as a sunscreen or as a photosensitizer. The aim of this study was to analyze the behavior of melanocytes from fair skin under irradiation mimicking environmental sunlight in terms of spectral power distribution. To do this, normal human Caucasian melanocytes in culture were exposed to simulated solar UV (SSUV, 300-400 nm). Even at relatively high doses (until 20 min exposure, corresponding to 12 kJ/m2 UV-B and 110 kJ/m2 UV-A), cell death was limited, as shown by cell viability and low occurrence of apoptosis (caspase-3 activation). Moreover, p53 accumulation was three times lower in melanocytes than in unpigmented cells such as fibroblasts after SSUV exposure. However, an important fraction of melanocyte population was arrested in G2-M phase, and this correlated well with a high induction level of the gene GADD45, 4 h after exposure. Among the genes involved in DNA repair, gene XPC was the most inducible because its expression increased more than two-fold 15 h after a 20 min exposure, whereas expression of P48 was only slightly increased. In addition, an early induction of Heme Oxygenase 1 (HO1) gene, a typical response to oxidative stress, was also observed for the first time in melanocytes. Interestingly, this induction remained significant when melanocytes were exposed to UV-A radiation only (320-400 nm), and stimulation of melanogenesis before irradiation further increased HO1 induction. These results were obtained with normal human cells after exposure to SSUV radiation, which mimicked natural sunlight

  17. Atypical dermoscopic presentation of an acral congenital melanocytic nevus in an adult: parallel ridge pattern and its histologic correlation

    PubMed Central

    Roldán-Marín, Rodrigo; González-de-Cossío-Hernández, Ana Cecilia; Lammoglia-Ordiales, Lorena; Martínez-Luna, Eduwiges; Toussaint-Caire, Sonia; Ferrara, Gerardo

    2015-01-01

    Acral melanoma is the most frequent subtype in the Asian and Mexican mestizo populations. Dermoscopy is a noninvasive diagnostic technique that helps the differential diagnosis of pigmented skin lesions on acral volar skin. We, herein, present a case of acral congenital melanocytic nevus with a parallel ridge dermoscopic pattern. Since the parallel ridge pattern in a melanocytic lesion of the acral skin is classically ascribed to melanoma, the present case can be definitely labeled as “atypical” and worth of being elucidated in its histopathological correlates. PMID:26693085

  18. Musicality: instinct or acquired skill?

    PubMed

    Marcus, Gary F

    2012-10-01

    Is the human tendency toward musicality better thought of as the product of a specific, evolved instinct or an acquired skill? Developmental and evolutionary arguments are considered, along with issues of domain-specificity. The article also considers the question of why humans might be consistently and intensely drawn to music if musicality is not in fact the product of a specifically evolved instinct.

  19. Duplicated Information Acquired by Libraries.

    ERIC Educational Resources Information Center

    White, Carl M.

    The object of this study is to make a start toward determining the extent of duplicated information that is being acquired in spite of customary precautions to avoid it. Referring to a specific case, the percentages in Table II show the frequency of appearance in five other works of 19 items in Mitchell's "Encyclopedia of American Politics." While…

  20. Acquired aplastic anemia in children.

    PubMed

    Hartung, Helge D; Olson, Timothy S; Bessler, Monica

    2013-12-01

    This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

  1. Land cover and forest formation distributions for St. Kitts, Nevis, St. Eustatius, Grenada and Barbados from decision tree classification of cloud-cleared satellite imagery

    USGS Publications Warehouse

    Helmer, E.H.; Kennaway, T.A.; Pedreros, D.H.; Clark, M.L.; Marcano-Vega, H.; Tieszen, L.L.; Ruzycki, T.R.; Schill, S.R.; Carrington, C.M.S.

    2008-01-01

    Satellite image-based mapping of tropical forests is vital to conservation planning. Standard methods for automated image classification, however, limit classification detail in complex tropical landscapes. In this study, we test an approach to Landsat image interpretation on four islands of the Lesser Antilles, including Grenada and St. Kitts, Nevis and St. Eustatius, testing a more detailed classification than earlier work in the latter three islands. Secondly, we estimate the extents of land cover and protected forest by formation for five islands and ask how land cover has changed over the second half of the 20th century. The image interpretation approach combines image mosaics and ancillary geographic data, classifying the resulting set of raster data with decision tree software. Cloud-free image mosaics for one or two seasons were created by applying regression tree normalization to scene dates that could fill cloudy areas in a base scene. Such mosaics are also known as cloud-filled, cloud-minimized or cloud-cleared imagery, mosaics, or composites. The approach accurately distinguished several classes that more standard methods would confuse; the seamless mosaics aided reference data collection; and the multiseason imagery allowed us to separate drought deciduous forests and woodlands from semi-deciduous ones. Cultivated land areas declined 60 to 100 percent from about 1945 to 2000 on several islands. Meanwhile, forest cover has increased 50 to 950%. This trend will likely continue where sugar cane cultivation has dominated. Like the island of Puerto Rico, most higher-elevation forest formations are protected in formal or informal reserves. Also similarly, lowland forests, which are drier forest types on these islands, are not well represented in reserves. Former cultivated lands in lowland areas could provide lands for new reserves of drier forest types. The land-use history of these islands may provide insight for planners in countries currently considering

  2. Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4.

    PubMed

    Costin, Gertrude-E; Valencia, Julio C; Vieira, Wilfred D; Lamoreux, M Lynn; Hearing, Vincent J

    2003-08-01

    Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the

  3. A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

    PubMed

    McDonnell, Kevin J; Gallanis, Gregory T; Heller, Kathleen A; Melas, Marilena; Idos, Gregory E; Culver, Julie O; Martin, Sue-Ellen; Peng, David H; Gruber, Stephen B

    2016-03-01

    Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

  4. Melanogenesis and antioxidant defense system in normal human melanocytes cultured in the presence of chlorpromazine.

    PubMed

    Otreba, Michał; Wrześniok, Dorota; Beberok, Artur; Rok, Jakub; Buszman, Ewa

    2015-02-01

    Chlorpromazine is used in the treatment of schizophrenia and psychotic disorders and belongs to phenothiazine class of neuroleptic drugs. It shows severe side effects such as extrapyramidal symptoms as well as ocular and skin disorders, but the mechanism is still not fully established. The aim of this study was to examine the effect of chlorpromazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. It has been demonstrated that chlorpromazine induces concentration dependent loss in cell viability. The value of EC(50) was calculated to be 2.53 μM. Chlorpromazine in lower concentrations (0.0001, 0.001 and 0.01 μM) increased the melanin and microphthalmia-associated transcription factor (MITF) content and tyrosinase activity, while changes of antioxidant enzymes activity were not observed. It suggests that long-term chlorpromazine therapy, even with low drug doses, may lead to hyperpigmentation disorders in skin and/or eye. The use of the analyzed drug in higher concentrations (0.1 and 1.0 μM) caused significant alterations of antioxidant enzymes activity in normal melanocytes, what may explain a potential role of chlorpromazine in the depletion of cellular antioxidant status leading to other adverse effects associated with the high-dose and/or long-term therapy.

  5. Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.

    PubMed

    Perier-Muzet, Marie; Thomas, Luc; Poulalhon, Nicolas; Debarbieux, Sébastien; Bringuier, Pierre-Paul; Duru, Gerard; Depaepe, Lauriane; Balme, Brigitte; Dalle, Stephane

    2014-05-01

    Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.

  6. Establishing a transport protocol for the delivery of melanocytes and keratinocytes for the treatment of vitiligo.

    PubMed

    Eves, Paula C; Baran, Marta; Bullett, Nial A; Way, Louise; Haddow, David; Mac Neil, Sheila

    2011-04-01

    We have previously developed a cell delivery and transfer technology for delivering autologous keratinocytes and melanocytes to patients with vitiligo. However, for this technology to benefit many patients geographically distant from the cell culture facility transportation issues need to be overcome. In this study we begin to investigate this by looking at what role surface chemistry and medium supplements, including fetal calf serum, CO₂ gassing, and temperature, play in influencing cell viability. Cells were maintained on carriers for up to 48 h outside of a CO₂ incubator at 37 °C and their subsequent ability to adhere and become organized into a new epithelium with appropriately located melanocytes was assessed. Consistently good viability and performance on an in vitro wound bed model was achieved by maintaining cells for 48 h adherent to a 20% acrylic acid coated carrier at lower (around 23 °C rather than 37 °C) temperatures in the medium preperfused with CO₂ before transport. Under these circumstances fetal calf serum was not required. In summary, the surface chemistry of the transport substrate and an appropriately CO₂ buffered medium at near room temperature can extend the effective performance life of these cultured cells to at least 48 h from when they leave standard incubator conditions.

  7. Ultradeformable cationic liposomes for delivery of small interfering RNA (siRNA) into human primary melanocytes.

    PubMed

    Geusens, B; Lambert, J; De Smedt, S C; Buyens, K; Sanders, N N; Van Gele, M

    2009-02-10

    The aim of this work was to develop a system that can deliver siRNA into cells present in the human epidermis. More specifically, we wanted to block the expression of a specific Myosin Va exon F containing isoform that is physiologically involved in melanosome transport in human melanocytes. Therefore, we prepared and investigated the capacity of ultradeformable cationic liposomes (UCLs) to deliver siRNA in hard-to-transfect human primary melanocytes. UCLs were formulated from different w:w ratios (6:1, 8:1 and 10:1) of the cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and the edge activator sodium cholate. Subsequently, UCL/siRNA complexes were prepared and their particle size, surface charge, deformability, cytotoxicity, transfection efficiency and long-term stability were tested. The best results were obtained with UCLs composed of a DOTAP/NaChol ratio of 6:1 (w:w) which are promising for future in vivo experiments.

  8. Melanocyte stimulating hormone peptides inhibit TNF-alpha signaling in human dermal fibroblast cells.

    PubMed

    Hill, R P; MacNeil, S; Haycock, J W

    2006-02-01

    Alpha-melanocyte stimulating hormone (alpha-MSH) has been identified as a potent anti-inflammatory in various tissues including the skin. It has previously been shown in skin cell keratinocytes and melanocytes/melanoma cells that MSH peptides inhibit TNF-alpha stimulated NF-kappaB activity and intercellular adhesion molecule-1 (ICAM-1) upregulation. However, the precise anti-inflammatory role of MSH peptides in dermal fibroblasts is unclear. Some studies report on pro-inflammatory responses, while others on anti-inflammatory responses. The present study confirms MC1R expression in cultured human dermal fibroblasts and reports that the MSH peptides alpha-MSH and KP(-D-)V inhibit TNF-alpha stimulated NF-kappaB activity and ICAM-1 upregulation, consistent with an anti-inflammatory role. However, involvement of IkappaB-alpha regulation by either peptide was not confirmed, supporting a mechanism independent of the NF-kappaB inhibitor. In conclusion, alpha-MSH and KP(-D-)V peptides have an anti-inflammatory action on dermal fibroblast signaling by inhibiting the pro-inflammatory activity of TNF-alpha in vitro.

