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Sample records for neural crest-derived melanocytes

  1. [Phenotypic plasticity of neural crest-derived melanocytes and Schwann cells].

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    Dupin, Elisabeth

    2011-01-01

    expression. This review considers the issue of whether neural crest-derived lineages are endowed with some phenotypic plasticity. Emphasis is put on the ability of pigment cells and Schwann cells to dedifferentiate and reprogram their fate in vitro. To address this question, we have studied the clonal progeny of differentiated Schwann cells and melanocytes after their isolation from the sciatic nerve and the back skin of quail embryos, respectively. When stimulated to proliferate in vitro in the presence of endothelin-3, both cell types were able to dedifferentiate and produce alternative neural crest-derived cell lineages. Individual Schwann cells isolated by FACS, using a glial-specific surface marker, gave rise in culture to pigment cells and myofibroblasts/smooth muscle cells. Treatment of the cultures with endothelin-3 was required for Schwann cell conversion into melanocytes, which involved acquisition of multipotency. Moreover, Schwann cell plasticity could also be induced in vivo: following transplantation into the branchial arch of a young chick host embryo, dedifferentiating Schwann cells were able to integrate the forming head structures of the host and, specifically, to contribute smooth muscle cells to the wall of cranial blood vessels. We also analyzed the in vitro behavior of individual pigment cells obtained by microdissection and enzymatic treatment of quail epidermis at embryonic and hatching stages. In single cell cultures treated with endothelin-3, pigment cells strongly proliferated while rapidly dedifferentiating into unpigmented cells, leading to the formation of large colonies that comprised glial cells and myofibroblasts in addition to melanocytes. By serially subcloning these primary colonies, we could efficiently propagate a bipotent glial-melanocytic precursor that is generated in the progeny of the melanocytic founder. These data therefore suggest that pigment cells have the ability to revert back to the state of self-renewing neural crest

  2. Regeneration of neural crest derivatives in the Xenopus tadpole tail

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    Slack Jonathan MW

    2007-05-01

    Full Text Available Abstract Background After amputation of the Xenopus tadpole tail, a functionally competent new tail is regenerated. It contains spinal cord, notochord and muscle, each of which has previously been shown to derive from the corresponding tissue in the stump. The regeneration of the neural crest derivatives has not previously been examined and is described in this paper. Results Labelling of the spinal cord by electroporation, or by orthotopic grafting of transgenic tissue expressing GFP, shows that no cells emigrate from the spinal cord in the course of regeneration. There is very limited regeneration of the spinal ganglia, but new neurons as well as fibre tracts do appear in the regenerated spinal cord and the regenerated tail also contains abundant peripheral innervation. The regenerated tail contains a normal density of melanophores. Cell labelling experiments show that melanophores do not arise from the spinal cord during regeneration, nor from the mesenchymal tissues of the skin, but they do arise by activation and proliferation of pre-existing melanophore precursors. If tails are prepared lacking melanophores, then the regenerates also lack them. Conclusion On regeneration there is no induction of a new neural crest similar to that seen in embryonic development. However there is some regeneration of neural crest derivatives. Abundant melanophores are regenerated from unpigmented precursors, and, although spinal ganglia are not regenerated, sufficient sensory systems are produced to enable essential functions to continue.

  3. Isolation and characterization of neural crest-derived stem cells from dental pulp of neonatal mice.

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    Kajohnkiart Janebodin

    Full Text Available Dental pulp stem cells (DPSCs are shown to reside within the tooth and play an important role in dentin regeneration. DPSCs were first isolated and characterized from human teeth and most studies have focused on using this adult stem cell for clinical applications. However, mouse DPSCs have not been well characterized and their origin(s have not yet been elucidated. Herein we examined if murine DPSCs are neural crest derived and determined their in vitro and in vivo capacity. DPSCs from neonatal murine tooth pulp expressed embryonic stem cell and neural crest related genes, but lacked expression of mesodermal genes. Cells isolated from the Wnt1-Cre/R26R-LacZ model, a reporter of neural crest-derived tissues, indicated that DPSCs were Wnt1-marked and therefore of neural crest origin. Clonal DPSCs showed multi-differentiation in neural crest lineage for odontoblasts, chondrocytes, adipocytes, neurons, and smooth muscles. Following in vivo subcutaneous transplantation with hydroxyapatite/tricalcium phosphate, based on tissue/cell morphology and specific antibody staining, the clones differentiated into odontoblast-like cells and produced dentin-like structure. Conversely, bone marrow stromal cells (BMSCs gave rise to osteoblast-like cells and generated bone-like structure. Interestingly, the capillary distribution in the DPSC transplants showed close proximity to odontoblasts whereas in the BMSC transplants bone condensations were distant to capillaries resembling dentinogenesis in the former vs. osteogenesis in the latter. Thus we demonstrate the existence of neural crest-derived DPSCs with differentiation capacity into cranial mesenchymal tissues and other neural crest-derived tissues. In turn, DPSCs hold promise as a source for regenerating cranial mesenchyme and other neural crest derived tissues.

  4. Isolation and Characterization of Neural Crest-Derived Stem Cells from Dental Pulp of Neonatal Mice

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    Janebodin, Kajohnkiart; Horst, Orapin V.; Ieronimakis, Nicholas; Balasundaram, Gayathri; Reesukumal, Kanit; Pratumvinit, Busadee; Reyes, Morayma

    2011-01-01

    Dental pulp stem cells (DPSCs) are shown to reside within the tooth and play an important role in dentin regeneration. DPSCs were first isolated and characterized from human teeth and most studies have focused on using this adult stem cell for clinical applications. However, mouse DPSCs have not been well characterized and their origin(s) have not yet been elucidated. Herein we examined if murine DPSCs are neural crest derived and determined their in vitro and in vivo capacity. DPSCs from neonatal murine tooth pulp expressed embryonic stem cell and neural crest related genes, but lacked expression of mesodermal genes. Cells isolated from the Wnt1-Cre/R26R-LacZ model, a reporter of neural crest-derived tissues, indicated that DPSCs were Wnt1-marked and therefore of neural crest origin. Clonal DPSCs showed multi-differentiation in neural crest lineage for odontoblasts, chondrocytes, adipocytes, neurons, and smooth muscles. Following in vivo subcutaneous transplantation with hydroxyapatite/tricalcium phosphate, based on tissue/cell morphology and specific antibody staining, the clones differentiated into odontoblast-like cells and produced dentin-like structure. Conversely, bone marrow stromal cells (BMSCs) gave rise to osteoblast-like cells and generated bone-like structure. Interestingly, the capillary distribution in the DPSC transplants showed close proximity to odontoblasts whereas in the BMSC transplants bone condensations were distant to capillaries resembling dentinogenesis in the former vs. osteogenesis in the latter. Thus we demonstrate the existence of neural crest-derived DPSCs with differentiation capacity into cranial mesenchymal tissues and other neural crest-derived tissues. In turn, DPSCs hold promise as a source for regenerating cranial mesenchyme and other neural crest derived tissues. PMID:22087335

  5. Physiological Plasticity of Neural-Crest-Derived Stem Cells in the Adult Mammalian Carotid Body

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    Valentina Annese

    2017-04-01

    Full Text Available Adult stem cell plasticity, or the ability of somatic stem cells to cross boundaries and differentiate into unrelated cell types, has been a matter of debate in the last decade. Neural-crest-derived stem cells (NCSCs display a remarkable plasticity during development. Whether adult populations of NCSCs retain this plasticity is largely unknown. Herein, we describe that neural-crest-derived adult carotid body stem cells (CBSCs are able to undergo endothelial differentiation in addition to their reported role in neurogenesis, contributing to both neurogenic and angiogenic processes taking place in the organ during acclimatization to hypoxia. Moreover, CBSC conversion into vascular cell types is hypoxia inducible factor (HIF dependent and sensitive to hypoxia-released vascular cytokines such as erythropoietin. Our data highlight a remarkable physiological plasticity in an adult population of tissue-specific stem cells and could have impact on the use of these cells for cell therapy.

  6. Physiological Plasticity of Neural-Crest-Derived Stem Cells in the Adult Mammalian Carotid Body.

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    Annese, Valentina; Navarro-Guerrero, Elena; Rodríguez-Prieto, Ismael; Pardal, Ricardo

    2017-04-18

    Adult stem cell plasticity, or the ability of somatic stem cells to cross boundaries and differentiate into unrelated cell types, has been a matter of debate in the last decade. Neural-crest-derived stem cells (NCSCs) display a remarkable plasticity during development. Whether adult populations of NCSCs retain this plasticity is largely unknown. Herein, we describe that neural-crest-derived adult carotid body stem cells (CBSCs) are able to undergo endothelial differentiation in addition to their reported role in neurogenesis, contributing to both neurogenic and angiogenic processes taking place in the organ during acclimatization to hypoxia. Moreover, CBSC conversion into vascular cell types is hypoxia inducible factor (HIF) dependent and sensitive to hypoxia-released vascular cytokines such as erythropoietin. Our data highlight a remarkable physiological plasticity in an adult population of tissue-specific stem cells and could have impact on the use of these cells for cell therapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

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    Sophie R. Miller

    2017-03-01

    Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

  8. Enrichment and Schwann Cell Differentiation of Neural Crest-derived Dental Pulp Stem Cells.

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    Al-Zer, Heba; Apel, Christian; Heiland, Max; Friedrich, Reinhard E; Jung, Ole; Kroeger, Nadja; Eichhorn, Wolfgang; Smeets, Ralf

    2015-01-01

    As already described in previous studies, neural crest stem cells (NCSCs) can be found in adult human dental pulp. The present study investigated the methodology for enrichment and differentiation-induction of the above mentioned cells. Dental pulp was extracted from human wisdom teeth of four patients and subsequently cultured as explants on fibronectin-coated plates in neurobasal medium supplemented with B27, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin, l-glutamine and neuregulin-β1. The cells were then characterized by immunofluorescence, while their differentiation-potential was tested by the attempt to induce cells into different lineages, i.e. osteogenic, melanocytic and glial. The enriched cell population expressed nestin, CD271 and SOX10, which are well-known markers for NCSCs. Consequently, the cells were successfully induced to differentiate into osteoblasts, melanocytes and Schwann cells, expressing the corresponding differentiation markers. Human adult dental pulp contains a population of stem cells with neural crest ontogeny, which can thus be recruited for multiple regenerative therapies. Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Neural crest-derived mesenchymal cells require Wnt signaling for their development and drive invagination of the telencephalic midline.

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    Youngshik Choe

    Full Text Available Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis.

  10. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

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    Myron S Ignatius

    Full Text Available The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  11. Intrastriatal transplantation of adult human neural crest-derived stem cells improves functional outcome in parkinsonian rats.

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    Müller, Janine; Ossig, Christiana; Greiner, Johannes F W; Hauser, Stefan; Fauser, Mareike; Widera, Darius; Kaltschmidt, Christian; Storch, Alexander; Kaltschmidt, Barbara

    2015-01-01

    Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate. Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Additional successful dopaminergic differentiation of ITSCs was subsequently followed by their transplantation into a unilaterally lesioned 6-hydroxydopamine rat PD model. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of rotational behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model. ©AlphaMed Press.

  12. Epigenetic marks define the lineage and differentiation potential of two distinct neural crest-derived intermediate odontogenic progenitor populations.

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    Gopinathan, Gokul; Kolokythas, Antonia; Luan, Xianghong; Diekwisch, Thomas G H

    2013-06-15

    Epigenetic mechanisms, such as histone modifications, play an active role in the differentiation and lineage commitment of mesenchymal stem cells. In the present study, epigenetic states and differentiation profiles of two odontogenic neural crest-derived intermediate progenitor populations were compared: dental pulp (DP) and dental follicle (DF). ChIP on chip assays revealed substantial H3K27me3-mediated repression of odontoblast lineage genes DSPP and dentin matrix protein 1 (DMP1) in DF cells, but not in DP cells. Mineralization inductive conditions caused steep increases of mineralization and patterning gene expression levels in DP cells when compared to DF cells. In contrast, mineralization induction resulted in a highly dynamic histone modification response in DF cells, while there was only a subdued effect in DP cells. Both DF and DP progenitors featured H3K4me3-active marks on the promoters of early mineralization genes RUNX2, MSX2, and DLX5, while OSX, IBSP, and BGLAP promoters were enriched for H3K9me3 or H3K27me3. Compared to DF cells, DP cells expressed higher levels of three pluripotency-associated genes, OCT4, NANOG, and SOX2. Finally, gene ontology comparison of bivalent marks unique for DP and DF cells highlighted cell-cell attachment genes in DP cells and neurogenesis genes in DF cells. In conclusion, the present study indicates that the DF intermediate odontogenic neural crest lineage is distinguished from its DP counterpart by epigenetic repression of DSPP and DMP1 genes and through dynamic histone enrichment responses to mineralization induction. Findings presented here highlight the crucial role of epigenetic regulatory mechanisms in the terminal differentiation of odontogenic neural crest lineages.

  13. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

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    Tan, Yu, E-mail: tanyu2048@163.com; Fu, Runqing, E-mail: furunqing@sjtu.edu.cn; Liu, Jiaqiang, E-mail: liujqmj@163.com; Wu, Yong, E-mail: wyonger@gmail.com; Wang, Bo, E-mail: wb228@126.com; Jiang, Ning, E-mail: 179639060@qq.com; Nie, Ping, E-mail: nieping1011@sina.com; Cao, Haifeng, E-mail: 0412chf@163.com; Yang, Zhi, E-mail: wcums1981@163.com; Fang, Bing, E-mail: fangbing@sjtu.edu.cn

    2016-07-08

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.

  14. In vitro cementoblast-like differentiation of postmigratory neural crest-derived p75{sup +} stem cells with dental follicle cell conditioned medium

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    Wen, Xiujie; Liu, Luchuan; Deng, Manjing; Liu, Rui; Zhang, Li; Nie, Xin, E-mail: dr.xinnie@gmail.com

    2015-09-10

    Cranial neural crest-derived cells (CNCCs) play important role in epithelial–mesenchymal interactions during tooth morphogenesis. However, the heterogeneity of CNCCs and their tendency to spontaneously differentiate along smooth muscle or osteoblast lineages in vitro limit further understanding of their biological properties. We studied the differentiation properties of isolated rat embryonic postmigratory CNCCs, expressing p75 neurotrophin receptor (p75NTR). These p75NTR positive (p75{sup +}) CNCCs, isolated using fluorescence activated cell sorter, exhibited fibroblast-like morphology and characteristics of mesenchymal stem cells. Incubation of p75{sup +} CNCCs in dental follicle cell conditioned medium (DFCCM) combined with dentin non-collagenous proteins (dNCPs), altered their morphological features to cementoblast-like appearance. These cells also showed low proliferative activity, high ALP activity and significantly increased calcified nodule formation. Markers related to mineralization or specific to cementoblast lineage were highly expressed in dNCPs/DFCCM-treated p75{sup +} cells, suggesting their differentiation along cementoblast-like lineage. p75{sup +} stem cells selected from postmigratory CNCCs represent a pure stem cell population and could be used as a stem cell model for in vitro studies due to their intrinsic ability to differentiate to neuronal cells and transform from neuroectoderm to ectomesenchyme. They can provide a potential stem cell resource for tooth engineering studies and help to further investigate mechanisms of epithelial–mesenchymal interactions in tooth morphogenesis. - Highlights: • Cranial neural crest-derived cells (CNCCs) take part in tooth morphogenesis. • positive (p75{sup +}) CNCCs are fibroblast-like and resemble mesenchymal stem cells. • p75{sup +} CNCCs in dental follicle cell medium (DFCCM/dNCP) appear like cementoblasts. • DFCCM/dNCP-treated p75{sup +} cells express cementoblast specific mineralization

  15. Neural crest-derived cells with stem cell features can be traced back to multiple lineages in the adult skin

    NARCIS (Netherlands)

    C.E. Wong (Christine); S. Paratore (Sabrina); M.T. Dours-Zimmermann (María); T. Rochat (Thierry); T. Pietri (Thomas); U. Suter (Ueli); D. Zimmermann (Dieter); S. Dufour (Sylvie); J.P. Thiery (Joachim); D.N. Meijer (Dies); C. Beermann (Christopher); Y. Barrandon (Yann); L. Sommer (Lukas)

    2006-01-01

    textabstractGiven their accessibility, multipotent skin-derived cells might be useful for future cell replacement therapies. We describe the isolation of multipotent stem cell-like cells from the adult trunk skin of mice and humans that express the neural crest stem cell markers p75 and Sox10 and

  16. Decreased proliferative, migrative and neuro-differentiative potential of postnatal rat enteric neural crest-derived cells during culture in vitro

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Pan, Wei-Kang; Zheng, Bai-Jun; Wang, Huai-Jie [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2016-05-01

    A growing body of evidence supports the potential use of enteric neural crest-derived cells (ENCCs) as a cell replacement therapy for Hirschsprung's disease. Based on previous observations of robust propagation of primary ENCCs, as opposed to their progeny, it is suggested that their therapeutic potential after in vitro expansion may be restricted. We therefore examined the growth and differentiation activities and phenotypic characteristics of continuous ENCC cultures. ENCCs were isolated from the intestines of postnatal rats and were identified using an immunocytochemical approach. During continuous ENCC culture expansion, proliferation, migration, apoptosis, and differentiation potentials were monitored. The Cell Counting Kit-8 was used for assessment of ENCC vitality, Transwell inserts for cell migration, immunocytochemistry for cell counts and identification, and flow cytometry for apoptosis. Over six continuous generations, ENCC proliferation potency was reduced and with prolonged culture, the ratio of migratory ENCCs was decreased. The percentage of apoptosis showed an upward trend with prolonged intragenerational culture, but showed a downward trend with prolonged culture of combined generations. Furthermore, the percentage of peripherin{sup +} cells decreased whilst the percentage of GFAP{sup +} cells increased with age. The results demonstrated that alterations in ENCC growth characteristics occur with increased culture time, which may partially account for the poor results of proposed cell therapies. - Highlights: • Differences were identified between primary and daughter ENCCs. • Daughter ENCCs had reduced proliferation, migration and differentiation. • Daughter ENCCs also had increased apoptosis. • These altered characteristics warrant further investigation.

  17. Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves

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    Jiao Jiao

    2016-08-01

    Full Text Available Individuals with bicuspid aortic valves (BAV are at a higher risk of developing thoracic aortic aneurysms (TAA than patients with trileaflet aortic valves (TAV. The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs in the ascending and descending aorta arise from neural crest (NC and paraxial mesoderm (PM, respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs-derived SMCs but not paraxial mesoderm cells (PMCs-derived SMCs contributes to the aortopathy associated with BAV. When induced pluripotent stem cells (iPSCs from BAV/TAA patients were differentiated into NCSC-derived SMCs, these cells demonstrated significantly decreased expression of marker of SMC differentiation (MYH11 and impaired contraction compared to normal control. In contrast, the PMC-derived SMCs were similar to control cells in these aspects. The NCSC-SMCs from the BAV/TAA also showed decreased TGF-β signaling based on phosphorylation of SMAD2, and increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation. Our data demonstrates that decreased differentiation and contraction of patient's NCSC-derived SMCs may contribute to that aortopathy associated with BAV.

  18. Depletion of Neural Crest-Derived Cells Leads to Reduction in Plasma Noradrenaline and Alters B Lymphopoiesis.

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    Tsunokuma, Naoki; Yamane, Toshiyuki; Matsumoto, Chiaki; Tsuneto, Motokazu; Isono, Kana; Imanaka-Yoshida, Kyoko; Yamazaki, Hidetoshi

    2017-01-01

    Hematopoietic stem cells and their lymphoid progenitors are supported by the bone marrow (BM) microenvironmental niches composed of various stromal cells and Schwann cells and sympathetic nerve fibers. Although neural crest (NC) cells contribute to the development of all the three, their function in BM is not well understood. In this study, NC-derived cells were ablated with diphtheria toxin in double-transgenic mice expressing NC-specific Cre and Cre-driven diphtheria toxin receptor with yellow fluorescent protein reporter. We found that yellow fluorescent protein-expressing, NC-derived nonhematopoietic cells in BM expressed hematopoietic factors Cxcl12 and stem cell factor The ablation of NC-derived cells led to a significant decrease in B cell progenitors but not in hematopoietic stem cells or myeloid lineage cells in BM. Interestingly, plasma noradrenaline was markedly decreased in these mice. The i.p. administration of 6-hydroxydopamine, a known neurotoxin for noradrenergic neurons, led to a similar phenotype, whereas the administration of a noradrenaline precursor in NC-ablated mice partially rescued this phenotype. Additionally, the continuous administration of adrenergic receptor β antagonists partially decreased the number of B cell progenitors while preserving B lymphopoiesis in vitro. Taken together, our results indicate that NC-derived cell depletion leads to abnormal B lymphopoiesis partially through decreased plasma noradrenaline, suggesting this as a novel mechanism regulated by molecules released by the sympathetic neurons. Copyright © 2016 by The American Association of Immunologists, Inc.

  19. Combination of exogenous cell transplantation and 5-HT{sub 4} receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Zheng, Bai-Jun; Pan, Wei-Kang; Wang, Huai-Jie; Xie, Chong; Zhao, Yu-Ying [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2017-02-01

    Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT{sub 4} receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT{sub 4} receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75{sup NTR} and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT{sub 4} receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. - Highlights: • Survival and differentiation of exogenous ENCCs in treated colons. • With longer times post-intervention, the number of ENCCs and their progeny cells gradually increased. • Exogenous ENCCs combined with the 5-HT4 receptor agonist ffectively induced ENCCs proliferation and differentiation.

  20. Cranial neural crest-derived mesenchymal proliferation is regulated by Msx1-mediated p19(INK4d) expression during odontogenesis.

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    Han, Jun; Ito, Yoshihiro; Yeo, Jae Yong; Sucov, Henry M; Maas, Richard; Chai, Yang

    2003-09-01

    Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in Msx1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of Msx1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in Msx1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of Msx1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene Msx1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of Msx1 may alternatively instruct the fate of these progenitor cells during craniofacial development.

  1. Characterization of a new, inducible transgenic mouse model with GFP expression in melanocytes and their precursors.

    Science.gov (United States)

    Joshi, Sandeep S; Tandukar, Bishal; Castaneda, Maira; Jiang, Shunlin; Diwakar, Ganesh; Hertzano, Ronna P; Hornyak, Thomas J

    2017-10-21

    Melanocytes are neural crest-derived cells that are responsible for mammalian hair follicle (HF) pigmentation. The Dct-LacZ transgenic mouse is extensively used to study melanocyte biology but lacks conditionally-inducible labelling and fluorescent labelling, enabling specific, viable isolation of melanocytes using fluorescence-activated cell sorting (FACS). Here, we have generated a Tet-off bitransgenic mouse model, Dct-H2BGFP, containing Dct-tTA and TRE-H2BGFP transgenes. Characterization of Dct-H2BGFP mice confirmed a pattern of Dct-H2BGFP expression in melanoblasts, melanocyte stem cells (McSCs), and terminally differentiated melanocytes similar to the expression pattern of previously published mouse models Dct-LacZ and iDct-GFP. GFP expression is regulated by doxycycline. GFP is shown to co-localize with melanocyte label-retaining cells (LRCs) identified through BrdU retention. The GFP-expressing cells identified in vivo in the bulge and the secondary hair germ of telogen HFs of Dct-H2BGFP mice express the melanocyte and melanocyte stem cell markers Dct and Kit. Using Dct-H2BGFP mice, we separated GFP-expressing cells from the telogen HF based on FACS and showed that GFP-expressing cells express high levels of Kit and Dct, and lower levels of HF epithelial keratin genes. We also show that GFP-expressing cells express high levels of the melanocyte differentiation genes Tyr, Tyrp1, and Pmel17, further substantiating their identity within the melanocyte lineage. Thus, Dct-H2BGFP mice are not only useful for the in vivo identification of melanocytic cells, but also for isolating them viably and studying their molecular and biological properties. Published by Elsevier B.V.

  2. Modeling Neural Crest Induction, Melanocyte Specification, and Disease-Related Pigmentation Defects in hESCs and Patient-Specific iPSCs

    Directory of Open Access Journals (Sweden)

    Yvonne Mica

    2013-04-01

    Full Text Available Melanocytes are pigment-producing cells of neural crest (NC origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC technology offers a promising 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 NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders.

  3. CtBP2 downregulation during neural crest specification induces expression of Mitf and REST, resulting in melanocyte differentiation and sympathoadrenal lineage suppression.

    Science.gov (United States)

    Liang, Hongzi; Fekete, Donna M; Andrisani, Ourania M

    2011-03-01

    Trunk neural crest (NC) cells differentiate to neurons, melanocytes, and glia. In NC cultures, cyclic AMP (cAMP) induces melanocyte differentiation while suppressing the neuronal sympathoadrenal lineage, depending on the signal intensity. Melanocyte differentiation requires activation of CREB and cAMP-dependent protein kinase A (PKA), but the role of PKA is not understood. We have demonstrated, in NC cultures, cAMP-induced transcription of the microphthalmia-associated transcription factor gene (Mitf) and the RE-1 silencing transcription factor gene (REST), both Wnt-regulated genes. In NC cultures and zebrafish, knockdown of the corepressor of Wnt-mediated transcription C-terminal binding protein 2 (CtBP2) but not CtBP1 derepressed Mitf and REST expression and enhanced melanocyte differentiation. cAMP in NC and B16 melanoma cells decreased CtBP2 protein levels, while inhibition of PKA or proteasome rescued CtBP2 degradation. Interestingly, knockdown of homeodomain-interacting protein kinase 2 (HIPK2), a CtBP stability modulator, increased CtBP2 levels, suppressed expression of Mitf, REST, and melanocyte differentiation, and increased neuronal gene expression and sympathoadrenal lineage differentiation. We conclude that cAMP/PKA via HIPK2 promotes CtBP2 degradation, leading to Mitf and REST expression. Mitf induces melanocyte specification, and REST suppresses neuron-specific gene expression and the sympathoadrenal lineage. Our studies identify a novel role for REST in NC cell differentiation and suggest cross talk between cAMP and Wnt signaling in NC lineage specification.

  4. CtBP2 Downregulation during Neural Crest Specification Induces Expression of Mitf and REST, Resulting in Melanocyte Differentiation and Sympathoadrenal Lineage Suppression ▿

    Science.gov (United States)

    Liang, Hongzi; Fekete, Donna M.; Andrisani, Ourania M.

    2011-01-01

    Trunk neural crest (NC) cells differentiate to neurons, melanocytes, and glia. In NC cultures, cyclic AMP (cAMP) induces melanocyte differentiation while suppressing the neuronal sympathoadrenal lineage, depending on the signal intensity. Melanocyte differentiation requires activation of CREB and cAMP-dependent protein kinase A (PKA), but the role of PKA is not understood. We have demonstrated, in NC cultures, cAMP-induced transcription of the microphthalmia-associated transcription factor gene (Mitf) and the RE-1 silencing transcription factor gene (REST), both Wnt-regulated genes. In NC cultures and zebrafish, knockdown of the corepressor of Wnt-mediated transcription C-terminal binding protein 2 (CtBP2) but not CtBP1 derepressed Mitf and REST expression and enhanced melanocyte differentiation. cAMP in NC and B16 melanoma cells decreased CtBP2 protein levels, while inhibition of PKA or proteasome rescued CtBP2 degradation. Interestingly, knockdown of homeodomain-interacting protein kinase 2 (HIPK2), a CtBP stability modulator, increased CtBP2 levels, suppressed expression of Mitf, REST, and melanocyte differentiation, and increased neuronal gene expression and sympathoadrenal lineage differentiation. We conclude that cAMP/PKA via HIPK2 promotes CtBP2 degradation, leading to Mitf and REST expression. Mitf induces melanocyte specification, and REST suppresses neuron-specific gene expression and the sympathoadrenal lineage. Our studies identify a novel role for REST in NC cell differentiation and suggest cross talk between cAMP and Wnt signaling in NC lineage specification. PMID:21199918

  5. Pax3 and Hippo Signaling Coordinate Melanocyte Gene Expression in Neural Crest

    Directory of Open Access Journals (Sweden)

    Lauren J. Manderfield

    2014-12-01

    Full Text Available Loss of Pax3, a developmentally regulated transcription factor expressed in premigratory neural crest, results in severe developmental defects and embryonic lethality. Although Pax3 mutations produce profound phenotypes, the intrinsic transcriptional activation exhibited by Pax3 is surprisingly modest. We postulated the existence of transcriptional coactivators that function with Pax3 to mediate developmental functions. A high-throughput screen identified the Hippo effector proteins Taz and Yap65 as Pax3 coactivators. Synergistic coactivation of target genes by Pax3-Taz/Yap65 requires DNA binding by Pax3, is Tead independent, and is regulated by Hippo kinases Mst1 and Lats2. In vivo, Pax3 and Yap65 colocalize in the nucleus of neural crest progenitors in the dorsal neural tube. Neural crest deletion of Taz and Yap65 results in embryo-lethal neural crest defects and decreased expression of the Pax3 target gene, Mitf. These results suggest that Pax3 activity is regulated by the Hippo pathway and that Pax factors are Hippo effectors.