  9. Matrigel supports neural, melanocytic and chondrogenic differentiation of trunk neural crest cells.

    PubMed

    Ramos-Hryb, Ana B; Da-Costa, Meline C; Trentin, Andréa G; Calloni, Giordano W

    2013-01-01

    The neural crest (NC) is composed of highly multipotent precursor cells able to differentiate into both neural and mesenchymal phenotypes. Until now, most studies focusing on NC cell differentiation have been performed with traditional two-dimensional (2D) cell culture systems. However, such culture systems do not reflect the complex three-dimensional (3D) microenvironments of in vivo NC cells. To address this limitation, we have developed a method of Matrigel™ coating to create 2D and 3D microenvironments in the same culture well. When we performed cultures of trunk neural crest cells (TNCCs) on three different lots of basement membrane matrix (Matrigel™), we observed that all analyzed Matrigel™ lots were equally efficient in allowing the appearance of glial cells, neurons, melanocytes, smooth muscle cells and chondrocytes. We further observed that chondrocytes were found predominantly in the 3D microenvironment, whereas smooth muscle cells were almost exclusively located in the 2D microenvironment. Glial cells were present in both environments, but with broader quantities on the 2D surface. Melanocytes and neurons were equally distributed in both 2D and 3D microenvironments, but with distinct morphologies. It is worth noting the higher frequency of chondrocytes detected in this study using the 3D Matrigel™ microenvironment compared to previous reports of chondrogenesis obtained from TNCCs on traditional 2D cultures. In conclusion, Matrigel™ represents an attractive scaffold to study NC multipotentiality and differentiation, since it permits the appearance of the major NC phenotypes.

  10. Non psammomatous melanocytic schwannoma presenting as a subcutaneous nodule: A rare presentation of a rare lesion

    PubMed Central

    Gulati, Harveen Kaur; Joshi, Avinash R.; Anand, Mani; Deshmukh, S. D.

    2016-01-01

    Melanocytic schwannoma (MS) is an extremely rare soft tissue tumor accounting for less than 1% of all primitive nerve sheath tumors, with a predilection for spinal nerve involvement. To date, only 20 cases of cutaneous/subcutaneous MS have been described in literature. Here, we describe a case of MS presenting as a subcutaneous nodule in a 22-year-old male in right thigh. On examination, the nodule measured 2.5 × 2.0 × 1.5 cm with overlying skin showing a bluish hue and an ulcer. With a preoperative diagnosis of hemangioma, the patient was taken up for wide local excision and was diagnosed as a case of non psammomatous melanocytic schwannoma based on clinical, histological, and immunohistochemical studies. Immunohistochemistry revealed positivity with S-100, HMB-45, and Melan A with pericellular Laminin positivity. Carney's syndrome was ruled out. MS needs to be differentiated from other pigmented lesions like pigmented neurofibroma, Bednar tumor, cellular blue neavus, and especially malignant melanoma, which has an obvious ominous prognosis. Since MS can show unpredictable behavior especially in absence of overt malignant features, a long term follow up with or without radiotherapy is recommended. PMID:27366278

  11. MC1R is a potent regulator of PTEN after UV exposure in melanocytes.

    PubMed

    Cao, Juxiang; Wan, Lixin; Hacker, Elke; Dai, Xiangpeng; Lenna, Stefania; Jimenez-Cervantes, Celia; Wang, Yongjun; Leslie, Nick R; Xu, George X; Widlund, Hans R; Ryu, Byungwoo; Alani, Rhoda M; Dutton-Regester, Ken; Goding, Colin R; Hayward, Nicholas K; Wei, Wenyi; Cui, Rutao

    2013-08-22

    The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

  12. Mapping of alpha-melanocyte-stimulating hormone-like immunoreactivity in the cat brainstem.

    PubMed

    Coveñas, R; de León, M; Narváez, J A; Aguirre, J A; Tramu, G

    2000-04-01

    The distribution of alpha-melanocyte-stimulating hormone-like immunoreactive structures was studied in the brainstem of the cat using an indirect immunoperoxidase technique. Immunoreactivity was observed in several brainstem nuclei of the cat in which no immunoreactivity had been previously reported. Immunoreactive fibres were observed in the following; the inferior central nucleus; the pontine gray nuclei; the Kölliker-Fuse nucleus; the motor trigeminal nucleus, the anteroventral cochlear nucleus; the abducens nucleus; the retrofacial nucleus; the superior, lateral, inferior, and medial vestibular nuclei; the lateral nucleus of the superior olive; the external cuneate nucleus; the nucleus of the trapezoid body; the postpyramidal nucleus of the raphe; the medial accessory inferior olive; the dorsal accessory nucleus of the inferior olive; the nucleus ambiguus; the principal nucleus of the inferior olive; the preolivary nucleus; the nucleus ruber; the substantia nigra; and in the area postrema. Our results point to a more widespread distribution of alpha-melanocyte-stimulating hormone-like immunoreactive structures in the cat brainstem than that reported in previous studies carried out in the same region of the cat, rat and humans.

  13. Nursing home-acquired pneumonia.

    PubMed

    El Solh, Ali A

    2009-02-01

    Nursing home-acquired pneumonia (NHAP) was first described in 1978. Since then there has been much written regarding NHAP and its management despite the lack of well-designed studies in this patient population. The most characteristic features of patients with NHAP are the atypical presentation, which may lead to delay in diagnosis and therapy. The microbial etiology of pneumonia encompasses a wide spectrum that spans microbes recovered from patients with community-acquired pneumonia to organisms considered specific only to nosocomial settings. Decision to transfer a nursing home patient to an acute care facility depends on a host of factors, which include the level of staffing available at the nursing home, patients' advance directives, and complexity of treatment. The presence of risk factors for multidrug-resistant pathogens dictates approach to therapy. Prevention remains the cornerstone of reducing the incidence of disease. Despite the advance in medical services, mortality from NHAP remains high.

  14. Occupationally Acquired American Cutaneous Leishmaniasis

    PubMed Central

    Felinto de Brito, Maria Edileuza; Andrade, Maria Sandra; de Almeida, Éricka Lima; Medeiros, Ângela Cristina Rapela; Werkhäuser, Roberto Pereira; de Araújo, Ana Isabele Freitas; Brandão-Filho, Sinval Pinto; Paiva de Almeida, Alzira Maria; Gomes Rodrigues, Eduardo Henrique

    2012-01-01

    We report two occupationally acquired cases of American cutaneous leishmaniasis (ACL): one accidental laboratory autoinoculation by contaminated needlestick while handling an ACL lesion sample, and one acquired during field studies on bird biology. Polymerase chain reaction (PCR) assays of patient lesions were positive for Leishmania, subgenus Viannia. One isolate was obtained by culture (from patient 2 biopsy samples) and characterized as Leishmania (Viannia) naiffi through an indirect immunofluorescence assay (IFA) with species-specific monoclonal antibodies (mAbs) and by multilocus enzyme electrophoresis (MLEE). Patients were successfully treated with N-methyl-glucamine. These two cases highlight the potential risks of laboratory and field work and the need to comply with strict biosafety procedures in daily routines. The swab collection method, coupled with PCR detection, has greatly improved ACL laboratory diagnosis. PMID:23227369

  15. [Acquired disorders of color vision].

    PubMed

    Lascu, Lidia; Balaş, Mihaela

    2002-01-01

    This article is a general view of acquired disorders of color vision. The revision of the best known methods and of the etiopathogenic classification is not very important in ophthalmology but on the other hand, the detection of the blue defect advertise and associated ocular pathology. There is a major interest in serious diseases as multiple sclerosis, AIDS, diabetes melitus, when the first ocular sign can be a defect in the color vision.

  16. Selective cytotoxicity of 4-S-cysteaminylphenol on follicular melanocytes of the black mouse: rational basis for its application to melanoma chemotherapy

    SciTech Connect

    Ito, Y.; Jimbow, K.

    1987-06-15

    We have previously shown that 4-S-cysteaminylphenol (4-S-CAP) causes a significant inhibition of in vivo melanoma growth. To clarify the mechanism of the in vivo antimelanoma effect, this study evaluated the cellular and subcellular changes of follicular melanocytes after s.c. administration of 4-S-CAP on the lumbar areas of black and albino mice. 4-S-CAP produced a prompt, selective swelling and lysis of melanocytes, resulting eventually in the necrosis of melanocytes and the depigmentation of black hair follicles. None of the degenerative changes were seen in melanocytes and keratinocytes of control albino follicles. Comparison of melanocytes in black and albino follicles revealed that melanin synthesis is highly active in the melanocytes of black follicles while melanin and tyrosinase synthesis is not seen in the melanocytes of albino follicles. The findings indicate that the selective melanocytotoxicity of 4-S-CAP is manifested by lysis and necrosis of cells which are actively engaged in melanin synthesis. 4-S-CAP appears to provide a new modality for rational chemotherapy of malignant melanoma.

  17. Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy

    NASA Astrophysics Data System (ADS)

    Weng, Wei-Hung; Liao, Yi-Hua; Tsai, Ming-Rung; Wei, Ming-Liang; Huang, Hsin-Yi; Sun, Chi-Kuang

    2016-07-01

    Morphology and distribution of melanocytes are critical imaging information for the diagnosis of melanocytic lesions. However, how to image intratumoral melanocytes noninvasively in pigmented skin tumors is seldom investigated. Third-harmonic generation (THG) is shown to be enhanced by melanin, whereas high accuracy has been demonstrated using THG microscopy for in vivo differential diagnosis of nonmelanocytic pigmented skin tumors. It is thus desirable to investigate if label-free THG microscopy was capable to in vivo identify intratumoral melanocytes. In this study, histopathological correlations of label-free THG images with the immunohistochemical images stained with human melanoma black (HMB)-45 and cluster of differentiation 1a (CD1a) were made. The correlation results indicated that the intratumoral THG-bright dendritic-cell-like signals were endogenously derived from melanocytes rather than Langerhans cells (LCs). The consistency between THG-bright dendritic-cell-like signals and HMB-45 melanocyte staining showed a kappa coefficient of 0.807, 84.6% sensitivity, and 95% specificity. In contrast, a kappa coefficient of -0.37, 21.7% sensitivity, and 30% specificity were noted between the THG-bright dendritic-cell-like signals and CD1a staining for LCs. Our study indicates the capability of noninvasive label-free THG microscopy to differentiate intratumoral melanocytes from LCs, which is not feasible in previous in vivo label-free clinical-imaging modalities.

  18. Modeling neural crest induction, melanocyte specification and disease-related pigmentation defects in hESCs and patient-specific iPSCs

    PubMed Central

    Mica, Yvonne; Lee, Gabsang; Chambers, Stuart M.; Tomishima, Mark; Studer, Lorenz

    2013-01-01

    SUMMARY Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Subsequent maturation of hESC-derived melanocytes yields pure populations matching the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak and Chediak-Higashi Syndrome patient-specific iPSCs faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. PMID:23583175

  19. UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6.

    PubMed

    Miyata, Maiko; Ichihara, Masatoshi; Tajima, Orie; Sobue, Sayaka; Kambe, Mariko; Sugiura, Kazumitsu; Furukawa, Koichi; Furukawa, Keiko

    2014-03-07

    Although expression of gangliosides and their synthetic enzyme genes in malignant melanomas has been well studied, that in normal melanocytes has been scarcely analyzed. In particular, changes in expression levels of glycosyltransferase genes responsible for ganglioside synthesis during evolution of melanomas from melanocytes are very important to understand roles of gangliosides in melanomas. Here, expression of glycosyltransferase genes related to the ganglioside synthesis was analyzed using RNAs from cultured melanocytes and melanoma cell lines. Quantitative RT-PCR revealed that melanomas expressed high levels of mRNA of GD3 synthase and GM2/GD2 synthase genes and low levels of GM1/GD1b synthase genes compared with melanocytes. As a representative exogenous stimulation, effects of ultraviolet B (UVB) on the expression levels of 3 major ganglioside synthase genes in melanocytes were analyzed. Although direct UVB irradiation of melanocytes caused no marked changes, culture supernatants of UVB-irradiated keratinocytes (HaCaT cells) induced definite up-regulation of GD3 synthase and GM2/GD2 synthase genes. Detailed examination of the supernatants revealed that inflammatory cytokines such as TNFα and IL-6 enhanced GD3 synthase gene expression. These results suggest that inflammatory cytokines secreted from UVB-irradiated keratinocytes induced melanoma-associated ganglioside synthase genes, proposing roles of skin microenvironment in the promotion of melanoma-like ganglioside profiles in melanocytes.