  6. Neural crest-derived dental stem cells--where we are and where we are going.

    Science.gov (United States)

    Mayo, Vera; Sawatari, Yoh; Huang, C-Y Charles; Garcia-Godoy, Franklin

    2014-09-01

    There are five types of post-natal human dental stem cells that have been identified, isolated and characterized. Here, we review the information available on dental stem cells as well as their potential applications in dentistry, regenerative medicine and the development of other therapeutic approaches. Data pertinent to dental stem cells and their applications, published in peer-reviewed journals from 1982 to 2013 in English were reviewed. Sources were retrieved from PubMed databases as well as related references that the electronic search yielded. Manuscripts describing the origin, retrieval, characterization and application of dental stem cells were obtained and reviewed. Dental stem cell populations present properties similar to those of mesenchymal stem cells, such as the ability to self-renew and the potential for multilineage differentiation. While they have greater capacity to give rise to odontogenic cells and regenerate dental pulp and periodontal tissue, they have the capacity to differentiate into all three germ line cells, proving that a population of pluripotent stem cells exists in the dental tissues. Dental stem cells have the capacity to differentiate into endoderm, mesoderm and ectoderm tissues. Consequently they do not only have applications in dentistry, but also neurodegenerative and ischemic diseases, diabetes research, bone repair, and other applications in the field of tissue regeneration. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Pax7 lineage contributions to the mammalian neural crest.

    Directory of Open Access Journals (Sweden)

    Barbara Murdoch

    Full Text Available Neural crest cells are vertebrate-specific multipotent cells that contribute to a variety of tissues including the peripheral nervous system, melanocytes, and craniofacial bones and cartilage. Abnormal development of the neural crest is associated with several human maladies including cleft/lip palate, aggressive cancers such as melanoma and neuroblastoma, and rare syndromes, like Waardenburg syndrome, a complex disorder involving hearing loss and pigment defects. We previously identified the transcription factor Pax7 as an early marker, and required component for neural crest development in chick embryos. In mammals, Pax7 is also thought to play a role in neural crest development, yet the precise contribution of Pax7 progenitors to the neural crest lineage has not been determined.Here we use Cre/loxP technology in double transgenic mice to fate map the Pax7 lineage in neural crest derivates. We find that Pax7 descendants contribute to multiple tissues including the cranial, cardiac and trunk neural crest, which in the cranial cartilage form a distinct regional pattern. The Pax7 lineage, like the Pax3 lineage, is additionally detected in some non-neural crest tissues, including a subset of the epithelial cells in specific organs.These results demonstrate a previously unappreciated widespread distribution of Pax7 descendants within and beyond the neural crest. They shed light regarding the regionally distinct phenotypes observed in Pax3 and Pax7 mutants, and provide a unique perspective into the potential roles of Pax7 during disease and development.

  8. Aebp2 as an epigenetic regulator for neural crest cells.

    Directory of Open Access Journals (Sweden)

    Hana Kim

    Full Text Available Aebp2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2. We generated a mutant mouse line disrupting the transcription of Aebp2 to investigate its in vivo roles. Aebp2-mutant homozygotes were embryonic lethal while heterozygotes survived to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin. In addition, many heterozygotes display a set of phenotypes, enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprung's disease and Waardenburg syndrome. These phenotypes are usually caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. ChIP analyses demonstrated that the majority of the genes involved in the migration and development process of neural crest cells are downstream target genes of AEBP2 and PRC2. Furthermore, expression analyses confirmed that some of these genes are indeed affected in the Aebp2 heterozygotes. Taken together, these results suggest that Aebp2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism.

  9. Involvement of Neptune in induction of the hatching gland and neural crest in the Xenopus embryo.

    Science.gov (United States)

    Kurauchi, Takayuki; Izutsu, Yumi; Maéno, Mitsugu

    2010-01-01

    Neptune, a Krüppel-like transcription factor, is expressed in various regions of the developing Xenopus embryo and it has multiple functions in the process of development in various organs. In situ hybridization analysis showed that Neptune is expressed in the boundary region between neural and non-neural tissues at the neurula stage, but little is known about the function of Neptune in this region. Here, we examined the expression and function of Neptune in the neural plate border (NPB) in the Xenopus embryo. Depletion of Neptune protein in developing embryos by using antisense MO caused loss of the hatching gland and otic vesicle as well as malformation of neural crest-derived cranial cartilages and melanocytes. Neptune MO also suppressed the expression of hatching gland and neural crest markers such as he, snail2, sox9 and msx1 at the neurula stage. Subsequent experiments showed that Neptune is necessary and sufficient for the differentiation of hatching gland cells and that it is located downstream of pax3 in the signal regulating the differentiation of these cells. Thus, Neptune is a new member of hatching gland specifier and plays a physiological role in determination and specification of multiple lineages derived from the NPB region.

  10. Stage-specific control of neural crest stem cell proliferation by the small rho GTPases Cdc42 and Rac1

    DEFF Research Database (Denmark)

    Fuchs, Sebastian; Herzog, Dominik; Sumara, Grzegorz

    2009-01-01

    The neural crest (NC) generates a variety of neural and non-neural tissues during vertebrate development. Both migratory NC cells and their target structures contain cells with stem cell features. Here we show that these populations of neural crest-derived stem cells (NCSCs) are differentially re...

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

    Energy Technology Data Exchange (ETDEWEB)

    Ernfors, Patrik, E-mail: patrik.ernfors@ki.se [Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm (Sweden)

    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.

  12. Hypoxia and MITF regulate KIT oncogenic properties in melanocytes.

    Science.gov (United States)

    Laugier, F; Delyon, J; André, J; Bensussan, A; Dumaz, N

    2016-09-22

    KIT mutations are frequent in acral, mucosal and chronic sun-damage (CSD) melanoma, but little is known about the mechanisms driving the transformation of KIT-mutated melanocytes into melanoma cells. We showed that exposition of melanocytes harboring the (L576P)KIT mutation to a hypoxic environment induced their transformation into malignant cells. Transformed (L576P)KIT melanocytes showed downregulation of MITF expression characteristic of melanoma initiating cells (MICs). In agreement, these cells were able to form spheres in neural crest cell medium and low-adherence conditions, also a characteristic of MICs. Downregulation of MITF by RNA interference induced transformation of KIT-mutated melanocytes in normoxia and acquisition of a MIC phenotype by these cells. Hence, low level of MITF cooperates with oncogenic KIT to transform melanocytes. Activation of the cAMP pathway in transformed (L576P)KIT melanocytes stimulated MITF expression, and reduced cellular proliferation and sphere formation. These findings highlight the essential role of MITF in revealing the oncogenic activity of KIT in melanocytes and suggest that the cAMP pathway is a therapeutic target in KIT-mutated melanoma.

  13. [Dysplastic melanocytic nevus].

    Science.gov (United States)

    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.

  14. Adipose stromal cells contain phenotypically distinct adipogenic progenitors derived from neural crest.

    Directory of Open Access Journals (Sweden)

    Yoshihiro Sowa

    Full Text Available Recent studies have shown that adipose-derived stromal/stem cells (ASCs contain phenotypically and functionally heterogeneous subpopulations of cells, but their developmental origin and their relative differentiation potential remain elusive. In the present study, we aimed at investigating how and to what extent the neural crest contributes to ASCs using Cre-loxP-mediated fate mapping. ASCs harvested from subcutaneous fat depots of either adult P0-Cre/or Wnt1-Cre/Floxed-reporter mice contained a few neural crest-derived ASCs (NCDASCs. This subpopulation of cells was successfully expanded in vitro under standard culture conditions and their growth rate was comparable to non-neural crest derivatives. Although NCDASCs were positive for several mesenchymal stem cell markers as non-neural crest derivatives, they exhibited a unique bipolar or multipolar morphology with higher expression of markers for both neural crest progenitors (p75NTR, Nestin, and Sox2 and preadipocytes (CD24, CD34, S100, Pref-1, GATA2, and C/EBP-delta. NCDASCs were able to differentiate into adipocytes with high efficiency but their osteogenic and chondrogenic potential was markedly attenuated, indicating their commitment to adipogenesis. In vivo, a very small proportion of adipocytes were originated from the neural crest. In addition, p75NTR-positive neural crest-derived cells were identified along the vessels within the subcutaneous adipose tissue, but they were negative for mural and endothelial markers. These results demonstrate that ASCs contain neural crest-derived adipocyte-restricted progenitors whose phenotype is distinct from that of non-neural crest derivatives.

  15. Giant Congenital Melanocytic Nevus

    DEFF Research Database (Denmark)

    Rasmussen, Bo Sonnich; Henriksen, Trine Foged; Kølle, Stig-Frederik Trojahn

    2015-01-01

    % versus 44% required unplanned additional surgery, respectively. Complications were noted in 25% and 67% of the patients, respectively. Cosmetic result was satisfying in 76% of patients without difference between the groups. No malignant transformation was found during a mean follow-up of 11 years......Giant congenital melanocytic nevi (GCMN) occur in 1:20,000 livebirths and are associated with increased risk of malignant transformation. The treatment of GCMN from 1981 to 2010 in a tertiary referral center was reviewed evaluating the modalities used, cosmetic results, associated complications......, and malignant transformation. Of 35 patients, 25 underwent surgery. Curettage was most frequently used (64%) followed by excision and tissue expansion (20%). Six percent of the patients treated with curettage, and 78% of the patients who received excision surgery required more than 1 planned procedure, and 25...

  16. Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc.

    Science.gov (United States)

    Pshenichnaya, Irina; Schouwey, Karine; Armaro, Marzia; Larue, Lionel; Knoepfler, Paul S; Eisenman, Robert N; Trumpp, Andreas; Delmas, Véronique; Beermann, Friedrich

    2012-05-01

    c-Myc is involved in the control of diverse cellular processes and implicated in the maintenance of different tissues including the neural crest. Here, we report that c-Myc is particularly important for pigment cell development and homeostasis. Targeting c-Myc specifically in the melanocyte lineage using the floxed allele of c-Myc and Tyr::Cre transgenic mice results in a congenital gray hair phenotype. The gray coat color is associated with a reduced number of functional melanocytes in the hair bulb and melanocyte stem cells in the hair bulge. Importantly, the gray phenotype does not progress with time, suggesting that maintenance of the melanocyte through the hair cycle does not involve c-Myc function. In embryos, at E13.5, c-Myc-deficient melanocyte precursors are affected in proliferation in concordance with a reduction in numbers, showing that c-Myc is required for the proper melanocyte development. Interestingly, melanocytes from c-Myc-deficient mice display elevated levels of the c-Myc paralog N-Myc. Double deletion of c-Myc and N-Myc results in nearly complete loss of the residual pigmentation, indicating that N-Myc is capable of compensating for c-Myc loss of function in melanocytes. © 2012 John Wiley & Sons A/S.

  17. Therapy of melanocytic conjunctival tumors.

    Science.gov (United States)

    Halas, Jr M; Svetlosakova, Z; Babal, P

    2013-01-01

    Clinical experience of our single center in dealing with pigmented epibulbar lesions - melanocytic conjunctival tumors is presented. Since 2008 we use the topical treatment with mitomycin C (MMC) as an alternative or adjunctive method for excision in the treatment of melanocytic neoplasia of the conjunctiva. The retrospective case series of 85 patients with pigmented lesions of the conjunctiva - melanocytic conjunctival tumors, histopathologically examined in the period 2001-2010 is presented. Since 2008 we started to apply MMC in the treatment of primary acquired melanosis (PAM) and dysplastic nevi. We apply MMC topically directly after an excision as 2-times five minutes application. In 85 patients with pigmented lesions of the conjunctiva histopathological findings after excision of the lesion showed in 68 (80 %) cases melanocytic nevocelullar nevus, out of which 55 cases were combined and 13 cases were junctional nevi. In 60 (80 %) cases of melanocytic nevi atypia was found in 25 patients (42 %), nevus without atypia was present in 35 cases (58 %). PAM with atypia was found in 16 patients (classified since 2000). During the period of application of MMC we diagnosed only one patient with primary conjunctival melanoma. There was no presence of relapse of the pigmented lesion either after primary excision or after excision with MMC. Resection of more than one quadrant of bulbar conjunctiva in patients with pigmented lesions of the conjunctiva in cases of conjunctival nevus with atypia and PAM with atypia combined with topical MMC chemotherapy is an alternative therapy for residual pigmented lesions. There was no presence of relapse of pigmentation in area of excision with or without using MMC during the surgery in patients with PAM. The number of our patients is not sufficient yet to draw a conclusion (Fig. 6, Ref. 21).

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

    Directory of Open Access Journals (Sweden)

    Amber N. Mull

    2015-12-01

    Full Text Available 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.

  19. Analysis of the effects of hydroquinone and arbutin on the differentiation of melanocytes.

    Science.gov (United States)

    Inoue, Yu; Hasegawa, Seiji; Yamada, Takaaki; Date, Yasushi; Mizutani, Hiroshi; Nakata, Satoru; Matsunaga, Kayoko; Akamatsu, Hirohiko

    2013-01-01

    Hydroquinone (HQ) is a chemical compound that inhibits the functions of melanocytes and has long been known for its skin-whitening effect. According to previous studies, the Tyrosinase (Tyr) activity inhibitory effect and melanocyte-specific cell toxicity are known depigmenting mechanisms; however, details of the underlying mechanisms are unknown. Arbutin (Arb) is also known for its Tyr activity inhibitory effect and is commonly used as a skin-whitening agent. However, the detailed depigmenting mechanism of Arb is also not yet fully understood. Few studies have attempted to elucidate the effects of HQ and Arb on undifferentiated melanocytes. In this study, we examined the effects of HQ and Arb throughout each stage of differentiation of melanocytes using a mouse embryonic stem cell (ESC) culture system to induce melanocytes. The results showed that HQ in particular downregulated the early stage of differentiation, in which neural crest cells were generated, and the late stage of differentiation, in which melanogenesis became active. On the other hand, Arb had no effect on the differentiation of melanocytes, and only suppressed melanogenesis by specifically suppressing elevations in Tyr expression in the late stage of differentiation.

  20. Sox proteins in melanocyte development and melanoma

    Science.gov (United States)

    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

  1. CHARGEd with neural crest defects.

    Science.gov (United States)

    Pauli, Silke; Bajpai, Ruchi; Borchers, Annette

    2017-10-30

    Neural crest cells are highly migratory pluripotent cells that give rise to diverse derivatives including cartilage, bone, smooth muscle, pigment, and endocrine cells as well as neurons and glia. Abnormalities in neural crest-derived tissues contribute to the etiology of CHARGE syndrome, a complex malformation disorder that encompasses clinical symptoms like coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are causative of CHARGE syndrome and loss-of-function data in different model systems have firmly established a role of CHD7 in neural crest development. Here, we will summarize our current understanding of the function of CHD7 in neural crest development and discuss possible links of CHARGE syndrome to other developmental disorders. © 2017 Wiley Periodicals, Inc.

  2. Neural crest contributions to the lamprey head

    Science.gov (United States)

    McCauley, David W.; Bronner-Fraser, Marianne

    2003-01-01

    The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

  3. Melanocyte colonization and pigmentation of breast carcinoma

    DEFF Research Database (Denmark)

    Mele, Marco; Laurberg, Tinne; Engberg Damsgaard, Tine

    2012-01-01

    Introduction. Melanocyte colonization of breast carcinoma by nonneoplastic melanocytes of epidermal origin is a rare and serious condition first described in 1977. We report on the exceptional clinical and pathological features of this migration phenomenon in a 74-year-old patient. Discussion...

  4. Bilateral diffuse uveal melanocytic proliferation

    DEFF Research Database (Denmark)

    Klemp, Kristian; Kiilgaard, Jens Folke; Heegaard, Steffen

    2017-01-01

    cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic...... investigations. The literature of BDUMP has not been reviewed since 2003, and there is a growing need for an updated review on diagnosis and management of BDUMP. We review the literature and report a case of BDUMP with a white ciliary body tumour, iris rubeosis, increased iris pigmentation and cataract....

  5. Developmental Pathways Activated in Melanocytes and Melanoma

    Science.gov (United States)

    Liu, Jianglan; Fukunaga-Kalabis, Mizuho; Li, Ling; Herlyn, Meenhard

    2014-01-01

    Cutaneous malignant melanomas originate primarily within epidermal melanocytic cells. Melanoma cells share many characteristics with melanocyte precursors, suggesting that melanoma cells utilize the developmental programs of their normal counterpart for their own progression. The pigmentation system provides an advantageous model to assess survival pathway interactions in the melanocytic lineage, as genetic alterations controlling melanocyte development can be easily detectable by coat color phenotype that do not affect the viability of an animal. By integrating combinatorial gene knockout approaches, cell-based assays and immunohistochemical observations, recent studies have illustrated several genes and pathways that play important roles both in melanocyte specification and maintenance and in melanoma formation and progression. We are reviewing those genes and pathways to understand the connection between normal and cancerous development and to reveal therapeutic potential of targeting developmental pathways for melanoma therapy. PMID:25109840

  6. A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.

    Directory of Open Access Journals (Sweden)

    Ichiro Yajima

    Full Text Available BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA, a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2 and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.

  7. A Subpopulation of Smooth Muscle Cells, Derived from Melanocyte-Competent Precursors, Prevents Patent Ductus Arteriosus

    Science.gov (United States)

    Puig, Isabel; Champeval, Delphine; Kumasaka, Mayuko; Belloir, Elodie; Bonaventure, Jacky; Mark, Manuel; Yamamoto, Hiroaki; Taketo, Mark M.; Choquet, Philippe; Etchevers, Heather C.; Beermann, Friedrich; Delmas, Véronique; Monassier, Laurent; Larue, Lionel

    2013-01-01

    Background Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes. PMID:23382837

  8. Translocation of latex beads after laser ablation of the avian neural crest.

    Science.gov (United States)

    Coulombe, J N; Bronner-Fraser, M

    1984-11-01

    Previous studies from this laboratory (M.E. Bronner-Fraser, 1982, Dev. Biol. 91, 50-63) have demonstrated that latex beads translocate ventrally after injection into avian embryos during the phase of neural crest migration, to settle in the vicinity of neural-crest-derived structures. In order to examine the role of host neural crest cells in the ventral translocation of implanted beads, latex beads have been injected into regions of embryos from which the neural crest cells have been ablated using a laser microbeam. Prior to their migratory phase, neural crest cells reside in the dorsal portion of the neural tube. Laser irradiation of the dorsal neural tube was used to reproducibly achieve either partial or complete ablation of neural crest cells from the irradiated regions. The effectiveness of the ablation was assessed by the degree of reduction in dorsal root ganglia, a neural crest derivative. Because of the rapidity and precision of this technique, it was possible to selectively remove neural crest cells without significantly altering other embryonic structures. The results indicate that, after injection of latex beads into the somites of embryos whose neural crest cells were removed by laser irradiation, the beads translocate ventrally in the absence of the endogenous neural crest.

  9. DNA methyltransferase 3b is dispensable for mouse neural crest development.

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    Bridget T Jacques-Fricke

    Full Text Available The neural crest is a population of multipotent cells that migrates extensively throughout vertebrate embryos to form diverse structures. Mice mutant for the de novo DNA methyltransferase DNMT3b exhibit defects in two neural crest derivatives, the craniofacial skeleton and cardiac ventricular septum, suggesting that DNMT3b activity is necessary for neural crest development. Nevertheless, the requirement for DNMT3b specifically in neural crest cells, as opposed to interacting cell types, has not been determined. Using a conditional DNMT3b allele crossed to the neural crest cre drivers Wnt1-cre and Sox10-cre, neural crest DNMT3b mutants were generated. In both neural crest-specific and fully DNMT3b-mutant embryos, cranial neural crest cells exhibited only subtle migration defects, with increased numbers of dispersed cells trailing organized streams in the head. In spite of this, the resulting cranial ganglia, craniofacial skeleton, and heart developed normally when neural crest cells lacked DNMT3b. This indicates that DNTM3b is not necessary in cranial neural crest cells for their development. We conclude that defects in neural crest derivatives in DNMT3b mutant mice reflect a requirement for DNMT3b in lineages such as the branchial arch mesendoderm or the cardiac mesoderm that interact with neural crest cells during formation of these structures.

  10. Reasons for rarity of anal melanocytic naevi.

    Science.gov (United States)

    Aljufairi, Eman; Alhilli, Fayek

    2017-11-01

    In the last 16 years only seven definite cases of anal melanocytic naevi have been reported in the literature. We describe three new cases, none of which were suspected clinically and were incidentally diagnosed on histological examination of haemorrhoidectomy specimens. The infrequency of these special site flexural melanocytic lesions may be related to changes in the involutionary mechanisms of the anal melanocyte proliferation. However, other factors related to the low detection rates by clinicians and pathologists need also to be considered. © 2017 The Australasian College of Dermatologists.

  11. Follicle and melanocyte stem cells, and their application in neuroscience: A Web of Science-based literature analysis.

    Science.gov (United States)

    Wu, Weifu

    2012-12-05

    To identify global research trends of follicle and melanocyte stem cells, and their application in neuroscience. We performed a bibliometric analysis of studies from 2002 to 2011 on follicle and melanocyte stem cells, and their application in neuroscience, which were retrieved from the Web of Science, using the key words follicle stem cell or melanocyte stem cell, and neural, neuro or nerve. (a) peer-reviewed published articles on follicle and melanocyte stem cells, and their application in neuroscience, which were indexed in the Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) a number of corrected papers from the total number of articles. (1) Distribution of publications on follicle and melanocyte stem cells by years, journals, countries, institutions, institutions in China, and most cited papers. (2) Distribution of publications on the application of follicle and melanocyte stem cells in neuroscience by years, journals, countries, institutions, and most cited papers. Of the 348 publications from 2002 to 2011 on follicle and melanocyte stem cells, which were retrieved from the Web of Science, more than half were from American authors and institutes. The most prolific institutions in China for publication of papers on follicle and melanocyte stem cells were the Fourth Military Medical University and Third Military Medical University. The most prolific journals for publication of papers on follicle and melanocyte stem cells were the Journal of Investigative Dermatology, Pigment Cell & Melanoma Research. Of the 63 publications from 2002 to 2011 on the application of follicle and melanocyte stem cells in neuroscience, which were retrieved from the Web of Science, more than half were from American authors and institutes, and no papers were

  12. Conjunctival Melanocytic Tumors-New Developments

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    Hülya Gökmen Soysal

    2014-09-01

    Full Text Available Melanocytic lesions of the conjunctiva represent a wide spectrum of tumors that include benign, premalignant, and malignant tumors. There are many ongoing arguments about the definition, classification, and therapeutic options of the conjunctival melanocytic tumors with many different suggestions. Conjunctival nevi are the most common melanocytic tumors and their risk of malignant transformation is less than1%. Primary acquired melanosis (PAM histopathologically includes various types of lesions from increased melanin pigmentation without melanocyte proliferation to melanoma in situ and is accepted as a clinical definition, so that a new classification is recommended which is based on more objective criteria than before. Although conjunctival melanoma is seen rarely, it is associated with a high mortality rate. Management of these tumors mainly involves surgery and adjuvant topical chemotherapy, cryotherapy, and radiation therapy that help improving the survival, however, new options are being investigated related to genetic and molecular researches. (Turk J Ophthalmol 2014; 44: Supplement 15-21

  13. Keratinocytes regulate the function of melanocytes

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    Tomohisa Hirobe

    2014-12-01

    Full Text Available Mammalian keratinocytes compose the bulk of the epithelium, undergo keratinization, and form the dead superficial layer of the skin. These superficial keratinized cells are continuously replaced by cells derived from mitotic cells in the lowest layer of the epidermis (i.e., the basal layer. Melanocytes locate in the basal layer and do not keratinize; however, they can produce melanin pigments. Melanin is accumulated in small granules called melanosomes. The melanosomes are transported to dendrites from which the melanosomes are transferred to keratinocytes. Epidermal invaginations such as keratinocytes and melanocytes extend to the dermis to form hair follicles. In addition to these two cells, dermal fibroblasts are also required for the formation of hair follicles. The homeostasis of the epidermis and hair follicle is primarily regulated by the cellular interaction between keratinocytes and melanocytes. Keratinocytes stimulate melanocyte functions such as proliferation, differentiation, melanogenesis, and dendritogenesis. Using the techniques of tissue culture, biochemistry, and molecular biology, factors that have been derived from keratinocytes are hormones, growth factors, and cytokines such as α-melanocyte-stimulating hormone, adrenocorticotrophic hormone, basic fibroblast growth factor, nerve growth factor, endothelins, granulocyte-macrophage colony-stimulating factor, stem cell factor, leukemia inhibitory factor, and hepatocyte growth factor. These keratinocyte-derived paracrine factors have a key role in regulating melanocyte function through receptor-mediated signaling pathways, followed by maintaining epidermal and hair follicular homeostasis.

  14. Agminated melanocytic nevus status post dabrafenib therapy for metastatic melanoma

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    Agulló, Alfredo; Hinds, Brian; Santesteban, Raquel; Mitxelena, Josune Mitxelena; Yanguas, Ignacio

    2016-01-01

    Agminated melanocytic nevus is an uncommon type of mole, characterized by a local group of macular or papular pigmented lesions, well demarcated, without a common pigmented background. This pattern has also been associated with Spitz nevi, dysplastic melanocytic nevi, and non-melanocytic lesions.We describe the onset of an acquired agminated melanocytic nevus after dabrafenib treatment. Our case highlights paradoxical MAPK activation in the setting of single-agent BRAF blockade and underscore...

  15. Congenital agminated melanocytic nevus--case report.

    Science.gov (United States)

    Rocha, Camila Roos Mariano da; 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.

  16. Congenital agminated melanocytic nevus - case report*

    Science.gov (United States)

    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

  17. Pediatric Melanoma and Atypical Melanocytic Neoplasms.

    Science.gov (United States)

    Sreeraman Kumar, Radhika; Messina, Jane L; Reed, Damon; Navid, Fariba; Sondak, Vernon K

    2016-01-01

    Melanoma is uncommon in the pediatric age range, but is increasing in frequency and often presents with atypical features compared to the classic ABCDE criteria common to adult melanoma cases. Moreover, many melanocytic neoplasms in childhood pose diagnostic challenges to the pathologist, and sometimes cannot be unequivocally classified as benign nevi or melanoma. This chapter addresses the evaluation and management of pediatric patients with melanoma and atypical melanocytic neoplasms, including the roles of and unresolved questions surrounding sentinel lymph node biopsy, completion lymphadenectomy, adjuvant therapy, and treatment of advanced disease.

  18. Clinicopathological and molecular aspects of cutaneous Melanoma

    NARCIS (Netherlands)

    Bogenrieder, T.