  20. Additive effect of heat on the UVB-induced tyrosinase activation and melanogenesis via ERK/p38/MITF pathway in human epidermal melanocytes.

    PubMed

    Gu, Wei-Jie; Ma, Hui-Jun; Zhao, Guang; Yuan, Xiao-Ying; Zhang, Ping; Liu, Wen; Ma, Li-Juan; Lei, Xiao-Bing

    2014-08-01

    Heat is known as an environmental factor that causes significant skin pigmentation, but its effects on melanogenesis have been poorly studied. It has been shown that mitogen-activated protein kinase (MAPK) is involved in ultraviolet B (UVB) and stress-induced melanogenesis in melanocytes. In this study, we investigated the effects of heat and UVB, on melanocyte melanogenesis, differentiation, and MAPK phosphorylation. The results showed that heat (1 h at 40 °C for 5 days) increased cell dendrites, enlarged cell bodies, and induced extracellular signal-regulated kinases (ERK)/p38/MITF activation but did not influence melanogenesis of human epidermal melanocytes from skin phototype III. UVB irradiation (20 mJ/cm(2) for 5 days) induced melanogenesis and c-jun N-terminal kinases (JNK)/p38/MITF/tyrosinase activation in melanocytes from skin phototype III. UVB combined with heat resulted in much more significant tyrosinase activation and melanogenesis as compared with UVB alone in melanocytes from skin phototype III. Furthermore, heat treatment and UVB irradiation induced JNK, ERK, and p38 activation but not melanogenic and morphological changes in melanocytes from skin phototype I. These findings suggested that heat promoted melanocyte differentiation, probably via heat-induced ERK/p38/MITF/activation. Furthermore, heat had an additive effect on the UVB-induced tyrosinase activation and melanogenesis. These results provide a new clue for dermatologists for the treatment of hypopigmented skin disease with heat combined with UVB irradiation.

  1. Polycaprolactone fiber meshes provide a 3D environment suitable for cultivation and differentiation of melanocytes from the outer root sheath of hair follicle.

    PubMed

    Savkovic, Vuk; Flämig, Franziska; Schneider, Marie; Sülflow, Katharina; Loth, Tina; Lohrenz, Andrea; Hacker, Michael Christian; Schulz-Siegmund, Michaela; Simon, Jan-Christoph

    2016-01-01

    Melanocytes differentiated from the stem cells of human hair follicle outer root sheath (ORS) have the potential for developing non-invasive treatments for skin disorders out of a minimal sample: of hair root. With a robust procedure for melanocyte cultivation from the ORS of human hair follicle at hand, this study focused on the identification of a suitable biocompatible, biodegradable carrier as the next step toward their clinical implementation. Polycaprolactone (PCL) is a known biocompatible material used for a number of medical devices. In this study, we have populated electrospun PCL fiber meshes with normal human epidermal melanocytes (NHEM) as well as with hair-follicle-derived human melanocytes from the outer root sheath (HUMORS) and tested their functionality in vitro. PCL fiber meshes evidently provided a niche for melanocytes and supported their melanotic properties. The cells were tested for gene expression of PAX3, PMEL, TYR and MITF, as well as for proliferation, expression of melanocyte marker proteins tyrosinase and glycoprotein 100 (gp100), L-DOPA-tautomerase enzymatic activity and melanin content. Reduced mitochondrial activity and PAX-3 gene expression indicated that the three-dimensional PCL scaffold supported differentiation rather than proliferation of melanocytes. The monitored melanotic features of both the NHEM and HUMORS cultivated on PCL scaffolds significantly exceeded those of two-dimensional adherent cultures.

  2. SCF/c-kit signaling is required in 12-O-tetradecanoylphorbol-13-acetate-induced migration and differentiation of hair follicle melanocytes for epidermal pigmentation.

    PubMed

    Qiu, Weiming; Yang, Ke; Lei, Mingxing; Yan, Hongtao; Tang, Hui; Bai, Xiufeng; Yang, Guihong; Lian, Xiaohua; Wu, Jinjin

    2015-05-01

    Hair follicle melanocyte stem cells (McSCs) are responsible for hair pigmentation and also function as a major melanocyte reservoir for epidermal pigmentation. However, the molecular mechanism promoting McSCs for epidermal pigmentation remains elusive. 12-O-tetradecanoylphorbol-13-acetate (TPA) mimics key signaling involved in melanocyte growth, migration and differentiation. We therefore investigated the molecular basis for the contribution of hair follicle McSCs to epidermal pigmentation using the TPA induction model. We found that repetitive TPA treatment of female C57BL/6 mouse dorsal skin induced epidermal pigmentation by increasing the number of epidermal melanocytes. Particularly, TPA treatment induced McSCs to initiate proliferation, exit the stem cell niche and differentiate. We also demonstrated that TPA promotes melanoblast migration and differentiation in vitro. At the molecular level, TPA treatment induced robust expression of stem cell factor (SCF) in keratinocytes and c-kit in melanoblasts and melanocytes. Administration of ACK2, a neutralizing antibody against the Kit receptor, suppressed mouse epidermal pigmentation, decreased the number of epidermal melanocytes, and inhibited melanoblast migration. Taken together, our data demonstrate that TPA promotes the expansion, migration and differentiation of hair follicle McSCs for mouse epidermal pigmentation. SCF/c-kit signaling was required for TPA-induced migration and differentiation of hair follicle melanocytes. Our findings may provide an excellent model to investigate the signaling mechanisms regulating epidermal pigmentation from mouse hair follicle McSCs, and a potential therapeutic option for skin pigmentation disorders.

  3. Retinoid-X-receptors (α/β) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.

    PubMed

    Coleman, Daniel J; Garcia, Gloria; Hyter, Stephen; Jang, Hyo Sang; Chagani, Sharmeen; Liang, Xiaobo; Larue, Lionel; Ganguli-Indra, Gitali; Indra, Arup K

    2014-05-01

    Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRβ, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/β. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/β. Loss of RXRs α/β specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.

  4. Label-Free Imaging of Female Genital Tract Melanocytic Lesions With Pump-Probe Microscopy: A Promising Diagnostic Tool

    PubMed Central

    Robles, Francisco E.; Deb, Sanghamitra; Fischer, Martin C.; Warren, Warren S.; Selim, Maria Angelica

    2017-01-01

    Objectives Melanomas of the female genital tract present a unique clinical challenge. Not only are these lesions in an anatomically sensitive area, but also they tend to be multifocal and have high recurrence rates. Furthermore, several benign melanocytic proliferations resemble early-stage melanoma clinically and/or histopathologically. Thus, there is a significant need for additional tools that can help correctly diagnose and stage these lesions. Here, we quantitatively and nondestructively analyze the chemical composition of melanin in excised pigmented lesions of the female genital tract using pump-probe microscopy, a high-resolution optical imaging technique that is sensitive to many biochemical properties of melanin. Materials and Methods Thirty-one thin (~5 μm) tissue sections previously excised from female genital tract melanocytic lesions were imaged with pump-probe microscopy and analyzed. Results We find significant quantitative differences in melanin type and structure between melanoma and nonmalignant melanocytic proliferations. Our analysis also suggests a link between the molecular signatures of melanins and lesion-specific genetic mutations. Finally, significant differences are found between metastatic and nonmetastatic melanomas. The limitations of this work include the fact that molecular information is restricted to melanin pigment and the sample size is relatively small. Conclusions Pump-probe microscopy provides unique information regarding the biochemical composition of genital tract melanocytic lesions, which can be used to improve the diagnosis and staging of vulvar melanomas. PMID:28157824

  5. Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45.

    PubMed

    Kim, Minjeong; Baek, Heung Soo; Lee, Miri; Park, Hyeonji; Shin, Song Seok; Choi, Dal Woong; Lim, Kyung-Min

    2016-04-01

    Rhododenol or rhododendrol (RD, 4-(4-hydroxyphenyl)-2-butanol) occurs naturally in many plants along with raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a ketone derivative, which include Nikko maple tree (Acer nikoense) and white birch (Betula platyphylla). De-pigmenting activity of RD was discovered and it was used as a brightening ingredient for the skin whitening cosmetics. Recently, cosmetics containing RD were withdrawn from the market because a number of consumers developed leukoderma, inflammation and erythema on their face, neck and hands. Here, we explored the mechanism underlying the toxicity of RD and RK against melanocytes using B16F10 murine melanoma cells and human primary epidermal melanocytes. Treatment with RD or RK resulted in the decreased cell viability in a dose-dependent manner which appeared from cell growth arrest. Consistently, ROS generation was significantly increased by RD or RK as determined by DCF-enhanced fluorescence. An antioxidant enzyme, glutathione peroxidase was depleted as well. In line with ROS generation, oxidative damages and the arrest of normal cell proliferation, GADD genes (Growth Arrest and DNA Damage) that include GADD45 and GADD153, were significantly up-regulated. Prevention of ROS generation with an anti-oxidant, N-acetylcysteine (NAC) significantly rescued RD and RK-suppressed melanocyte proliferation. Consistently, up-regulation of GADD45 and GADD153 was significantly attenuated by NAC, suggesting that increased ROS and the resultant growth arrest of melanocytes may contribute to RD and RK-induced leukoderma.

  6. Paraganglioma-like dermal melanocytic tumor: a unique entity distinct from cellular blue nevus, clear cell sarcoma, and cutaneous melanoma.

    PubMed

    Deyrup, Andrea T; Althof, Pamela; Zhou, Ming; Morgan, Michael; Solomon, Alvin R; Bridge, Julia A; Weiss, Sharon W

    2004-12-01

    We are reporting a previously undescribed primary dermal melanocytic tumor identified by reviewing all dermal melanocytic tumors referred in consultation that did not qualify histologically as a previously described entity. From these cases, 8 were remarkably similar. We termed them "paraganglioma-like dermal melanocytic tumor" (PDMT) based on their nested growth pattern. This term is used descriptively and does not imply any histogenetic or biologic similarity to true paraganglioma. PDMT is primarily a tumor of the extremities of adult females (18-53 years, mean 35 years; males 2; females 6) which present as a dermal nodule (range, 0.5-4.2 cm; mean, 1.4 cm) composed of nests of clear to amphophilic oval cells separated by delicate fibrous strands. Nuclear atypia was mild and mitotic activity low (1-4 mitoses/10 HPF). Melanin was not obvious on light microscopy. Tumors expressed S-100 protein (8 of 8), Melan-A (4 of 8), HMB-45 (8 of 8), and microphthalmia transcription factor (8 of 8) and lacked pancytokeratin (8 of 8) and smooth muscle actin (8 of 8). FISH analysis of 5 cases revealed an intact EWS gene locus, supporting absence of the clear cell sarcoma 12;22 translocation. Follow-up information in 8 patients (range, 35-92 months; mean, 54 months) indicated that all were alive without disease. PDMT comprises a clinically and pathologically unique subtype of dermal melanocytic tumors. Our study suggests a benign course, although a lesion of low malignant potential cannot be excluded.

  7. Skeletal muscle-melanocyte association during tadpole tail resorption in a tropical frog, Clinotarsus curtipes Jerdon (Anura, Ranoidea).