    2009-01-01

    Clinicopathological and molecular aspects of cutaneous melanoma. Melanoma arises form the transformation of neural crest-derived melanocytes, the pigment cells of the skin, which reside in the basal layer of the epidermis. Melanoma is the deadliest form of skin cancer and one of the most aggressive

  19. Hair follicle melanocyte cells as a renewable source of melanocytes for culture and transplantation.

    Science.gov (United States)

    Kwon, Ho; Liu, Perry H; Lew, Dae-Hyun; Nishimura, Emi; Orgill, Dennis P

    2008-01-01

    Advances in melanocyte culture techniques have not yet led to reliable clinical methods for treating hypopigmentation disorders. We hypothesized that melanocytes harvested from plucked hair follicles may provide a renewable source of melanocytes for the treatment of hypopigmentation. Hairs with attached cells from the follicles were plucked from Yucatan pigs and implanted in a collagen-glycosaminoglycan matrix for either immediate or delayed implantation into full-thickness excisional porcine wounds. Wounds were allowed to heal and were biopsied at 2 and 4 weeks, respectively. Fully healed wounds with transplanted hair follicles showed central areas of dark pigmentation corresponding to the location of implanted hair follicles. Corresponding collagen-glycosaminoglycan matrix wounds showed no central areas of pigmentation. Hair follicle--derived melanocytes may potentially serve as a renewable source of pigment-producing cells for treating hypopigmentation disorders.

  20. Agminated melanocytic nevus status post dabrafenib therapy for metastatic melanoma.

    Science.gov (United States)

    Agulló, Alfredo; Hinds, Brian; Santesteban, Raquel; Mitxelena, Josune Mitxelena; Yanguas, Ignacio

    2016-07-15

    Agminated melanocytic nevus is an uncommon type of mole, characterized by a local group of macular or papular pigmented lesions, well demarcated, without a common pigmented background. This pattern has also been associated with Spitz nevi, dysplastic melanocytic nevi, and non-melanocytic lesions.We describe the onset of an acquired agminated melanocytic nevus after dabrafenib treatment. Our case highlights paradoxical MAPK activation in the setting of single-agent BRAF blockade and underscores the importance of characterizing the diverse side effects of selective BRAF inhibitors. This is the first case, to our knowledge, of agminated melanocytic nevus in association with dabrafenib.

  1. Gene expression analysis of zebrafish melanocytes, iridophores, and retinal pigmented epithelium reveals indicators of biological function and developmental origin.

    Directory of Open Access Journals (Sweden)

    Charles W Higdon

    Full Text Available 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. Automatic evaluation of skin histopathological images for melanocytic features

    Science.gov (United States)

    Koosha, Mohaddeseh; Hoseini Alinodehi, S. Pourya; Nicolescu, Mircea; Safaei Naraghi, Zahra

    2017-03-01

    Successfully detecting melanocyte cells in the skin epidermis has great significance in skin histopathology. Because of the existence of cells with similar appearance to melanocytes in hematoxylin and eosin (HE) images of the epidermis, detecting melanocytes becomes a challenging task. This paper proposes a novel technique for the detection of melanocytes in HE images of the epidermis, based on the melanocyte color features, in the HSI color domain. Initially, an effective soft morphological filter is applied to the HE images in the HSI color domain to remove noise. Then a novel threshold-based technique is applied to distinguish the candidate melanocytes' nuclei. Similarly, the method is applied to find the candidate surrounding halos of the melanocytes. The candidate nuclei are associated with their surrounding halos using the suggested logical and statistical inferences. Finally, a fuzzy inference system is proposed, based on the HSI color information of a typical melanocyte in the epidermis, to calculate the similarity ratio of each candidate cell to a melanocyte. As our review on the literature shows, this is the first method evaluating epidermis cells for melanocyte similarity ratio. Experimental results on various images with different zooming factors show that the proposed method improves the results of previous works.

  3. Melanocytic Nevi in Children: A Review.

    Science.gov (United States)

    Levy, Rebecca; Lara-Corrales, Irene

    2016-08-01

    Common moles on the skin, known scientifically as melanocytic nevi, are seen frequently in the pediatric population. They are broadly grouped into two groups: congenital (generally present at birth or in infancy) or acquired. Congenital melanocytic nevi (CMN) are classified based on size and morphologic features. Neurocutaneous melanosis and melanoma represent two important complications, with overall risk affected by nevus size, location, appearance, and number of satellite lesions. Regular lifelong skin surveillance is required for high-risk CMN. Acquired melanocytic nevi (AMN) tend to appear in childhood and increase in number through adolescence. Risk factors for melanoma in children with moles include having more than 50 AMN, clinically atypical AMN, family history of melanoma, excessive ultraviolet light exposure, lightly pigmented skin, and immunosuppression. Children with risk factors should be monitored regularly. The periodic health examination presents an opportunity to perform total body skin examination to screen for concerning lesions and to provide anticipatory guidance about sun protection. [Pediatr Ann. 2016;45(8):e293-e298.]. Copyright 2016, SLACK Incorporated.

  4. Dermoscopic Features of Acral Melanocytic Nevi

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    Filiz

    2011-12-01

    Full Text Available Background and Design: Compared to nevi in other regions, acral melanocytic nevi have special dermoscopic features due to their anatomical localizations. It may be difficult to distinguish the melanocytic nevi in these regions from early acral melanoma. For this reason, it is important to know the dermoscopic patterns of acral melanocytic nevi. Our aim was to evaluate the dermoscopic patterns and distribution features of acral melanocytic nevi.Material and Method: One hundred ninety-six acquired acral melanocytic nevi of 131 patients were evaluated retrospectively in this study. The demographic features such as age and sex, localization and pattern of nevi were recorded.Results: Of the 131 patients, 77 (58.7% were female and 54 (41.3% were male. Of all nevi, 92 (46.9% were present on the palms, 104 (53.1% were present on the soles. The localizations of acral nevi were as follows: inner arch (20%, finger (18.4%, hypothenar (12.8%, middle region (12.8%, thenar (11.7%, outer arch (10.2%, metatarsal region (8.7% and heel (5.6%. The most common dermoscopic pattern was parallel furrow pattern (40.8%. The other patterns seen were homogeneous (15.8%, latticelike (11.7%, fibrillar (9.7%, globular (9.7%, reticular (5.6%, nontypical (3.6%, the pattern suggestive of malignancy (2.0% and transition pattern (1%. Parallel furrow pattern, fibrillar and homogenous patterns were significantly more frequent on fingers, inner arch and outer arch, given in decreasing order (p<0.01, p<0.01, p=0.02, respectively. The four lesions suggestive of malignancy (2.0% were excised and diagnosed as compound nevus, dermal nevus, dysplastic nevus and malignant melanoma. Conclusion: The three most frequently observed patterns were parallel furrow, homogenous and latticelike patterns, in decreasing order. The nevi were most frequently located on the inner arch. Parallel furrow pattern was mostly located on the fingers, fibrillar pattern and homogenous pattern were mostly seen on

  5. The Effect of Otic Melanocyte Destruction on Auditory and Vestibular Function: a Study on Vitiligo Patients

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    Parvane Mahdi

    2016-03-01

    Full Text Available The hallmark of vitiligo is the disappearance of melanocytes from the skin. As a result, of melanocytes presence in the auditory and vestibular apparatus, the involvement of these systems in vitiligo which targets the melanocytes of the whole body is possible; suggesting that vitiligo is a systemic disease rather than a purely cutaneous problem. A total of 21 patients with vitiligo were enrolled in this study. A group of 20 healthy subjects served as a control group. Pure tone audiometry (PTA, auditory brainstem responses (ABR and vestibular evoked myogenic potentials (VEMP were carried out in all participants. High frequency sensory neural hearing loss was seen in 8 (38.09% patients. ABR analysis revealed 10 (47.61% had an abnormal increase in latency of wave III, and 6 (28.57% had an abnormal prolongation of IPL I-III, however, regarding our VEMP findings, there were no recorded responses on left ear of 1 (4.76% patient and latency of p13 was prolonged in 5(23.80% patients. There was no correlation between ages, duration of disease, and any of the recorded parameters (P>0.05. In the present survey, we highlighted the auditory and vestibular involvement in vitiligo patients.

  6. Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3.

    Science.gov (United States)

    Boissy, Raymond E; Richmond, Bonnie; Huizing, Marjan; Helip-Wooley, Amanda; Zhao, Yang; Koshoffer, Amy; Gahl, William A

    2005-01-01

    Hermansky-Pudlak Syndrome-type 3 (HPS-3) is a relatively mild subtype of HPS with minimal cutaneous and ocular depigmentation. The HPS-3 gene encodes a novel protein of unknown function with a predicted molecular weight of 114 kd. To assess the role of the HPS3 protein in melanization, cultured melanocytes developed from HPS-3 patients were evaluated biochemically and histologically for activity and localization of melanocyte-specific proteins. Endogenous tyrosinase activity of HPS-3 melanocytes was substantial, but tyrosinase activity and melanin synthesis was suppressed in intact melanocytes. However, the level of suppression, as well as extent to which up-regulation by isobutylmethylxanthine and cholera toxin was muted, was less that in HPS-1 melanocytes. Ultrastructurally, HPS-3 melanocytes contained morphologically normal melanosomes, predominantly of stage I and II with minimal stage III and few stage IV melanosomes. Dihydroxyphenylalanine (DOPA) histochemistry demonstrated an increase in melanization of melanosomes. Unique to HPS-3 melanocytes were numerous DOPA-positive 50-nm vesicles and tubular elements present throughout the cell body and dendrites. Tyrosinase, tyrosinase-related protein-1 (Tyrp1), dopachrome tautomerase (Dct), and LAMP1 and 3 localization in HPS-3 melanocytes, as evaluated by immunocytochemistry and confocal microscopy, demonstrated a fine, floccular distribution in contrast to the coarse, granular distribution characteristic of control melanocytes. The localization profile of other proteins expressed by melanocytes (ie, Silver/Pmel17, Melan-A/MART-1, LAMP2, Rab 27, transferrin, c-kit, adaptin-3, and the HPS1 protein) appeared normal. These results suggest that a specific subset of melanocyte proteins are aberrantly trafficked throughout the HPS-3 melanocyte and may be responsible for the reduction in melanin synthesis.

  7. UV induction of cyclobutane thymine dimers in the DNA of cultured melanocytes from foreskin, common melanocytic nevi and dysplastic nevi

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    Noz, K.C.; Bergman, W.; Schothorst, A.A. (Univ. Hospital Leiden (Netherlands). Dept. of Dermatology); Roza, L. (TNO Medical Biological Lab., Rijswijk (Netherlands)); Darroudi, F. (Rijksuniversiteit Leiden (Netherlands). Lab. voor Stralengenetica en Chemische Mutagenese)

    1994-05-01

    We compared the induction of cyclobutane thymine dimers after exposure to 302 nm UV in foreskin-derived melanocytes and melanocytes from nevocellular nevi, as well as in melanocytes cultured from dysplastic nevi, precursor lesions of melanoma, derived from four, three and four individuals, respectively. Cyclobutane thymine dimers were quantified in situ by means of an immunofluorescence assay with a specific monoclonal antibody. A method was developed to compare separately performed experiments in a standardized manner. For melanocytes from each source, we demonstrated a linear relationship between UV dose and immunofluorescence. In nevocellular and dysplastic nevi, two subpopulations could be detected, distinguished by their nuclear size. Large nucleated nevocellular nevus cells were most susceptible to the induction of thymine dimers (49% higher induction compared to induction in foreskin melanocytes), while in normal-sized nuclei of these nevus cells the same induction of thymine dimers was found as in nuclei from foreskin melanocytes. In contrast, large nucleated dysplastic nevus melanocytes did not differ from the foreskin melanocytes, while normal-sized nuclei of dysplastic nevus cells showed a lower induction (32% lower induction than in foreskin melanocytes). (Author).

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

    Science.gov (United States)

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

    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.

  9. Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

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    Paige Snider

    2007-01-01

    Full Text Available Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators. Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest

  10. A study of autologous melanocyte transfer in treatment of stable vitiligo

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    Pandya Vishvabhavan

    2005-01-01

    Full Text Available Background: Replenishing melanocytes selectively in vitiliginous macules by autologous melanocytes is a promising treatment. With expertise in culturing melanocytes, it has now become possible to treat larger recipient areas with smaller skin samples. Aim: To study the extent of repigmentation after autologous melanocyte transplantation in patients with stable vitiligo. Methods: The melanocytes were harvested as an autologous melanocyte rich cell suspension from a donor split thickness graft. Melanocyte culture was performed in selected cases where the melanocyte cell count was insufficient to meet the requirement of the recipient area. These cells were then transplanted to the recipient area that had been superficially dermabraded. Results: An excellent response was seen in 52.17% cases with the autologous melanocyte rich cell suspension (AMRCS technique and in 50% with the melanocyte culture (MC technique. Conclusion: Autologous melanocyte transplantation can be an effective form of surgical treatment in stable but recalcitrant lesions of vitiligo.

  11. Neurotized congenital melanocytic nevus resembling a pigmented neurofibroma

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    Nidhi Singh

    2015-01-01

    Full Text Available Neurotized congenital melanocytic nevus and pigmented neurofibroma (PNF are close mimics and pose a clinicopathological challenge. We present a case of pigmented hypertrichotic plaque over lumbosacral region and discuss the differential diagnosis and its clinical, histopathological and immunohistochemistry features which may aid in differentiation. We highlight the difficulties faced in differentiating neurotized congenital melanocytic nevus from pigmented neurofibroma.

  12. Cytotoxic T lymphocyte responses against melanocytes and melanoma

    Directory of Open Access Journals (Sweden)

    Schwartz Erich J

    2011-07-01

    Full Text Available Abstract Background Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs against melanoma commonly target melanoma-associated antigens (MAAs which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels. Methods To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines. Results CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR and immunohistochemistry. Conclusions Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.

  13. [Treatment and management of congenital melanocytic naevi].

    Science.gov (United States)

    Bahn, Kamille-Amalie; Hædersdal, Merete; Schmidt, Grethe; Hölmich, Lisbet Rosenkrantz

    2016-09-19

    Congenital melanocytic naevi (CMN) appear in approximately 2.6% of Caucasians. There is a major demand for treatment but no vital indication. Laser therapy, curettage and excision are available treatment modalities, but there is no ideal treatment with documented long-term effect and without side effects, and the level of evidence for the treatment options is generally low. The risk of malignancy has probably been overestimated, and furthermore new research shows that untreated CMN often show spontaneous lightening. We review the literature for pros and cons of different treatments.