    PubMed

    Divya, Lekha; Beyo, Reston S; Sreejith, Parameswaran; Akbarsha, Mohammad A; Oommen, Oommen V

    2010-05-01

    We tested the hypothesis that melanin has a role as a molecule within the thyroid-mediated cascade. Light microscopic and ultrastructural changes in the skeletal muscle during tail resorption in tadpoles of the tropical frog Clinotarsus curtipes Jerdon (Anura: Ranoidea) were observed. Light microscopic analysis at metamorphic stage XVIII showed a melanized epidermis. A gradual migration of melanocytes from the epidermis to the dermis and filopodia of melanocytes pervading the skeletal muscle preceded tail resorption. The invasion of melanocytes into the muscle bundles coincided with the breakdown of the muscle bundles into sarcolytes and the arrival of macrophages at this site. This would suggest that the melanocyte-sarcolyte association signals the arrival of macrophages at these sites as metamorphosis progressed. Melanophages, macrophages with melanin granules, were observed at the climax stage of XXIII. The sarcolytes and the melanin granules were phagocytosed by macrophages so as to completely cleanse the exocytic muscle debris and the melanin granules. The presence of large melanomacrophage centers in the tadpole liver at metamorphic climax suggests that these phagocytic macrophages were further processed in the liver and, likely, in the spleen. It is proposed that melanin, a byzantine molecule, has a role in the cascade of events leading to tail resorption in anuran tadpoles.

  8. Regional Fluctuation in the Functional Consequence of LINE-1 Insertion in the Mitf Gene: The Black Spotting Phenotype Arisen from the Mitfmi-bw Mouse Lacking Melanocytes.

    PubMed

    Takeda, Kazuhisa; Hozumi, Hiroki; Ohba, Koji; Yamamoto, Hiroaki; Shibahara, Shigeki

    2016-01-01

    Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of melanoblasts, precursors to melanocytes. The mouse homozygous for the black-eyed white (Mitfmi-bw) allele is characterized by the white-coat color and deafness with black eyes due to the lack of melanocytes. The Mitfmi-bw allele carries LINE-1, a retrotransposable element, which results in the Mitf deficiency. Here, we have established the black spotting mouse that was spontaneously arisen from the homozygous Mitfmi-bw mouse lacking melanocytes. The black spotting mouse shows multiple black patches on the white coat, with age-related graying. Importantly, each black patch also contains hair follicles lacking melanocytes, whereas the white-coat area completely lacks melanocytes. RT-PCR analyses of the pigmented patches confirmed that the LINE-1 insertion is retained in the Mitf gene of the black spotting mouse, thereby excluding the possibility of the somatic reversion of the Mitfmi-bw allele. The immunohistochemical analysis revealed that the staining intensity for beta-catenin was noticeably lower in hair follicles lacking melanocytes of the homozygous Mitfmi-bw mouse and the black spotting mouse, compared to the control mouse. In contrast, the staining intensity for beta-catenin and cyclin D1 was higher in keratinocytes of the black spotting mouse, compared to keratinocytes of the control mouse and the Mitfmi-bw mouse. Moreover, the keratinocyte layer appears thicker in the Mitfmi-bw mouse, with the overexpression of Ki-67, a marker for cell proliferation. We also show that the presumptive black spots are formed by embryonic day 15.5. Thus, the black spotting mouse provides the unique model to explore the molecular basis for the survival and death of developing melanoblasts and melanocyte stem cells in the epidermis. These results indicate that follicular melanocytes are responsible for maintaining the epidermal homeostasis; namely, the present study has provided

  9. Effects of low-dose γ-rays on the embryonic development of mouse melanoblasts and melanocytes in the epidermis and hair bulbs.

    PubMed

    Hirobe, Tomohisa; Eguchi-Kasai, Kiyomi; Sugaya, Kimihiko; Murakami, Masahiro

    2011-06-01

    The effects of low-dose γ-rays on the embryonic development of animal cells are not well studied. The mouse melanocyte is a good model to study the effects of low-dose γ-rays on the development of animal cells, as it possesses visible pigment (melanin) as a differentiation marker. The aim of this study is to investigate in detail the effects of low-dose γ-rays on embryonic development of mouse melanoblasts and melanocytes in the epidermis and hair bulbs at cellular level. Pregnant females of C57BL/10J mice at nine days of gestation were whole-body irradiated with a single acute dose of γrays (0.1, 0.25, 0.5, and 0.75 Gy), and the effects of γ-rays were studied by scoring changes in the development of epidermal melanoblasts and melanocytes, hair follicles, and hair bulb melanocytes at 18 days in gestation. The number of epidermal melanoblasts and melanocytes, hair follicles, and hair bulb melanocytes in the dorsal and ventral skins was markedly decreased even at 0.1 Gy-treated embryos (P < 0.001), and gradually decreased as dose increased. The effects on the ventral skin were greater than those on the dorsal skin. The dramatic reduction in the number of melanocytes compared to melanoblasts was observed in the ventral skin, but not in the dorsal skin. These results suggest that low-dose γ-rays provoke the death of melanoblasts and melanocytes, or inhibit the proliferation and differentiation of melanoblasts and melanocytes, even at the low dose.

  10. Acquired Upper Extremity Growth Arrest.

    PubMed

    Gauger, Erich M; Casnovsky, Lauren L; Gauger, Erica J; Bohn, Deborah C; Van Heest, Ann E

    2016-09-29

    This study reviewed the clinical history and management of acquired growth arrest in the upper extremity in pediatric patients. The records of all patients presenting from 1996 to 2012 with radiographically proven acquired growth arrest were reviewed. Records were examined to determine the etiology and site of growth arrest, management, and complications. Patients with tumors or hereditary etiology were excluded. A total of 44 patients (24 boys and 20 girls) with 51 physeal arrests who presented at a mean age of 10.6 years (range, 0.8-18.2 years) were included in the study. The distal radius was the most common site (n=24), followed by the distal humerus (n=8), metacarpal (n=6), distal ulna (n=5), proximal humerus (n=4), radial head (n=3), and olecranon (n=1). Growth arrest was secondary to trauma (n=22), infection (n=11), idiopathy (n=6), inflammation (n=2), compartment syndrome (n=2), and avascular necrosis (n=1). Twenty-six patients (59%) underwent surgical intervention to address deformity caused by the physeal arrest. Operative procedures included ipsilateral unaffected bone epiphysiodesis (n=21), shortening osteotomy (n=10), lengthening osteotomy (n=8), excision of physeal bar or bone fragment (n=2), angular correction osteotomy (n=1), and creation of single bone forearm (n=1). Four complications occurred; 3 of these required additional procedures. Acquired upper extremity growth arrest usually is caused by trauma or infection, and the most frequent site is the distal radius. Growth disturbances due to premature arrest can be treated effectively with epiphysiodesis or osteotomy. In this series, the specific site of anatomic growth arrest was the primary factor in determining treatment. [Orthopedics. 201x; xx(x):xx-xx.].

  11. The inhibition of acquired fear.

    PubMed

    Izquierdo, Iván; Cammarota, Martín; Vianna, Mónica M R; Bevilaqua, Lía R M

    2004-01-01

    A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is at the root of a variety of mental disorders, among which phobias, generalized anxiety, the posttraumatic stress disorder (PTSD) and some forms of depression. The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS alone, so that a new association, CS-"no US", will eventually overcome the previously acquired CS-US association. Extinction was first described by Pavlov as a form of "internal inhibition" and was recommended by Freud and Ferenczi in the 1920s (who called it "habituation") as the treatment of choice for phobic disorders. It is used with success till this day, often in association with anxiolytic drugs. Extinction has since then been applied, also successfully and also often in association with anxiolytics, to the treatment of panic, generalized anxiety disorders and, more recently, PTSD. Extinction of learned fear involves gene expression, protein synthesis, N-methyl-D-aspartate (NMDA) receptors and signaling pathways in the hippocampus and the amygdala at the time of the first CS-no US association. It can be enhanced by increasing the exposure to the "no US" component at the time of behavioral testing, to the point of causing the complete uninstallment of the original fear response. Some theorists have recently proposed that reiteration of the CS alone may induce a reconsolidation of the learned behavior instead of its extinction. Reconsolidation would preserve the original memory from the labilization induced by its retrieval. If true, this would of course be disastrous for the psychotherapy of fear-motivated disorders. Here we show that neither the CS nor retrieval cause anything remotely like reconsolidation, but just extinction. In fact, our findings indicate that the reconsolidation hypothesis is essentially incorrect, at least for the form of contextual fear most

  12. Foodborne listeriosis acquired in hospitals.

    PubMed

    Silk, Benjamin J; McCoy, Morgan H; Iwamoto, Martha; Griffin, Patricia M

    2014-08-15

    Listeriosis is characterized by bacteremia or meningitis. We searched for listeriosis case series and outbreak investigations published in English by 2013, and assessed the strength of evidence for foodborne acquisition among patients who ate hospital food. We identified 30 reports from 13 countries. Among the case series, the median proportion of cases considered to be hospital-acquired was 25% (range, 9%-67%). The median number of outbreak-related illnesses considered to be hospital-acquired was 4.0 (range, 2-16). All patients were immunosuppressed in 18 of 24 (75%) reports with available data. Eight outbreak reports with strong evidence for foodborne acquisition in a hospital implicated sandwiches (3 reports), butter, precut celery, Camembert cheese, sausage, and tuna salad (1 report each). Foodborne acquisition of listeriosis among hospitalized patients is well documented internationally. The number of listeriosis cases could be reduced substantially by establishing hospital policies for safe food preparation for immunocompromised patients and by not serving them higher-risk foods.

  13. EPR spectroscopy of chlorpromazine-induced free radical formation in normal human melanocytes.

    PubMed

    Otręba, Michał; Zdybel, Magdalena; Pilawa, Barbara; Beberok, Artur; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2015-07-01

    The purpose of this study was to estimate the effect of chlorpromazine on free radical concentration in HEMn-DP melanocytes using electron paramagnetic resonance (EPR) spectroscopy. It was found that chlorpromazine at concentrations of 1 × 10(-7) and 1 × 10(-6) M contributed to the formation of free radicals (g values ~2) in a dose-dependent manner. The increase in free radical formation was accompanied by an increase in cytotoxicity, as shown by a tetrazolium assay. Homogeneous broadening of EPR lines, slow spin-lattice relaxation processes, and strong dipolar interactions characterized all the tested cellular samples. The performed examination of free radical formation in cells exposed to different chlorpromazine concentrations confirmed the usefulness of electron paramagnetic resonance spectroscopy to determine the effect of a drug on free radical production in a cellular model system in vitro.

  14. Anti-melanogenic effects of black, green, and white tea extracts on immortalized melanocytes

    PubMed Central

    Choi, So Young; Park, Eun Ye

    2015-01-01

    Tea contains polyphenols and is one of the most popular beverages consumed worldwide. Because most tyrosinase inhibitors that regulate melanogenesis are phenol/catechol derivatives, this study investigated the inhibitory effects of Camellia sinensis water extracts (CSWEs), including black tea, green tea, and white tea extracts, on melanogenesis using immortalized melanocytes. CSWEs inhibited melanin accumulation and melanin synthesis along with tyrosinase activity in a concentration-dependent manner. These inhibitory effects were superior to those of arbutin, a well-known depigmenting agent. The anti-melanogenic activity of black (fermented) tea was higher than that of a predominant tea catecholamine, epigallocatechin gallate. CSWEs, especially black tea extract, decreased tyrosinase protein levels in a concentration-dependent manner. These results suggest that the anti-melanogenic effect of CSWEs is mediated by a decrease in both tyrosinase activity and protein expression, and may be augmented by fermentation. Thus, CSWEs could be useful skin-whitening agents in the cosmetic industry. PMID:25643794

  15. Differential effects of selenite and selenate on human melanocytes, keratinocytes, and melanoma cells.

    PubMed

    Bandura, Laura; Drukala, Justyna; Wolnicka-Glubisz, Agnieszka; Björnstedt, Mikael; Korohoda, Wlodzimierz

    2005-04-01

    Among the substances that attracted the attention of oncologists in recent years are selenium-containing compounds, both inorganic and organic. Several epidemiological studies have shown an inverse correlation between selenium intake and cancer incidence. In the experiments reported here, we compared the effects of 2 inorganic selenium-containing salts that differed in the level of selenium oxidation, selenite IV and selenate VI. We tested the effects of these 2 compounds on cell survival and growth, cell cycle processing, cell morphology, cytoskeleton, and lipid peroxidation in 3 human skin cell types: normal keratinocytes, melanocytes, and human melanoma cell line HTB140. The different effects of selenite and selenate on the viability, growth, and morphology of normal cells and tumor cells are reported and provide a base for future research and treatment of some neoplastic diseases. The attention is paid to cell apoptosis induced by selenite and not by selenate, and the effects of tested substances on thioredoxin reductase system are postulated.

  16. Resolution and recurrence of vitiligo following excision of congenital melanocytic nevus.

    PubMed

    Workman, Meredith; Sawan, Kamal; El Amm, Christian

    2013-01-01

    Vitiligo associated with halo congenital melanocytic nevus (CMN) is rare. There are limited reports in the literature, especially with regard to CMN excision. We present the case of a 5-year-old girl who presented with vitiligo of the periorbital and axillary regions and halo formation around CMN of the buttock. The lesion was excised, and all areas of vitiligo improved, but 18 months postoperatively, a halo of depigmentation appeared around the excision scar and later in the periorbital and axillary regions. In review of literature, there is only one report of excision of halo CMN and resultant improvement of vitiligo. Although initial resolution of vitiligo in this case was promising, the recurrence indicates that this complex process is not reliably controlled with excision of the inciting lesion.

  17. Efficacy of five human melanocytic cell lines in experimental rabbit choroidal melanoma.

    PubMed

    López-Velasco, Rosario; Morilla-Grasa, Antonio; Saornil-Alvarez, María A; Ordóñez, José L; Blanco, Gonzalo; Rábano, Guillermo; Fernández, Nieves; Almaraz, Ana

    2005-02-01

    This study was undertaken to compare the ability of five uveal melanocytic cell lines to produce primary and metastatic uveal melanomas in immunosuppressed rabbits and to determine whether animal survival was improved by antibiotic administration. One hundred albino rabbit eyes, five groups of 20, were implanted in the suprachoroidal space with four melanoma cell lines (MKT-BR, OCM-1, 92-1 and SP 6.5) and one melanocytic line (UW-1). Rabbits were immunosuppressed with cyclosporin A (CsA) at a dosage of 15 mg/kg/day, decreased to 10 mg/kg/day after the fourth week. Prophylactic penicillin G, 10 to 2 x 10 IU, was administered intramuscularly at 5-day intervals. Animals were followed for 12 weeks and the ophthalmoscopic findings, weight and general well-being were recorded weekly. Autopsies were performed to study the eyes, liver and lungs under light microscopy. The mean global survival time in the groups was 43+/-4 days. Ophthalmoscopic intraocular tumours developed in 37% of the MKT-BR group, 50% of the OCM-1 group, 100% of the 92-1 group, 23% of the UW-1 group and 75% of the SP 6.5 group; histologically, tumours appeared in 36.8%, 45%, 100%, 58.8% and 100%, respectively. The 92-1 and SP 6.5 cell lines were associated with the most aggressive local behaviour. Lung metastases developed in the OCM-1 group (5%), 92-1 group (61.1%), UW-1 group (7.1%) and SP 6.5 group (42.1%), but were not present in the MKT-BR group. The 92-1 and SP 6.5 cell lines were the most efficient in local and metastatic tumour production. Prophylactic antibiotic administration did not improve animal survival.

  18. Interaction between omega 3 PUFA and UVB radiation: Photoprotective effect in normal and tumoral murine melanocytes?

    PubMed

    Vasconcelos, Renata Ottes; Bustos, Silvina Odete; Gonzalez, Juliana Ramos; Soares, Camila Wink; Barbosa, Makely Daiane; Chammas, Roger; Votto, Ana Paula de Souza; Trindade, Gilma Santos

    2016-11-01

    Omega 3 polyunsaturated fatty acids (omega 3 PUFA) are attracting a growing interest as potential adjuvants for cancer prevention and treatment. There is evidence about photoprotection in normal cells, but few previous studies have evaluated it in tumoral cells. Therefore, this study investigated the effect of α-linolenic acid (ALA) in normal murine melanocytic cells (Melan-a) and in tumoral murine melanocytic cells (B16F10) exposed to UVB radiation. Our results showed that ALA exhibited an antiproliferative effect in B16F10 cells, and had minimal effect in Melan-a cells, as demonstrated by MTT assay. On the other hand, the combination of ALA (7.5μM) and UVB (0.01J/cm(2)) showed a protective effect for both cell lines, Melan-a and B16F10. ALA and UVB combined or UVB alone induced an accumulation of cell lines at the S/G2/M phase. In addition, the combination of ALA and UVB, and UVB alone, both induced cell death in 24h; and in 48h, ALA attenuated this effect in both cells. Further to these findings, it was demonstrated that ALA did not alter ROS levels in both cells exposed to UVB radiation. The effect of an omega 6 PUFA, linoleic acid, under the same conditions of ALA were tested. It was not protective in either cell line. Therefore, our results can be very important since it was shown another role to an omega 3 PUFA as a photoprotective agent in a melanoma cell.

  19. Regulation of type I-interferon responses in the human epidermal melanocyte cell line SKMEL infected by the Ross River alphavirus.

    PubMed

    Assi, Mohamad; Thon-Hon, Vincent Gérard; Jaffar-Bandjee, Marie-Christine; Martinez, Audrey; Gasque, Philippe

    2015-12-01

    Melanocytes are melanin-producing cells and with emerging innate immune functions including the expression of antiviral interferon-type I cytokines. We herein ascertained the susceptibility of the human melanocytes to Ross River alphavirus (RRV) infection and analyzed the subsequent immune responses. We demonstrated for the first time that (1) SKMEL-28 melanocyte cell line was susceptible to RRV infection and displaying major cytopathic activities and (2) RRV interfered with the interferon-type I response by altering nuclear translocation of pSTAT1 and pSTAT2 in infected SKMEL-28. These results suggest that the human melanoma cell line SKMEL-28 is a valuable model to analyze the mechanisms involved in severe skin manifestations and melanocyte's immunity at the portal of entry of major infection by arboviruses.

  20. The effect of MC1R variants and sunscreen on the response of human melanocytes in vivo to ultraviolet radiation and implications for melanoma.

    PubMed

    Hacker, Elke; Boyce, Zachary; Kimlin, Michael G; Wockner, Leesa; Pollak, Thomas; Vaartjes, Sam A; Hayward, Nicholas K; Whiteman, David C

    2013-11-01

    We conducted a clinical trial to compare the molecular and cellular responses of human melanocytes and keratinocytes in vivo to solar-simulated ultraviolet radiation (SSUVR) in 57 Caucasian participants grouped according to MC1R genotype. We found that, on average, the density of epidermal melanocytes 14 days after exposure to 2 minimal erythemal dose (MED) SSUVR was twofold higher than baseline (unirradiated) skin. However, the change in epidermal melanocyte counts among people carrying germline MC1R variants (97% increase) was significantly less than those with wild-type MC1R (164% increase; P = 0.01). We also found that sunscreen applied to the skin before exposure to 2 MED SSUVR completely blocked the effects of DNA damage, p53 induction, and cellular proliferation in both melanocytes and keratinocytes.

  1. Bejel: acquirable only in childhood?

    PubMed

    Rothschild, Bruce M; Rothschild, Christine; Naples, Virginia; Billard, Michel; Panero, Barbara

    2006-10-01

    Bejel clearly has a long history in the Middle East and the Sudan, but was it transmitted to Europe? As the major manifestation of bejel is presence of periosteal reaction in 20-40% of afflicted populations, absence of significant population frequency of periosteal reaction in Europe would exclude that diagnosis. Examination of skeletal populations from continental Europe revealed no significant periosteal reaction at the time of and immediately subsequent to the Crusades. Thus, there is no evidence for bejel in Europe, in spite of clear contact (the mechanism of bejel transmission in children) between warring groups, at least during the Crusades. This supports the hypothesis that bejel is a childhood-acquired disease and apparently cannot be contracted in adulthood.

  2. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  3. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  4. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  5. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  6. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  7. Acquired haemophilia in recipients of depot thioxanthenes.

    PubMed

    Stewart, A J; Manson, L M; Dasani, H; Beddall, A; Collins, P; Shima, M; Ludlam, C A

    2000-11-01

    We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.

  8. Differential Impact of P16 Mutations with or without Coexpression of MC1R Mutation on the UV Response of Melanocytes and Hence on the Risk for Melanoma

    DTIC Science & Technology

    2015-10-01

    the response of mutant melanocytes to chronic UV exposure, which might overwhelm their compensatory mechanisms and drive their malignant...early onset of melanoma and increases the penetrance of the mutant p16. However, the molecular mechanism(s) by which mutations in these two genes...whether or not melanocyte cultures expressing a mutant p16 allele, and either wild type or loss-of- function MC1R variant efficiently repair UV

  9. Rare Skin Adnexal and Melanocytic Tumors Arising in Ovarian Mature Cystic Teratomas: A Report of 3 Cases and Review of the Literature.

    PubMed

    Moulla, Alexandra A; Magdy, Nesreen; Francis, Nicholas; Taube, Janis; Ronnett, Brigitte M; El-Bahrawy, Mona

    2016-09-01

    Mature teratoma of the ovary is the most common primary ovarian tumor accounting for 15% (10%-20%) of all ovarian neoplasms. Skin and skin adnexal structures are the most common elements identified in mature teratomas. Benign and malignant skin tumors can arise in ovarian teratomas, the most common being epithelial tumors. Melanocytic and adnexal tumors developing in a teratoma are rare and can be easily overlooked. We report 3 cases and review melanocytic and skin adnexal tumors encountered in ovarian teratomas.