  14. Melanocyte Transformation Associated with Substrate Adhesion Impediment

    Directory of Open Access Journals (Sweden)

    Sueli M. Oba-Shinjo

    2006-03-01

    Full Text Available Exclude experimental models of malignant transformation employ chemical and physical carcinogens or genetic manipulations to study tumor progression. In this work, different melanoma cell lines were established after submitting a nontumorigenic melanocyte lineage (melan-a to sequential cycles of forced anchorage impediment. The great majority of these cells underwent anoikis when maintained in suspension. After one deadhesion cycle, phenotypic alterations were noticeable in the few surviving cells, which became more numerous and showed progressive alterations after each adhesion impediment step. No significant differences in cell surface expression of integrins were detected, but a clear electrophoretic migration shift, compatible with an altered glycosylation pattern, was observed for β1 chain in transformed cell lines. In parallel, a progressive enrichment of tri- and tetra-antennary N-glycans was apparent, suggesting increased N-acetylglucosaminyl-transferase V activity. Alterations both in proteoglycan glycosylation pattern and core protein expression were detected during the transformation process. In conclusion, this model corroborates the role of adhesion state as a promoting agent in transformation process and demonstrates that cell adhesion disturbances may act as carcinogenic stimuli, at least for a nontumorigenic immortalized melanocyte lineage. These findings have intriguing implications for in vivo carcinogenesis, suggesting that anchorage independence may precede, and contribute to, neoplastic conversion.

  15. Heterogeneity of expression of epithelial-mesenchymal transition (EMT markers in melanocytes and melanoma cell lines

    Directory of Open Access Journals (Sweden)

    Ji Eun eKim

    2013-05-01

    Full Text Available The epithelial-mesenchymal transition (EMT describes a reversible switch from an epithelial-like to a mesenchymal-like phenotype. It is essential for the development of the normal epithelium and also contributes to the invasive properties of carcinomas. At the molecular level, the EMT transition is characterised by a series of coordinated changes including downregulation of the junctional protein E-cadherin (CDH1, up-regulation of transcriptional repressors of E-cadherin such as Snail (SNAI1 and Slug (SNAI2, and up-regulation of N-cadherin. We wished to determine whether cultured normal melanocytes and melanoma cell lines, which are derived from the neural crest, showed signs of a similarly coordinated phenotypic switch. We investigated normal melanocytes and 25 cell lines derived from New Zealand patients with metastatic melanoma. Most lines had been previously genotyped for common mutations such as BRAF, NRAS, PIK3CA, TP53 and CDKN2A. Expression of E-cadherin, N-cadherin, MITF, Snail, Slug, Axl, p53 and Hdm2 was compared by western blotting. Normal melanocytes expressed each of these proteins except for Snail, while normal melanocytes and almost every melanoma line expressed Slug. Expression of individual markers among different melanoma lines varied from high to low or undetectable. Quantitation of western blots showed that expression of MITF-M, the melanocyte-specific isoform of MITF, was positively related to that of E-cadherin but inversely related to that of N-cadherin and Axl. There was also no apparent relationship between expression of any particular marker and the presence of BRAF, NRAS, PIK3CA, TP53 or CDKN2A mutations. The results suggest that melanomas do not show the classical epithelial and mesenchymal phenotypes but rather display either high E-cadherin/high MITF-M expression on one hand, or high N-cadherin/high Axl expression on the other. These may correspond to differentiated and invasive phenotypes in vivo.

  16. Levels of dopachrome tautomerase in human melanocytes cultured in vitro.

    Science.gov (United States)

    Bernd, A; Ramirez-Bosca, A; Kippenberger, S; Martinez-Liarte, J H; Holzmann, H; Solano, F

    1994-10-01

    Several reports have been published about the level of activity and possible functions of dopachrome tautomerase (DCT) in mouse melanoma cells. Data about the levels of this activity in human melanocytes in culture are still scarce, and, as far as we know, a comparison between mouse and human melanocytes, or between normal and malignant melanocytes, has never been published. We have measured the tyrosinase and DCT activities, as well as the melanin content, in mouse Cloudman melanoma cells, two lines of human melanoma, and three lines of normal human melanocytes obtained from fetal skin. Although more cell lines should be tested to draw a general conclusion, our results suggest that normal melanocytes contained much higher tyrosinase activity and melanin content but lower DCT activity than malignant melanocytes. The two lines of human melanoma cells tested had lower levels of DCT activity than Cloudman melanoma cells. Finally, the low level of DCT activity found in normal human melanocytes cultured in vitro cannot be explained by any of the necessary stimulatory factors added to the cell culture media.

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

    Science.gov (United States)

    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

  18. Conditions for the differentiation of melanocyte-precursor cells from ...

    African Journals Online (AJOL)

    Conditions for the differentiation of melanocyte-precursor cells from human cord blood-derived mesenchymal stem cells. Jienny Lee, Jongsung Lee, Kyungbaeg Roh, Myeong-Ok Kim, Ju-Duck Kim, Deokhoon Park ...

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

    Science.gov (United States)

    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.

  20. Intradermal Melanocytic Nevus Containing Bone Metaplasia: A Case Report

    Directory of Open Access Journals (Sweden)

    Recep Bedir

    2013-06-01

    Full Text Available Melanocytic nevi in the bone metaplasia is not a common case. The majority of these lesions tend to be located in the upper part of the body, as in our case. There is a higher incidence of females. In the pathogenesis usually is thought to develop seconder damage of the hair follicles. We report a 46-year-old woman who presented a case of osseous metaplasia within a benign intradermal melanocytic nevus was excised from the face.

  1. Role of Melanin in Melanocyte Dysregulation of Reactive Oxygen Species

    Directory of Open Access Journals (Sweden)

    Noah C. Jenkins

    2013-01-01

    Full Text Available We have recently reported a potential alternative tumor suppressor function for p16 relating to its capacity to regulate oxidative stress and observed that oxidative dysregulation in p16-depleted cells was most profound in melanocytes, compared to keratinocytes or fibroblasts. Moreover, in the absence of p16 depletion or exogenous oxidative insult, melanocytes exhibited significantly higher basal levels of reactive oxygen species (ROS than these other epidermal cell types. Given the role of oxidative stress in melanoma development, we speculated that this increased susceptibility of melanocytes to oxidative stress (and greater reliance on p16 for suppression of ROS may explain why genetic compromise of p16 is more commonly associated with predisposition to melanoma rather than other cancers. Here we show that the presence of melanin accounts for this differential oxidative stress in normal and p16-depleted melanocytes. Thus the presence of melanin in the skin appears to be a double-edged sword: it protects melanocytes as well as neighboring keratinocytes in the skin through its capacity to absorb UV radiation, but its synthesis in melanocytes results in higher levels of intracellular ROS that may increase melanoma susceptibility.

  2. Melanocyte-Specific Proteins Are Aberrantly Trafficked in Melanocytes of Hermansky-Pudlak Syndrome-Type 3

    OpenAIRE

    Boissy, Raymond E.; Richmond, Bonnie; Huizing, Marjan; Helip-Wooley, Amanda; Zhao, Yang; Koshoffer, Amy; GAHL, WILLIAM A.

    2005-01-01

    Hermansky-Pudlak Syndrome-type 3 (HPS-3) is a relatively mild subtype of HPS with minimal cutaneous and ocular depigmentation. The HPS-3 gene encodes a novel protein of unknown function with a predicted molecular weight of 114 kd. To assess the role of the HPS3 protein in melanization, cultured melanocytes developed from HPS-3 patients were evaluated biochemically and histologically for activity and localization of melanocyte-specific proteins. Endogenous tyrosinase activity of HPS-3 melanocy...

  3. The role of the Hippo pathway in melanocytes and melanoma

    Directory of Open Access Journals (Sweden)

    Bruce Charles Baguley

    2013-05-01

    Full Text Available The Hippo signalling pathway comprises a series of cytoplasmic tumour suppressor proteins including Merlin and the Lats1/2 and MST1/2 kinases, and is thought to play a critical role in determining the sizes of organs and tissues. The Hippo pathway is regulated upstream by extracellular mechanosensory signalling arising from cell shape and polarity, as well as by a variety of extracellular signalling molecules. When active, the pathway maintains the transcriptional activators YAP and TAZ in phosphorylated forms in the cytoplasm, preventing cell proliferation. When the Hippo pathway is inactivated, YAP and TAZ are translocated to the nucleus and induce the expression of a variety of proteins concerned with entry into the cell division cycle, such as cyclin D1 and Fox M1, as well as the inhibition of apoptosis. The failure of the Hippo pathway has been implicated in the development of many different types of cancer but there is limited information available as to its involvement in melanoma. We hypothesise here firstly that the Hippo pathway is involved in maintaining density of cutaneous melanocytes on the basement membrane at the junction of the epidermis and the dermis, and secondly, that its function is disturbed in melanoma. We have analysed a series of 23 low passage human melanoma lines as well as in cultures of normal melanocytes, and find that melanocytes, as well as all melanoma cell lines examined express TAZ. Melanocytes and most melanoma lines also express YAP. E-cadherin, an upstream regulator of the Hippo pathway, and Axl, a receptor tyrosine kinase regulated by the Hippo pathway, are expressed in melanocytes and in several melanoma cell lines. These observations, together with published evidence for the presence of Merlin, Lats1/2 and MST1/2 in melanocytes and melanoma cells, support the hypothesis that the Hippo pathway is an important component of melanocyte and melanoma behaviour.

  4. Prediction of Dermoscopy Patterns for Recognition of both Melanocytic and Non-Melanocytic Skin Lesions

    Directory of Open Access Journals (Sweden)

    Qaisar Abbas

    2016-06-01

    Full Text Available A differentiation between all types of melanocytic and non-melanocytic skin lesions (MnM–SK is a challenging task for both computer-aided diagnosis (CAD and dermatologists due to the complex structure of patterns. The dermatologists are widely using pattern analysis as a first step with clinical attributes to recognize all categories of pigmented skin lesions (PSLs. To increase the diagnostic accuracy of CAD systems, a new pattern classification algorithm is proposed to predict skin lesions patterns by integrating the majority voting (MV–SVM scheme with multi-class support vector machine (SVM. The optimal color and texture features are also extracted from each region-of-interest (ROI dermoscopy image and then these normalized features are fed into an MV–SVM classifier to recognize seven classes. The overall system is evaluated using a dataset of 350 dermoscopy images (50 ROIs per class. On average, the sensitivity of 94%, specificity of 84%, 93% of accuracy and area under the receiver operating curve (AUC of 0.94 are achieved by the proposed MnM–SK system compared to state-of-the-art methods. The obtained result indicates that the MnM–SK system is successful for obtaining the high level of diagnostic accuracy. Thus, it can be used as an alternative pattern classification system to differentiate among all types of pigmented skin lesions (PSLs.

  5. Does Melanoma Begin in a Melanocyte Stem Cell?

    Directory of Open Access Journals (Sweden)

    James D. Hoerter

    2012-01-01

    Full Text Available What is the cellular origin of melanoma? What role do melanocyte stem cells (MSC and other melanocyte precursors play in the development of melanoma? Are MSCs and other latent melanocyte precursors more susceptible to solar radiation? These and many other questions can be very effectively addressed using the zebrafish model. Zebrafish have a robust regenerative capability, permitting the study of how MSCs are regulated and recruited at specific times and places to generate the pigment pattern following fin amputation or melanocyte ablation. They can be used to determine the effects of environmental radiation on the proliferation, survival, repair, and differentiation of MSCs. Our lab is using zebrafish to investigate how UVA- (320–400 nm and UVB- (290–320 nm induced damage to MSCs may contribute to the development of melanoma. A review is given of MSCs in zebrafish as well as experimental techniques and drugs for manipulating MSC populations. These techniques can be used to design experiments to help answer many questions regarding the role of MSCs or melanocyte precursors in the formation of melanoma stem cells and tumors following exposure to UVA/UVB radiation.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects

    NARCIS (Netherlands)

    Blokx, Willeke Am M.; van Dijk, Marcory C. R. F.; Ruiter, Dirk J.

    This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect

  8. Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects.

    NARCIS (Netherlands)

    Blokx, W.A.M.; Dijk, M.C.R.F. van; Ruiter, D.J.

    2010-01-01

    This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect

  9. Neural Crest Stem Cells from Dental Tissues: A New Hope for Dental and Neural Regeneration

    Directory of Open Access Journals (Sweden)

    Gaskon Ibarretxe

    2012-01-01

    Full Text Available Several stem cell sources persist in the adult human body, which opens the doors to both allogeneic and autologous cell therapies. Tooth tissues have proven to be a surprisingly rich and accessible source of neural crest-derived ectomesenchymal stem cells (EMSCs, which may be employed to repair disease-affected oral tissues in advanced regenerative dentistry. Additionally, one area of medicine that demands intensive research on new sources of stem cells is nervous system regeneration, since this constitutes a therapeutic hope for patients affected by highly invalidating conditions such as spinal cord injury, stroke, or neurodegenerative diseases. However, endogenous adult sources of neural stem cells present major drawbacks, such as their scarcity and complicated obtention. In this context, EMSCs from dental tissues emerge as good alternative candidates, since they are preserved in adult human individuals, and retain both high proliferation ability and a neural-like phenotype in vitro. In this paper, we discuss some important aspects of tissue regeneration by cell therapy and point out some advantages that EMSCs provide for dental and neural regeneration. We will finally review some of the latest research featuring experimental approaches and benefits of dental stem cell therapy.

  10. Transcription of melanogenesis enzymes in melanocytes: dependence upon culture conditions and co-cultivation with keratinocytes.