  10. Acquiring Evolving Technologies: Web Services Standards

    DTIC Science & Technology

    2016-06-30

    2006 Carnegie Mellon University Acquiring Evolving Technologies : Web Services Standards Harry L. Levinson Software Engineering Institute Carnegie...Acquiring Evolving Technologies : Web Services Standards 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 2 Acquiring Evolving Technologies : Web Services Standards © 2006 Carnegie Mellon University Acquiring

  11. Human epithelial cells induce human melanocyte growth in vitro but only skin keratinocytes regulate its proper differentiation in the absence of dermis

    PubMed Central

    1988-01-01

    Human keratinocytes isolated from a skin biopsy and cultured in vitro reconstitute a stratified squamous epithelium suitable for grafting on burned patients. Melanocytes coisolated from the same skin biopsy also proliferate under these culture conditions and maintain differentiated functions (i.e., synthesize melanin granules, regularly intersperse in the basal layer of the cultured epidermis, and transfer melanosomes in the cytoplasm of contiguous keratinocytes) (De Luca, M., A. T. Franzi, F. D'Anna, A. Zicca, E. Albanese, S. Bondanza, and R. Cancedda. 1988. Eur. J. Cell Biol. 46:176-180). Isolated melanocytes in culture grow in the presence of specific growth factors with a mean population doubling time of 4-10 d. In this paper we show that (a) human keratinocytes and oral epithelial cells possess strong and specific melanocyte growth stimulating activity (doubling time, 24 h); (b) melanocyte growth is not autonomous but requires close keratinocyte contact and is regulated to maintain a physiological melanocytes/keratinocytes ratiol and (c) pure skin keratinocytes, but not oral epithelial cells, have all the information required for the proper physiological location and differentiation of melanocytes in the epidermis. PMID:2460471

  12. Tissue Inhibitor of Metalloproteinase 1 Expression Associated with Gene Demethylation Confers Anoikis Resistance in Early Phases of Melanocyte Malignant Transformation1

    PubMed Central

    Ricca, Tatiana I; Liang, Gangning; Suenaga, Ana Paula M; Han, Sang W; Jones, Peter A; Jasiulionis, Miriam G

    2009-01-01

    Although anoikis resistance has been considered a hallmark of malignant phenotype, the causal relation between neoplastic transformation and anchorage-independent growth remains undefined. We developed an experimental model of murine melanocyte malignant transformation, where a melanocyte lineage (melan-a) was submitted to sequential cycles of anchorage blockade, resulting in progressive morphologic alterations, and malignant transformation. Throughout this process, cells corresponding to premalignant melanocytes and melanoma cell lines were established and show progressive anoikis resistance and increased expression of Timp1. In melan-a melanocytes, Timp1 expression is suppressed by DNA methylation as indicated by its reexpression after 5-aza-2′-deoxycytidine treatment. Methylation-sensitive single-nucleotide primer extension analysis showed increased demethylation in Timp1 in parallel with its expression along malignant transformation. Interestingly, TIMP1 expression has already been related with negative prognosis in some human cancers. Although described as a MMP inhibitor, this protein has been associated with apoptosis resistance in different cell types. Melan-a cells overexpressing Timp1 showed increased survival in suspension but were unable to form tumors in vivo, whereas Timp1-overexpressing melanoma cells showed reduced latency time for tumor appearance and increased metastatic potential. Here, we demonstrated for the first time an increment in Timp1 expression since the early phases of melanocyte malignant transformation, associated to a progressive gene demethylation, which confers anoikis resistance. In this way, Timp1 might be considered as a valued marker for melanocyte malignant transformation. PMID:19956395

  13. Genital melanocytic nevus arising in a background of lichen sclerosus in a 7-year-old female: the diagnostic pitfall with malignant melanoma. A literature review.

    PubMed

    Pinto, Andre; Mclaren, Son H; Poppas, Dix P; Magro, Cynthia M

    2012-12-01

    Genital melanocytic nevus represents a distinct form of melanocytic proliferation, which can exhibit significant atypia, both clinically and histologically. In a background of lichen sclerosus (LS), the histologic changes could be misconstrued as indicative of malignant melanoma. We present herein a case of the atypical genital nevus of childhood complicated by LS, and a review of the literature is performed. Tissue was available for routine light microscopy and immunohistochemical evaluation to assess the expression of soluble adenylyl cyclase. Fluorescent in situ hybridization studies were conducted to assess for abnormalities in Myb1, CCND1, RREB1 and CEP6. The specimen showed an atypical compound melanocytic proliferation arising in a background of LS. The lesion exhibited significant architectural atypia based on the high-density confluent nature of the junctional melanocytic proliferation with epidermal effacement, rare areas of pagetoid ascent, and the heavily pigmented epithelioid quality of the melanocytes. Fluorescent in situ hybridization studies were normal. The soluble adenylyl cyclase antibody preparation demonstrated a benign nevus-like pattern. The lesion was felt to represent an atypical genital melanocytic nevus, which can resemble a partially regressed melanoma in a background of LS. It is very important for the pathologist to be aware of this entity to avoid misdiagnosis.

  14. Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia.

    PubMed

    Vucic, Steve; Cheah, Benjamin C; Yiannikas, Con; Vincent, Angela; Kiernan, Matthew C

    2010-09-01

    Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity

  15. Parameterization using Fourier series expansion of the diffuse reflectance of human skin to vary the concentration of the melanocytes

    NASA Astrophysics Data System (ADS)

    Narea, J. Freddy; Muñoz, Aarón A.; Castro, Jorge; Muñoz, Rafael A.; Villalba, Caroleny E.; Martinez, María. F.; Bravo, Kelly D.

    2013-11-01

    Human skin has been studied in numerous investigations, given the interest in knowing information about physiology, morphology and chemical composition. These parameters can be determined using non invasively optical techniques in vivo, such as the diffuse reflectance spectroscopy. The human skin color is determined by many factors, but primarily by the amount and distribution of the pigment melanin. The melanin is produced by the melanocytes in the basal layer of the epidermis. This research characterize the spectral response of the human skin using the coefficients of Fourier series expansion. Simulating the radiative transfer equation for the Monte Carlo method to vary the concentration of the melanocytes (fme) in a simplified model of human skin. It fits relating the Fourier series coefficient a0 with fme. Therefore it is possible to recover the skin biophysical parameter.

  16. Poised Regeneration of Zebrafish Melanocytes Involves Direct Differentiation and Concurrent Replenishment of Tissue-Resident Progenitor Cells.

    PubMed

    Iyengar, Sharanya; Kasheta, Melissa; Ceol, Craig J

    2015-06-22

    Efficient regeneration following injury is critical for maintaining tissue function and enabling organismal survival. Cells reconstituting damaged tissue are often generated from resident stem or progenitor cells or from cells that have dedifferentiated and become proliferative. While lineage-tracing studies have defined cellular sources of regeneration in many tissues, the process by which these cells execute the regenerative process is largely obscure. Here, we have identified tissue-resident progenitor cells that mediate regeneration of zebrafish stripe melanocytes and defined how these cells reconstitute pigmentation. Nearly all regeneration melanocytes arise through direct differentiation of progenitor cells. Wnt signaling is activated prior to differentiation, and inhibition of Wnt signaling impairs regeneration. Additional progenitors divide symmetrically to sustain the pool of progenitor cells. Combining direct differentiation with symmetric progenitor divisions may serve as a means to rapidly repair injured tissue while preserving the capacity to regenerate.

  17. Associative Learning Through Acquired Salience

    PubMed Central

    Treviño, Mario

    2016-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  18. Inherited or acquired metabolic disorders.

    PubMed

    Eichler, Florian; Ratai, Eva; Carroll, Jason J; Masdeu, Joseph C

    2016-01-01

    This chapter starts with a description of imaging of inherited metabolic disorders, followed by a discussion on imaging of acquired toxic-metabolic disorders of the adult brain. Neuroimaging is crucial for the diagnosis and management of a number of inherited metabolic disorders. Among these, inherited white-matter disorders commonly affect both the nervous system and endocrine organs. Magnetic resonance imaging (MRI) has enabled new classifications of these disorders that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. Beyond the classic leukodystrophies, we are increasingly recognizing new hereditary leukoencephalopathies such as the hypomyelinating disorders. Conventional imaging can be unrevealing in some metabolic disorders, but proton magnetic resonance spectroscopy (MRS) may be able to directly visualize the metabolic abnormality in certain disorders. Hence, neuroimaging can enhance our understanding of pathogenesis, even in the absence of a pathologic specimen. This review aims to present pathognomonic brain MRI lesion patterns, the diagnostic capacity of proton MRS, and information from clinical and laboratory testing that can aid diagnosis. We demonstrate that applying an advanced neuroimaging approach enhances current diagnostics and management. Additional information on inherited and metabolic disorders of the brain can be found in Chapter 63 in the second volume of this series.

  19. Cysteine-dependent 5-S-cysteinyldopa formation and its regulation by glutathione in normal epidermal melanocytes.

    PubMed

    Benathan, M; Labidi, F

    1996-10-01

    Recent evidence suggests that the melanogenesis intermediate 5-S-cysteinyldopa (5-S-CD) could display antioxidative activity. In the present study, the synthesis of 5-S-CD was examined in human epidermal melanocytes isolated from dark skin type VI (MT) and from white skin type III (GT). The MT melanocytes showed the higher melanin content and dopa oxidase activity. In addition, they produced eumelanin as shown by their ultrastructure, and the solubility and UV/visible absorption of the isolated pigment. Both MT and GT cells showed high levels of 5-S-CD (5.5-6.9 nmol/mg protein). 5-S-CD was also detected in culture supernatants from MT cells; the secretion rate was estimated to be 2.5 nmol/mg protein per 24 h. The role of cysteine and glutathione in 5-S-CD formation was investigated by exposing the melanocytes to the gamma-glutamylcysteine synthetase inhibitor L-buthionine sulfoximine (BSO). A strong reduction in glutathione levels (4-8% of the untreated controls) associated with an increase in cysteine levels (152-154%) was observed. In addition, BSO induced a moderate increase in the cellular levels of 5-S-CD (114-129%) and a decrease in dopa oxidase activity (75-83%). Our results indicate that the direct addition of cysteine to dopaquinone is the main source of 5-S-CD in human epidermal melanocytes. It is proposed that the synthesis of 5-S-CD is a mechanism regulating dopaquinone levels during pigment formation and/or a defence mechanism against oxidative stress.

  20. Effect of Uveal Melanocytes on Choroidal Morphology in Rhesus Macaques and Humans on Enhanced-Depth Imaging Optical Coherence Tomography

    PubMed Central

    Yiu, Glenn; Vuong, Vivian S.; Oltjen, Sharon; Cunefare, David; Farsiu, Sina; Garzel, Laura; Roberts, Jeffrey; Thomasy, Sara M.

    2016-01-01

    Purpose To compare cross-sectional choroidal morphology in rhesus macaque and human eyes using enhanced-depth imaging optical coherence tomography (EDI-OCT) and histologic analysis. Methods Enhanced-depth imaging–OCT images from 25 rhesus macaque and 30 human eyes were evaluated for choriocapillaris and choroidal–scleral junction (CSJ) visibility in the central macula based on OCT reflectivity profiles, and compared with age-matched histologic sections. Semiautomated segmentation of the choriocapillaris and CSJ was used to measure choriocapillary and choroidal thickness, respectively. Multivariate regression was performed to determine the association of age, refractive error, and race with choriocapillaris and CSJ visibility. Results Rhesus macaques exhibit a distinct hyporeflective choriocapillaris layer on EDI-OCT, while the CSJ cannot be visualized. In contrast, humans show variable reflectivities of the choriocapillaris, with a distinct CSJ seen in many subjects. Histologic sections demonstrate large, darkly pigmented melanocytes that are densely distributed in the macaque choroid, while melanocytes in humans are smaller, less pigmented, and variably distributed. Optical coherence tomography reflectivity patterns of the choroid appear to correspond to the density, size, and pigmentation of choroidal melanocytes. Mean choriocapillary thickness was similar between the two species (19.3 ± 3.4 vs. 19.8 ± 3.4 μm, P = 0.615), but choroidal thickness may be lower in macaques than in humans (191.2 ± 43.0 vs. 266.8 ± 78.0 μm, P < 0.001). Racial differences in uveal pigmentation also appear to affect the visibility of the choriocapillaris and CSJ on EDI-OCT. Conclusions Pigmented uveal melanocytes affect choroidal morphology on EDI-OCT in rhesus macaque and human eyes. Racial differences in pigmentation may affect choriocapillaris and CSJ visibility, and may influence the accuracy of choroidal thickness measurements. PMID:27792810

  1. Estradiol differently affects melanin synthesis of malignant and normal melanocytes: a relationship with clock and clock-controlled genes.