    Science.gov (United States)

    Kippenberger, S; Bernd, A; Bereiter-Hahn, J; Ramirez-Bosca, A; Kaufmann, R; Holzmann, H

    1996-08-01

    Eumelanogenesis of human skin melanocytes requires at least three enzymes: tyrosinase, TRP 1, and TRP 2. The regulation of these enzymes on transcriptional level was detected in a semiquantitative attempt. The total RNA of melanocytes was reverse-transcripted and followed by a PCR with degenerated primers for all three enzymes. The amplification products were related to each other densitometrically. We examined five different culture conditions: 1) melanocytes in a popular phorbolester containing F-10-medium, 2) melanocytes in a co-culture medium with EGF, 3) melanocytes in a co-culture medium with high calcium, 4) melanocytes co-cultured with keratinocytes in EGF containing co-culture medium, and 5) melanocytes co-cultured with keratinocytes in co-culture medium with high calcium. Melanocytes cultured in phorbolester containing F-10-medium featured transcripts of tyrosinase, TRP 1, and TRP 2 in the ratio 45:45:10. The same results were obtained for melanocytes co-cultured with keratinocytes under the two different culture conditions. In melanocytes cultured alone in co-culture media only TRP 1-transcripts were present. It is likely that under co-culture conditions a keratinocyte-derived factor supports the transcription of all three enzymes. For melanocytes in the phorbolester-containing melanocyte medium a proteinkinase C dependent regulation of transcription seems possible.

  11. File list: InP.Epd.20.AllAg.Melanocytes [Chip-atlas[Archive

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  1. File list: ALL.Epd.10.AllAg.Melanocytes [Chip-atlas[Archive

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  6. The epidermal melanocyte system in individuals of Scandinavian origin, determined by DOPA-staining and TEM

    DEFF Research Database (Denmark)

    Drzewiecki, K T; Piltz-Drzewiecka, J

    1979-01-01

    The quantitative evaluation of DOPA-positive epidermal melanocytes in 16 patients of Scandinavian origin showed both individual and regional differences in the melanocyte count. Our data is in agreement with other published studies. The distribution in the number of melanocytes varies significant...... concerning the presence of the epidermal melanin unit....

  7. The epidermal melanocyte system in individuals of Scandinavian origin, determined by DOPA-staining and TEM

    DEFF Research Database (Denmark)

    Drzewiecki, K T; Piltz-Drzewiecka, J

    1979-01-01

    The quantitative evaluation of DOPA-positive epidermal melanocytes in 16 patients of Scandinavian origin showed both individual and regional differences in the melanocyte count. Our data is in agreement with other published studies. The distribution in the number of melanocytes varies significantly...

  8. Fibronectin-Containing Extracellular Vesicles Protect Melanocytes against Ultraviolet Radiation-Induced Cytotoxicity.

    Science.gov (United States)

    Bin, Bum-Ho; Kim, Dae-Kyum; Kim, Nan-Hyung; Choi, Eun-Jeong; Bhin, Jinhyuk; Kim, Sung Tae; Gho, Yong Song; Lee, Ai-Young; Lee, Tae Ryong; Cho, Eun-Gyung

    2016-05-01

    Skin melanocytes are activated by exposure to UV radiation to secrete melanin-containing melanosomes to protect the skin from UV-induced damage. Despite the continuous renewal of the epidermis, the turnover rate of melanocytes is very slow, and they survive for long periods. However, the mechanisms underlying the survival of melanocytes exposed to UV radiation are not known. Here, we investigated the role of melanocyte-derived extracellular vesicles in melanocyte survival. Network analysis of the melanocyte extracellular vesicle proteome identified the extracellular matrix component fibronectin at a central node, and the release of fibronectin-containing extracellular vesicles was increased after exposure of melanocytes to UVB radiation. Using an anti-fibronectin neutralizing antibody and specific inhibitors of extracellular vesicle secretion, we demonstrated that extracellular vesicles enriched in fibronectin were involved in melanocyte survival after UVB radiation. Furthermore, we observed that in the hyperpigmented lesions of patients with melasma, the extracellular space around melanocytes contained more fibronectin compared with normal skin, suggesting that fibronectin is involved in maintaining melanocytes in pathological conditions. Collectively, our findings suggest that melanocytes secrete fibronectin-containing extracellular vesicles to increase their survival after UVB radiation. These data provide important insight into how constantly stimulated melanocytes can be maintained in pathological conditions such as melasma. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents

    OpenAIRE

    Trolle, Carl; Abrahamsson, Ninnie; König, Niclas; Vasylovska, Svitlana; Kozlova, Elena

    2014-01-01

    The boundary cap is a transient group of neural crest-derived cells located at the presumptive dorsal root transitional zone (DRTZ) when sensory axons enter the spinal cord during development. Later, these cells migrate to dorsal root ganglia and differentiate into subtypes of sensory neurons and glia. After birth when the DRTZ is established, sensory axons are no longer able to enter the spinal cord. Here we explored the fate of mouse bNCSCs implanted to the uninjured DRTZ after dorsal root ...

  10. Amelanotic melanoma in the vicinity of acquired melanocytic nevi and not arising from agminated melanocytic nevi: Masquerading as pyogenic granuloma

    Directory of Open Access Journals (Sweden)

    Angoori Gnaneshwar Rao

    2016-01-01

    Full Text Available 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.

  11. Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

    Science.gov (United States)

    Budi, Erine H.; Patterson, Larissa B.; Parichy, David M.

    2009-01-01

    SUMMARY Vertebrate pigment cells are derived from neural crest cells and are a useful system for studying neural crest-derived traits during post-embryonic development. In zebrafish, neural crest-derived melanophores differentiate during embryogenesis to produce stripes in the early larva. Dramatic changes to the pigment pattern occur subsequently during the larva-to-adult transformation, or metamorphosis. At this time, embryonic melanophores are replaced by newly differentiating metamorphic melanophores that form the adult stripes. Mutants with normal embryonic/early larval pigment patterns but defective adult patterns identify factors required uniquely to establish, maintain, or recruit the latent precursors to metamorphic melanophores. We show that one such mutant, picasso, lacks most metamorphic melanophores and results from mutations in the ErbB gene erbb3b, encoding an EGFR-like receptor tyrosine kinase. To identify critical periods for ErbB activities, we treated fish with pharmacological ErbB inhibitors and also knocked-down erbb3b by morpholino injection. These analyses reveal an embryonic critical period for ErbB signaling in promoting later pigment pattern metamorphosis, despite the normal patterning of embryonic/early larval melanophores. We further demonstrate a peak requirement during neural crest migration that correlates with early defects in neural crest pathfinding and peripheral ganglion formation. Finally, we show that erbb3b activities are both autonomous and non-autonomous to the metamorphic melanophore lineage. These data identify a very early, embryonic, requirement for erbb3b in the development of much later metamorphic melanophores, and suggest complex modes by which ErbB signals promote adult pigment pattern development. PMID:18508863

  12. Human fibroblasts treated with hydrogen peroxide stimulate human melanoblast proliferation and melanocyte differentiation, but inhibit melanocyte proliferation in serum-free co-culture system.

    Science.gov (United States)

    Hirobe, Tomohisa; Shibata, Tatako; Sato, Kiyoshi

    2016-12-01

    Oxidative stress caused by hydrogen peroxide (H2O2) elicits harmful effects on human melanocytes such as DNA damage and cell death. On the contrary, H2O2 is known to possess beneficial effects on melanocytes. However, mechanisms of the beneficial effects of H2O2 on melanocytes have not been fully understood, especially the indirect effects on melanocyte proliferation and differentiation from cells constituting surrounding tissue environment such as fibroblasts. The aim of this study was to clarify whether H2O2-treated human fibroblasts affect the proliferation and differentiation of human melanocytes using serum-free co-culture system. Epidermal melanoblasts and melanocytes were co-cultured with H2O2-treated or control fibroblasts in serum-free culture media. The effects of H2O2-treated fibroblasts were detected by changes in the proliferation and differentiation of melanoblasts/melanocytes. H2O2-treated fibroblasts stimulated the proliferation of melanoblasts and the differentiation, melanogenesis, and dendritogenesis of melanocytes, but inhibited the proliferation of melanocytes. In the melanocytes co-cultured with H2O2-treated fibroblasts, the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and KIT was increased, whereas TYRP2 and microphthalmia-associated transcription factor showed no change. These results suggest that H2O2-treated fibroblasts can produce and release some mitogenic and melanogenic factors toward melanoblasts in addition to some proliferation-inhibiting factors toward melanocytes. The stimulation of melanocyte differentiation seems to be performed through the upregulation of TYR, TYRP1, and KIT. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  13. Candida albicans suppresses transcription of melanogenesis enzymes in cultured melanocytes.

    Science.gov (United States)

    Kippenberger, S; Bernd, A; Menzel, I; Loitsch, S; Ramirez-Bosca, A; Kaufmann, R

    1997-12-01

    Human skin can be colonized by different yeasts that may have an impact on skin pigmentation. In order to study this effect normal human melanocytes were cultured with different yeasts. Reverse transcription polymerase chain reaction (RT-PCR) analysis gives evidence that Candida albicans suppresses the transcription of melanogenesis enzymes.

  14. Effects of Coccoloba uvifera L. on UV-stimulated melanocytes.

    Science.gov (United States)

    Silveira, Jéssica Eleonora Pedroso Sanches; Pereda, Maria del Carmen Velazquez; Eberlin, Samara; Dieamant, Gustavo Campos; Di Stasi, Luiz Claudio

    2008-12-01

    Exposure to ultraviolet (UV) radiation induces generation of reactive oxygen species, production of proinflammatory cytokines and melanocyte-stimulating hormone (MSH) as well as increase in tyrosinase activity. The potential photoprotective effects of Coccoloba uvifera extract (CUE) were evaluated in UV-stimulated melanocytes. Human epidermal melanocytes were used as an in vitro model to evaluate the effects of CUE on the production interleukin-1alpha (IL-1alpha), tumor necrosis factor alpha (TNF-alpha), and alpha-MSH under basal and UV-stimulated conditions. Antioxidant and anti-tyrosinase activities were also evaluated in membrane lipid peroxidation and mushroom tyrosinase assay, respectively. Coccoloba uvifera L. showed antioxidant and anti-tyrosinase activities and also inhibited the production of IL-1alpha, TNF-alpha and alpha-MSH in melanocytes subjected to UV radiation (P<0.01). Moreover, CUE inhibited the activity of tyrosine kinase in cell culture under basal and UV radiation conditions (P<0.001), corroborating the findings of the mushroom tyrosinase assay. This study supports the photoprotective potential of CUE.

  15. Automatic Differential Diagnosis of Melanocytic Skin Tumors Using Ultrasound Data.

    Science.gov (United States)

    Andrėkutė, Kristina; Linkevičiūtė, Gintarė; Raišutis, Renaldas; Valiukevičienė, Skaidra; Makštienė, Jurgita

    2016-12-01

    We describe a novel automatic diagnostic system based on quantitative analysis of ultrasound data for differential diagnosis of melanocytic skin tumors. The proposed method has been tested on 160 ultrasound data sets (80 of malignant melanoma and 80 of benign melanocytic nevi). Acoustical, textural and shape features have been evaluated for each segmented lesion. Using parameters selected according to Mahalanobis distance and linear support vector machine classifier, we are able to differentiate malignant melanoma from benign melanocytic skin tumors with 82.4% accuracy (sensitivity = 85.8%, specificity = 79.6%). The results indicate that high-frequency ultrasound has the potential to be used for differential diagnosis of melanocytic skin tumors and to provide supplementary information on lesion penetration depth. The proposed system can be used as an additional tool for clinical decision support to improve the early-stage detection of malignant melanoma. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  16. Molecular biology of normal melanocytes and melanoma cells.

    Science.gov (United States)

    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. Epidemiologic Study of Melanocytic Disorders in Hamadan in 2002

    Directory of Open Access Journals (Sweden)

    A. Zamanian

    2006-01-01

    Full Text Available Introduction & Objective: Melanocytic nevi are very frequent and there is a relationship between these nevi and malignant melanoma. So we need to know the prevalence and kinds of these nevi in our country. The aim of this study was to clarify the prevalence and kinds of melanocytic nevi in rural areas of Hamadan in the west of Iran.Materials & Methods: A cluster random sampling was followed. The survey included 9450 rural inhabitant of all ages and both sexes from representative of 33 villages of Hamadan. The data were collected through personal interview and examination at homes in 2002.Results: This study showed melanocytic nevi in 88% of population, lentigo in 50%, freckling in 12.7% and café-au-lait spots in 6.7% of studied subjects. The range of age in the patients was 1-75 years with the mean of 35.7 year. Conclusion: Due to relation of melanocytic nevi with malignant melanoma avoiding sun exposure and health education are important , especially for high risk people.

  18. alpha-Melanocyte-stimulating-hormone precursors in the pig pituitary

    DEFF Research Database (Denmark)

    Fenger, M

    1986-01-01

    The occurrence of intermediates from the processing of ACTH-(1-39) [adrenocorticotropic hormone-(1-39)] to alpha-melanocyte-stimulating hormone was investigated in normal pig pituitaries by the use of sensitive and specific radioimmunoassays for ACTH-(1-13), ACTH-(1-14), ACTH-(1-13)-NH2 and ACTH-(1...

  19. The mechanism of melanocyte dendrite formation: the impact of differentiating keratinocytes.

    Science.gov (United States)

    Kippenberger, S; Bernd, A; Bereiter-Hahn, J; Ramirez-Bosca, A; Kaufmann, R

    1998-02-01

    In human epidermis one dendritic melanocyte interacts with about 36 keratinocytes and supplies them with melanin. In contrast to the vivo situation melanocytes in culture are far less dendritic. In the present study different culture systems were tested in order to observe the mechanism of melanocyte dendrite formation. In particular, we focused on the role of keratinocytes in this process. Time lapse studies revealed that only differentiated keratinocytes enhance melanocyte dendricity. Differentiated keratinocytes form connected cell sheets, which attach to part of the melanocyte plasma membrane. By contraction and retraction of keratinocyte units, new dendrites were drawn out from the melanocytes. Melanocytes remain passive during this process, which is indicated by the observation that sometimes extended dendrites could not withstand the tension and shear.