    PubMed

    Poletini, Maristela Oliveira; de Assis, Leonardo Vinicius Monteiro; Moraes, Maria Nathalia; Castrucci, Ana Maria de Lauro

    2016-10-01

    Melanin production within melanocytes is regulated, among others, by estradiol, whose effects on melanogenesis are still not completely elucidated. Here we show that although 10(-7) M 17β-estradiol (E2) increased tyrosinase mRNA levels in B16-F10 malignant melanocytes, there was a transient decrease and abolishment of the temporal variation of melanin content. Both parameters were much higher in the malignant than in normal Melan-a cells. Considering that silencing clock machinery in human melanocytes increases melanogenesis, we investigated clock gene expression in those cell lines. Except for Melan-a Bmal1 and B16-F10 Per2 expression of control cells, Per1, Per2, and Bmal1 expression increased independently of cell type or E2 treatment after 24 h. However, melanoma cells showed a marked increase in Per1 and Bma11 expression in response to E2 at the same time points, what may rule out E2 as a synchronizer agent since the expression of those genes were not in antiphase. Next, we investigated the expression of Xpa, a clock-controlled gene, which in Melan-a cells, peaked at 18 h, and E2 treatment shifted this peak to 24 h, whereas B16-F10 Xpa expression peaked at 24 h in both control and E2 group, and it was higher compared to Melan-a cells in both groups. Therefore, malignant and normal melanocytes display profound differences on core elements of the local clock, and how they respond to E2, what is most probably determinant of the differences seen on melanin synthesis and Tyrosinase and Xpa expression. Understanding these processes at the molecular level could bring new strategies to treat melanoma.

  2. Is congenital melanocytic naevus a link between Hirayama disease and moyamoya pattern: a new syndrome or a co-incidence?

    PubMed

    Puri, Inder; Vibha, Deepti; Prasad, Kameshwar; Bhatia, Rohit

    2016-01-08

    A 22-year-old man presented with a history of progressive weakness and wasting of the right hand and forearm for 12 months followed by similar symptoms in the left upper limb for the past 5 months. He also gave a history of episodes of loss of consciousness for the past 5 years with a frequency of one per 3 months. On examination, there were melanocytic naevi-one large lesion in the nape of the neck and multiple satellite lesions. On investigation, the cervical cord MRI was normal. The brain MRI and angiography showed a moyamoya pattern. Thus, this patient had congenital melanocytic naevi with Hirayama disease and moyamoya pattern. He was treated with extracranial-intracranial bypass for moyamoya disease. During 6-month follow-up, he has been stable. Although moyamoya syndrome has been associated with several systemic diseases and conditions, the coexistence of a moyamoya pattern with Hirayama disease and melanocytic naevi has not been described so far.

  3. Stimulated human melanocytes express and release interleukin-8, which is inhibited by luteolin: relevance to early vitiligo.

    PubMed

    Miniati, A; Weng, Z; Zhang, B; Therianou, A; Vasiadi, M; Nicolaidou, E; Stratigos, A J; Antoniou, C; Theoharides, T C

    2014-01-01

    Vitiligo is a disorder of depigmentation, for which the pathogenesis is as yet unclear. Interleukin (IL)-8 (CXCL8) is a key inflammatory chemokine. We investigated the regulation of IL-8 production in human melanocytes, and the IL-8 serum levels and skin gene expression in patients with vitiligo and in controls. Cultured melanocytes were stimulated for 24 h with tumour necrosis factor (TNF) 100 ng/mL and IL-1β 10 ng/mL, with or without pretreatment with luteolin 50 μmol/L for 30 min, and IL-8 release was measured by ELISA. Serum cytokines were measured by a microbead array. Skin biopsies were taken from healthy subjects (n = 14) as well as from marginal lesional and nonlesional skin from patients with vitiligo (n = 15). IL-8 gene expression was evaluated by quantitative real time PCR. Both TNF and IL-1β stimulated significant IL-8 release (P < 0.01) from melanocytes, whereas pretreatment with luteolin significantly inhibited this effect (P < 0.01). IL-8 gene expression was significantly increased in vitiligo compared with control skin (P < 0.05). IL-8 may be involved in vitiligo inflammation. Inhibition by luteolin of IL-8 release could be useful for vitiligo therapy.

  4. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes.

    PubMed

    Abdel-Malek, Zalfa A; Ruwe, Andrew; Kavanagh-Starner, Renny; Kadekaro, Ana Luisa; Swope, Viki; Haskell-Luevano, Carrie; Koikov, Leonid; Knittel, James J

    2009-10-01

    One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified alpha-MSH core His(6)-d-Phe(7)-Arg(8), which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked alpha-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.

  5. Solution structures of the melanocyte-stimulating hormones by two-dimensional NMR spectroscopy and dynamical simulated-annealing calculations.

    PubMed

    Lee, J H; Lim, S K; Huh, S H; Lee, D; Lee, W

    1998-10-01

    Melanocortins, which are involved in melanocyte pigmentation control and glucocorticoid stimulation, have functional roles in various physiological mechanisms and have been shown to participate in higher cortical functions. Recently, it has also been reported that melanocyte-stimulating hormone (MSH) and melanocortin 4 receptor (MC4R) are the key components of the hypothalamic response to obesity. The solution structures of both melanocyte-stimulating hormone alpha-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its analog alpha-MSH-ND (Ac-Ahx-Asp-His-DPhe-Arg-Trp-Lys-NH2) (Ahx, 2-aminohexanoic acid) have been determined by two-dimensional NMR spectroscopy and simulated-annealing calculations. The NMR data revealed that alpha-MSH forms a hairpin loop conformation which includes conserved message sequences, whereas alpha-MSH-ND prefers a type I beta-turn comprising residues of Asp2-His3-DPhe4-Arg5. Final simulated-annealing structures of both alpha-MSH-ND and alpha-MSH peptides converged with rmsd of 0.07 nm for alpha-MSH-ND and 0.1 nm for alpha-MSH between backbone atoms, respectively. This result will provide the structural bases of melanocortin functions as well as valuable information for structure-based drug design involving the regulation of obesity and feeding.

  6. N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of UV-induced melanoma in mice

    PubMed Central

    Cotter, Murray A.; Thomas, Joshua; Cassidy, Pamela; Robinette, Kyle; Jenkins, Noah; Scott, R. Florell; Leachman, Sancy; Samlowski, Wolfram E.; Grossman, Douglas

    2008-01-01

    UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. In melan-a cells, a mouse melanocyte line, NAC (1–10 mM) conferred protection from several UV-induced oxidative sequelae including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine (8-OG), and depletion of free reduced thiols (primarily glutathione). Mice transgenic for hepatocyte growth factor and Survivin, previously shown to develop melanoma following a single neonatal dose of UV irradiation, were administered NAC (7 mg/ml, mother’s drinking water) transplacentally and through nursing until two weeks after birth. Delivery of NAC in this manner reduced thiol depletion and blocked formation of 8-OG in skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared to control mice (21 vs. 14 weeks, p=0.0003). Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma, and suggest that NAC may be useful as a chemopreventive agent. PMID:17908992

  7. Rab11b mediates melanin transfer between donor melanocytes and acceptor keratinocytes via coupled exo/endocytosis.

    PubMed

    Tarafder, Abul K; Bolasco, Giulia; Correia, Maria S; Pereira, Francisco J C; Iannone, Lucio; Hume, Alistair N; Kirkpatrick, Niall; Picardo, Mauro; Torrisi, Maria R; Rodrigues, Inês P; Ramalho, José S; Futter, Clare E; Barral, Duarte C; Seabra, Miguel C

    2014-04-01

    The transfer of melanin from melanocytes to keratinocytes is a crucial process underlying maintenance of skin pigmentation and photoprotection against UV damage. Here, we present evidence supporting coupled exocytosis of the melanin core, or melanocore, by melanocytes and subsequent endocytosis by keratinocytes as a predominant mechanism of melanin transfer. Electron microscopy analysis of human skin samples revealed three lines of evidence supporting this: (1) the presence of melanocores in the extracellular space; (2) within keratinocytes, melanin was surrounded by a single membrane; and (3) this membrane lacked the melanosomal membrane protein tyrosinase-related protein 1 (TYRP1). Moreover, co-culture of melanocytes and keratinocytes suggests that melanin exocytosis is specifically induced by keratinocytes. Furthermore, depletion of Rab11b, but not Rab27a, caused a marked decrease in both keratinocyte-stimulated melanin exocytosis and transfer to keratinocytes. Thus, we propose that the predominant mechanism of melanin transfer is keratinocyte-induced exocytosis, mediated by Rab11b through remodeling of the melanosome membrane, followed by subsequent endocytosis by keratinocytes.

  8. Endothelin-1 protects human melanocytes from UV-induced DNA damage by activating JNK and p38 signalling pathways.

    PubMed

    von Koschembahr, Anne M; Swope, Viki B; Starner, Renny J; Abdel-Malek, Zalfa A

    2015-04-01

    Endothelin-1 is a paracrine factor with mitogenic, melanogenic and survival effects on cultured human melanocytes. We report that endothelin-1 signalling reduced the generation and enhanced the repair of ultraviolet radiation (UV)-induced DNA photoproducts, and inhibited apoptosis of human melanocytes, without increasing cAMP levels, melanin content or proliferation. Treatment with endothelin-1 activated the MAP kinases JNK and p38, as evidenced by phosphorylation of their target, activating transcription factor-2 (ATF-2). Endothelin-1 also enhanced the phosphorylation of JNK, p38 and ATF-2 by UV. The effects of endothelin-1 were dependent on increasing intracellular calcium mobilization by endothelin B receptor signalling. Activation of both JNK and p38 was required for reducing DNA photoproducts, but only JNK partially contributed to the survival effect of endothelin-1. ATF-2 activation depended mainly on JNK, yet was not sufficient for the effect of endothelin-1 on UV-induced DNA damage, suggesting the requirement for other JNK and p38 targets for this effect. Our results underscore the significance of endothelin-1 and endothelin B receptor signalling in reducing the genotoxic effects of UV via activating JNK and p38, hence restoring genomic stability of melanocytes.

  9. High-throughput, high-content screening for novel pigmentation regulators using a keratinocyte/melanocyte co-culture system.

    PubMed

    Lee, Ju Hee; Chen, Hongxiang; Kolev, Vihren; Aull, Katherine H; Jung, Inhee; Wang, Jun; Miyamoto, Shoko; Hosoi, Junichi; Mandinova, Anna; Fisher, David E

    2014-02-01

    Skin pigmentation is a complex process including melanogenesis within melanocytes and melanin transfer to the keratinocytes. To develop a comprehensive screening method for novel pigmentation regulators, we used immortalized melanocytes and keratinocytes in co-culture to screen large numbers of compounds. High-throughput screening plates were subjected to digital automated microscopy to quantify the pigmentation via brightfield microscopy. Compounds with pigment suppression were secondarily tested for their effects on expression of microphthalmia transcription factor (MITF) and several pigment regulatory genes, and further validated in terms of non-toxicity to keratinocytes/melanocytes and dose-dependent activity. The results demonstrate a high-throughput, high-content screening approach, which is applicable to the analysis of large chemical libraries using a co-culture system. We identified candidate pigmentation inhibitors from 4000 screened compounds including zoxazolamine, 3-methoxycatechol and alpha-mangostin, which were also shown to modulate expression of MITF and several key pigmentation factors and are worthy of further evaluation for potential translation to clinical use.

  10. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  11. Acquired immune deficiency syndrome: review.

    PubMed

    Scully, C; Cawson, R A; Porter, S R

    1986-07-19

    Acquired immunodeficiency syndrome (AIDS) is reviewed for dental practitioners, with an emphasis on oral findings; the clinical course, diagnosis, reporting, treatment, prognosis, transmission, and epidemiology are also covered. HIV infection has an incubation period that may be associated with glandular fever, a prodrome called AIDS-Related Complex (ARC) characterized by lymphadenopathy, low fever, weight loss, night sweats, diarrhea, oral candidosis, nonproductive cough and recurrent infections. AIDS is characterized by opportunistic infections. Over 50% present with pneumocystis carinii pneumonia, 21% with Kaposi's sarcoma, and 6% have both. The AIDS virus causes direct neurological symptoms in some cases. Oral candidosis (thrush) in a young male without a local cause such as xerostomia or immune suppression is strongly suggestive of AIDS. Other oral manifestations are severe herpes simplex, varicella-zoster, Epstein-Barr virus, cytomegalovirus, venereal warts, aphthous ulceration, mycobacterial oral ulcers, oral histoplasmosis, sinusitis and osteomyelitis of the jaw. Hairy leukoplakia, usually seen on the lateral border of the tongue, is probably caused by Epstein-Barr virus. Kaposi's sarcoma, an endothelial cell tumor, is characteristic of AIDS, and in 50% of patients is oral or perioral. Cervical lymph node enlargement will be seen in those with ARC as well as AIDS. No guidelines have been issued by the Department of Health and Social Security for dental surgeons in the UK for reporting AIDS cases. Although HIV virions have been isolated from saliva, there are no known incidents of transmission via saliva. HIV is less likely to be transmitted by needle stick injuries than, for example hepatitis B (25% risk), especially if the blood is from a carrier rather than a full blown AIDS case.

  12. Clinicopathological associations of acquired erythroblastopenia

    PubMed Central

    Gunes, Gursel; Malkan, Umit Yavuz; Yasar, Hatime Arzu; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin; Demiroglu, Haluk; Sayinalp, Nilgun; Aksu, Salih; Etgul, Sezgin; Aslan, Tuncay; Goker, Hakan; Ozcebe, Osman Ilhami; Buyukasik, Yahya

    2015-01-01

    Introduction: Acquired erythroblastopenia (AE) is a rare clinical situation. It is characterized by the reduction of erythroid precursors in the bone marrow together with the low reticulocyte counts in the peripheral blood. Background: Main secondary causes of AE are drugs, Parvovirus B19 and other infectious reasons, lymphoid and myeloid neoplasia, autoimmune diseases, thymoma and pregnancy. The aim of this study is to assess the frequencies and clinical associations of AE via analyzing 12340 bone marrow samples in a retrospective manner. Material and method: Bone marrow aspirations which were obtained from patients who applied to Hacettepe University Hematology Clinic between 2002 and 2013, were analyzed retrospectively. Results: Thirty four erythroblastopenia cases were found. Patients ranged in age from 16 to 80 years with a median of 38 years. Fifteen patients were men (44%) and nineteen were women (56%). In these patients, detected causes of erythroblastopenia were MDS, idiopathic pure red cell aplasia (PRCA), parvovirus infection, post chemotherapy aplasia, plasma proliferative diseases, copper deficiency due to secondary amyloidosis, fever of unknown origin, hemophagocytic syndrome, enteric fever and legionella pneumonia. We found that between those reasons the most common causes of erythroblastopenia are MDS (17.7%) and idiopathic PRCA (17.7%). Discussion: As a result, erythroblastopenia in the bone marrow may be an early sign of MDS. In those AE cases possibility of being MDS must be kept in mind as it can be mistaken for PRCA. Conclusion: To conclude, in adults MDS without excess blast is one of the most common causes of erythroblastopenia in clinical practice and in case of erythroblastopenia the presence of MDS should be investigated. PMID:26885236

  13. αB-crystallin is mutant B-RAF regulated and contributes to cyclin D1 turnover in melanocytic cells

    PubMed Central

    Hu, Rong; Aplin, Andrew E.

    2010-01-01

    Summary The serine/threonine kinase, B-RAF, is frequently mutated in melanoma and is required for cell proliferation. Proteasomal turnover of cyclins and cyclin-dependent kinase inhibitors via E3 ubiquitin ligases regulates cell cycle progression. We previously showed that B-RAF regulates Cks1, a co-factor for the F-box protein Skp2. Recently, a second F-box protein cofactor was identified, αB-crystallin, that binds Fbx4 and promotes cyclin D1 degradation. Here, we demonstrate that αB-crystallin is down-regulated in mutant B-RAF melanoma cells compared to melanocytes in a B-RAF and MEK-dependent manner. In a subset of lines, MEK inhibition was sufficient to up-regulate αB-crystallin protein levels; whereas in other lines combined MEK and proteasome inhibition was required. αB-crystallin knockdown partially stabilized cyclin D1 in melanocytes. Expression of αB-crystallin in mutant B-RAF melanoma cells did not promote cyclin D1 turnover under normal conditions, but did enhance turnover following etoposide-induced DNA damage. Together, these data show that αB-crystallin is highly expressed in melanocytes contributing, in part, to cyclin D1 turnover. Furthermore, αB-crystallin is down-regulated in a B-RAF-dependent manner in melanoma cells and its re-expression regulates cyclin D1 turnover after DNA damage. Significance αB-crystallin has been implicated in cellular functions as a heat shock protein and, more recently, as a cofactor for an E3 ligase ubiquitin ligase complex that degrades the cell cycle protein, cyclin D1. In this study we identify αB-crystallin as a target of aberrant B-RAF-MEK signaling that is hyper-activated in the majority of melanomas through mutation of B-RAF. Furthermore, we provide evidence for a functional role of αB-crystallin in contributing to the turnover of cyclin D1 in melanocytes and in melanoma cells following DNA damage inducing signals. These findings further our understanding of the regulation of cyclin D1 in melanocytic

  14. MC1R variant allele effects on UVR-induced phosphorylation of p38, p53, and DDB2 repair protein responses in melanocytic cells in culture.

    PubMed

    Wong, Shu Shyan; Ainger, Stephen A; Leonard, J Helen; Sturm, Richard A

    2012-05-01

    Variant alleles of the human melanocortin 1 receptor (MC1R) reduce the ability of melanocytes to produce the dark pigment eumelanin, with R alleles being most deficient. Cultured melanocytes of MC1R R/R variant genotype give reduced responses to [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-MSH) ligand stimulation and lower levels of DNA repair than MC1R wild-type strains. p38 controls xeroderma pigmentosum (XP)-C recruitment to DNA damage sites through regulating ubiquitylation of the DNA damage-binding protein 2 (DDB2) protein, and p53 is implicated in the nuclear excision repair process through its regulation of XP-C and DDB2 protein expression. We report the effects of MC1R ligand treatment and UVR exposure on phosphorylation of p38 and p53, and DDB2 protein expression in MC1R variant strains. Wild-type MC1R melanocyte strains grown together with keratinocytes in coculture, when treated with NDP-MSH and exposed to UVR, gave synergistic activation of p38 and p53 phosphorylation, and were not replicated by R/R variant melanocytes, which have lower basal levels of phosphorylated forms of p38. Minor increases in p38 phosphorylation status in R/R variant melanocyte cocultures could be attributed to the keratinocytes alone. We also found that MC1R wild-type strains regulate DDB2 protein levels through p38, but MC1R R/R variant melanocytes do not. This work confirms the important functional role that the MC1R receptor plays in UVR stress-induced DNA repair.

  15. Mobile teledermatology is a valid method to estimate prevalence of melanocytic naevi in children.

    PubMed

    Karlsson, Maria A; Lindelöf, Bernt; Wahlgren, Carl-Fredrik; Wiklund, Kerstin; Rodvall, Ylva

    2015-03-01

    The prevalence of melanocytic naevi in children correlates with sun exposure and may serve as an objective population risk indicator of future melanoma incidence. The aim was to investigate if mobile teledermatology could offer a valid methodology compared with standard manual, face-to-face counting of naevi on the back of children. Ninety-seven children aged 7-16 years were enrolled. One dermatologist performed manual naevi counting and imaging of the child's back using an iPhone 4S comprising a safe-coded mobile application. Two other dermatologists independently counted naevi from the images. Cohen's weighted kappa (κw) coefficient demonstrated substantial agreement for both dermatologists: κw = 0.69 (0.57-0.81 [95% confidence intervals]) and κw = 0.78 (0.70-0.86), compared with the manual assessment. Inter-rater reliability was also substantial (κw = 0.80 [0.73-0.87]). Use of mobile teledermatology proved valid for estimating naevi prevalence on the back and could provide a more feasible methodology following trends in sun exposure in children.

  16. GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats.

    PubMed

    Rao, T Lakshmi; Kokare, Dadasaheb M; Sarkar, Sumit; Khisti, Rahul T; Chopde, Chandrabhan T; Subhedar, Nishikant

    2003-12-01

    Alpha-melanocyte stimulating hormone (alpha-MSH) is a hypothalamic peptide believed to play a tonic inhibitory role in feeding and energy homeostasis. Systemic administration of alpha-MSH is known to produce anorexia and anxiety. Since synaptic contacts between gamma-aminobutyric acid (GABA)ergic terminals and alpha-MSH neurons in the hypothalamus have been reported, the present work was undertaken to refine our knowledge on the role of GABAergic systems in anxiety and anorexia induced by intracerebroventricular (icv) administration of alpha-MSH in rats. The anxiety was assessed by elevated plus maze, and spontaneous food consumption was monitored during dark cycle. Prior administration of diazepam and muscimol that promote the function of GABA(A) receptors reversed the anxiogenic response and decreased food intake elicited by alpha-MSH. In contrast, bicuculline, the GABA(A) receptor antagonist, not only enhanced the effects of alpha-MSH but also prevented the influence of GABAergic drugs on alpha-MSH-induced anorexia and anxiety. These findings suggest that alpha-MSH-induced anxiety and anorexia are due to its negative influence on GABAergic system.

  17. Effect of tetracycline and UV radiation on melanization and antioxidant status of melanocytes.

    PubMed

    Rok, Jakub; Buszman, Ewa; Delijewski, Marcin; Otręba, Michał; Beberok, Artur; Wrześniok, Dorota

    2015-07-01

    Tetracycline is a semisynthetic antibiotic and is used in several types of infections against both gram-positive and gram-negative bacteria. This therapy is often associated with phototoxic reactions that occur after exposure to UV radiation and lead to photo-onycholysis, pseudoporphyria, solar urticaria and the fixed drug eruption in the skin. The phototoxic reactions may be related to the melanin content which, on one side may bind drugs - leading to their accumulation, and on the other side, they have photoprotective and antioxidant properties. In this study the effect of tetracycline and UVA irradiation on cell viability, biosynthesis of melanin and antioxidant defense system in cultured normal human epidermal melanocytes (HEMn-DP) was analyzed. The viability of the cells treated with tetracycline and exposed to UVA radiation decreased in a drug concentration-dependent manner. At the same time, the induction of the melanization process was observed. The significant alterations in antioxidant defense system, on the basis of changes in SOD, CAT and GPx activities, were stated. The obtained results may give explanation for the phototoxic effects of tetracycline therapy observed in skin cells exposed to UVA radiation.