  20. Optimal management of common acquired melanocytic nevi (moles: current perspectives

    Directory of Open Access Journals (Sweden)

    Sardana K

    2014-03-01

    Full Text Available Kabir Sardana, Payal Chakravarty, Khushbu Goel Department of Dermatology and STD, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, Delhi, India Abstract: Although common acquired melanocytic nevi are largely benign, they are probably one of the most common indications for cosmetic surgery encountered by dermatologists. With recent advances, noninvasive tools can largely determine the potential for malignancy, although they cannot supplant histology. Although surgical shave excision with its myriad modifications has been in vogue for decades, the lack of an adequate histological sample, the largely blind nature of the procedure, and the possibility of recurrence are persisting issues. Pigment-specific lasers were initially used in the Q-switched mode, which was based on the thermal relaxation time of the melanocyte (size 7 µm; 1 µsec, which is not the primary target in melanocytic nevus. The cluster of nevus cells (100 µm probably lends itself to treatment with a millisecond laser rather than a nanosecond laser. Thus, normal mode pigment-specific lasers and pulsed ablative lasers (CO2/erbium [Er]:yttrium aluminum garnet [YAG] are more suited to treat acquired melanocytic nevi. The complexities of treating this disorder can be overcome by following a structured approach by using lasers that achieve the appropriate depth to treat the three subtypes of nevi: junctional, compound, and dermal. Thus, junctional nevi respond to Q-switched/normal mode pigment lasers, where for the compound and dermal nevi, pulsed ablative laser (CO2/Er:YAG may be needed. If surgical excision is employed, a wide margin and proper depth must be ensured, which is skill dependent. A lifelong follow-up for recurrence and melanoma is warranted in predisposed individuals, although melanoma is decidedly uncommon in most acquired melanocytic nevi, even though histological markers may be seen on evaluation. Keywords: lasers, surgery, nevus, melanoma

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

  3. Asymmetry and irregularity border as discrimination factor between melanocytic lesions

    Science.gov (United States)

    Sbrissa, David; Pratavieira, Sebastião.; Salvio, Ana Gabriela; Kurachi, Cristina; Bagnato, Vanderlei Salvadori; Costa, Luciano Da Fontoura; Travieso, Gonzalo

    2015-06-01

    Image processing tools have been widely used in systems supporting medical diagnosis. The use of mobile devices for the diagnosis of melanoma can assist doctors and improve their diagnosis of a melanocytic lesion. This study proposes a method of image analysis for melanoma discrimination from other types of melanocytic lesions, such as regular and atypical nevi. The process is based on extracting features related with asymmetry and border irregularity. It were collected 104 images, from medical database of two years. The images were obtained with standard digital cameras without lighting and scale control. Metrics relating to the characteristics of shape, asymmetry and curvature of the contour were extracted from segmented images. Linear Discriminant Analysis was performed for dimensionality reduction and data visualization. Segmentation results showed good efficiency in the process, with approximately 88:5% accuracy. Validation results presents sensibility and specificity 85% and 70% for melanoma detection, respectively.

  4. Melanocytes in vitro: how do they undergo mitosis?

    Science.gov (United States)

    Kippenberger, S; Bernd, A; Bereiter-Hahn, J; Ramirez-Bosca, A; Kaufmann, R

    1997-01-01

    Human melanocytes of the adult skin are slow-cycling cells with a highly dendritic morphology. Nevertheless in vitro proliferation can be achieved using adequate stimulators. Time lapse studies revealed the morphologic changes during melanocyte mitosis: dendrites are drawn back into the cell body, the cell becomes spherical and detaches from the support. Cell division takes place while the cell is suspended. Consecutively the two cells reattach to the support and form new dendrites. About 1% cells per culture are detached from the support and ca. 70% of these cells are viable and putative within mitosis. By every medium change mitotic cells become withdrawn supporting selection of G0-cells, Therefore we recommend centrifugation of exhausted medium in order to add mitotic cells back to the culture.

  5. Melanocytic lesions and dermoscopy in childhood: diagnosis, therapy and foloving

    Directory of Open Access Journals (Sweden)

    Irdina Drljević

    2016-01-01

    Full Text Available Early detection of malignant skin tumors, particularly malignant melanoma in childhood, which is most malignant of all, is of utmost importance for the prevention, treatment and outcome of the disease. If an observed lesion is characterized as melanocytic, the second step can be performed in the so called “two-step dermoscopy” algorithm, which includes the differentiation between a benign pigmented lesion (nevus and a malignant lesion (melanoma. Gigantic nevi, as a subgroup of large congenital nevi, may pose a huge psycho-social burden for children and their parents, primarily because of potential complications. Melanoma can develop in healthy children but also in those with identified genetic disorder or immune diseases. Dermoscopy, at the same time, has reduced the number of unnecessary biopsies and excisions of benign melanocytic lesions in childhood.

  6. [The effects of aloesin and arbutin on cultured melanocytes in a synergetic method].

    Science.gov (United States)

    Yang, Zhuang-qun; Wang, Zheng-hui; Tu, Jun-bo; Li, Peng; Hu, Xiao-yi

    2004-09-01

    To study the effects of aloesin and arbutin on normal cultured human melanocytes in synergetic method. Building up the system of cultured human melanocytes. The cultured melanocytes in vitro were treated with the mixture of aloesin and arbutin. The cell viability and tyrosinase activity was measured by MTT assay, utilization of L-Dopa as the substrate respectively; melanin content was measured by image analysis system. Furthermore, the effects of the mixture on melanocytes were compared with that of aloesin and arbutin. The mixture of aloesin and arbutin showed an inhibition on tyrosinase activity of human melanocytes and reduced significantly melanin content. Between the mixture and the single use of aloesin or arbutin, there is significant difference (P arbutin can significantly inhibit the tyrosinase activity and melanogenesis of cultured human melanocytes. It showed the effects of aloesin and arbutin in a synergistic manner. It is worth to give farther study later.

  7. Histopathological spectrum of benign melanocytic nevi – our experience in a tertiary care centre

    Directory of Open Access Journals (Sweden)

    Shivanand Gundalli

    2016-01-01

    Full Text Available Introduction: Melanocytic lesions show great morphological diversity in their architecture and the cytomorphological appearance of their composite cells. Histological assessment of these melanocytic nevi constitutes a substantial proportion of a dermatopathologist’s daily workload. The aim of our study was to observe the histological spectrum and types of benign melanocytic nevi and melanoma and also to identify the unusal/atypical histological features in these melanocytic nevi. Results: Intradermal nevus was the most common benign melanocytic nevi comprising 11 (62.5% out of the total 13 cases. In ten cases lesions were located on head and neck region. Maximum number (60% of cases were seen between 30-40 years of age. Conclusion: Melanocytic lesions of the skin are of notorious challengefor the pathologist. Face was the most common site and intradermal nevus was the most common lesion in our study.

  8. Apoptosis, Fas and Fas-ligand expression in melanocytic tumors.

    Science.gov (United States)

    Sprecher, E; Bergman, R; Meilick, A; Kerner, H; Manov, L; Reiter, I; Shafer, Y; Maor, G; Friedman-Birnbaum, R

    1999-02-01

    Impaired regulation of apoptosis is known to be associated with the development of various forms of cancer. Fas binding to its ligand, Fas ligand (Fas-L), has been shown to trigger apoptosis in various cell types. Fas-L is expressed by melanoma cells and has been suggested to play a role in melanoma escape from immune surveillance. In the present study, we assessed apoptotic activity and examined Fas and Fas-L expression in malignant melanomas, Spitz nevi and ordinary melanocytic nevi. We evaluated apoptotic activity using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Apoptotic activity was found to be minimal in melanomas and moderate in Spitz nevi. In contrast, common nevi demonstrated significant levels of apoptosis in the deep parts of the tumor. Fas was found to be expressed by all Spitz nevi, most melanocytic nevi and approximately half of the malignant melanoma specimens. Fas expression was also significantly more pronounced in Spitz nevus cells as compared with the two other tumors. The anti-Fas-L antibody was found to stain all three melanocytic tumors. Staining was shown to be stronger and more frequent in melanoma cells as compared to the nevus cells. Using the Spearman test, no significant correlation between Fas-L expression in melanoma cells and apoptosis in MM-infiltrating mononuclear cells was found, suggesting that Fas-L expression in melanoma cells may not be instrumental in their ability to escape immune mechanisms of defense. In contrast, increased levels of apoptosis in the deep parts of melanocytic nevi may reflect and possibly contribute to their benign nature.

  9. [Mixed breast carcinoma with melanocytic differentiation in a man].

    Science.gov (United States)

    Kallel, Rim; Bahri, Ibticem; Abid, Najla; Feki, Jihène; Mellouli, Manel; Ayadi, Lobna; Boudawara, Tahya

    2014-04-01

    Male breast cancer is rare; the lobular type is exceptional. Only one case of mixed ductal and lobular type is reported in the literature. This is the first report on a mixed ductal and lobular carcinoma with melanocytic differentiation in a man. The aim of our study is to describe the clinicopathological characteristics of this rare type of breast tumor and to discuss its histogenesis. A 63-year-old man presented with cutaneous ulceration of the left breast. Ultrasound of the breast revealed a solid hypoechoic lesion, 13 mm in diameter. Microscopic evaluation of the biopsy showed an invasive ductal carcinoma. The patient received three cycles of chemotherapy and lost of view. Then consulted for increasing of the tumor size reaching 3 cm. Histological examination of the mastectomy specimen showed a mixed ductal and lobular carcinoma with melanocytic differentiation, confirmed by the immunohistochemical study. The patient received adjuvant chemotherapy and the evolution was favorable with an average follow-up of 9 months. Breast carcinoma with melanocytic differentiation is extremely rare; only seven cases are reported in the literature and all occurs in females. Its histogenesis is unclear; tumors exhibiting this combination of cell types may occur as collision or composite tumors. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Epithelioid melanocytic nevus with tubule and pseudoacini formation.

    Science.gov (United States)

    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. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Melanoma and melanocytic nevi in decorative tattoos: three case reports.

    Science.gov (United States)

    Varga, Erika; Korom, Irma; Varga, János; Kohán, József; Kemény, Lajos; Oláh, Judit

    2011-12-01

    In response to the demands of style and fashion, the number of decorative tattoos has been increasing worldwide. This has been paralleled by a rising incidence of melanocytic proliferations, including melanoma. The coincidence of various dermatological diseases and skin tumors with tattoos has been documented with some frequency, but reports of melanoma associated with tattoos are exceedingly rare. To date, only 13 cases have been documented in the English language literature. The possibility of an association between melanocytic proliferations and tattoos remains an area for further study. This report presents two cases of melanocytic nevi and one of melanoma occurring in association with a decorative tattoos. At present, the pathogenesis of melanoma developing in a tattoo is unknown. Mere coincidence cannot be ruled out. However, trauma, ultraviolet light exposure, a photoallergic effect, or an inflammatory reaction may promote malignant transformation. Clinicians and histopathologists should be aware of the clinical and pathological features if they are to make a correct diagnosis. Copyright © 2011 John Wiley & Sons A/S.

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

    Directory of Open Access Journals (Sweden)

    Saioa López

    2015-12-01

    Full Text Available 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.

  13. Melanocyte Colonization and Pigmentation of Breast Carcinoma: Pathological and Clinical Aspects

    Directory of Open Access Journals (Sweden)

    Marco Mele

    2012-01-01

    Full Text Available Introduction. Melanocyte colonization of breast carcinoma by nonneoplastic melanocytes of epidermal origin is a rare and serious condition first described in 1977. We report on the exceptional clinical and pathological features of this migration phenomenon in a 74-year-old patient. Discussion. The pathogenesis by which melanocyte migration takes place is not known, but a breached basement membrane is considered essential. Conclusion. Histological examination and additional staining of skin are essential to differentiate breast cancer melanosis from malignant melanoma.

  14. Melanocytic Nevi and the Genetic and Epigenetic Control of Oncogene-Induced Senescence.

    Science.gov (United States)

    Huang, Jennifer M; Chikeka, Ijeuru; Hornyak, Thomas J

    2017-01-01

    Melanocytic nevi represent benign clonal proliferations of the melanocytes in the skin that usually remain stable in size and behavior or disappear during life. Infrequently, melanocytic nevi undergo malignant transformation to melanoma. Understanding molecular and cellular mechanisms underlying oncogene-induced senescence should help identify pathways underlying melanoma development, leading to the development of new strategies for melanoma prevention and early detection. Published by Elsevier Inc.

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

    Directory of Open Access Journals (Sweden)

    Paula Reemann

    Full Text Available 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.

  16. Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity.

    Science.gov (United States)

    Mahanty, Sarmistha; Kawali, Ankush A; Dakappa, Shruthi Shirur; Mahendradas, Padmamalini; Kurian, Mathew; Kharbanda, Varun; Shetty, Rohit; Setty, Subba Rao Gangi

    2017-09-01

    Antibiotics such as fluoroquinolones (FQLs) are commonly used to treat ocular infections but are also known to cause dermal melanocyte toxicity. The release of dispersed pigments from the iris into the aqueous humor has been considered a possible ocular side effect of the systemic administration of FQLs such as Moxifloxacin, and this condition is known as bilateral acute iris transillumination (BAIT). Bilateral acute depigmentation of iris (BADI) is a similar condition, with iris pigment released into the aqueous, but it has not been reported as a side effect of FQL. Iris pigments are synthesized by the melanogenic enzyme tyrosinase (TYR) and can be detected but not quantified by using slit-lamp biomicroscopy. The correlation between dispersed pigments in the aqueous and the extent of melanocyte toxicity due to topical antibiotics in vivo is not well studied. Here, we aimed to study the effect of topical FQLs on iris tissue, the pigment release in the aqueous humor and the development of clinically evident iris atrophic changes. We evaluated this process by measuring the activity of TYR in the aqueous humor of 82 healthy eyes undergoing cataract surgery following topical application of FQLs such as Moxifloxacin (27 eyes, preservative-free) or Ciprofloxacin (29 eyes, with preservative) or the application of non-FQL Tobramycin (26 eyes, with preservative) as a control. In addition, the patients were questioned and examined for ocular side effects in pre- and post-operative periods. Our data showed a significantly higher mean TYR activity in the aqueous humor of Ciprofloxacin-treated eyes compared to Moxifloxacin- (preservative free, p humor from both Ciprofloxacin- and Moxifloxacin-treated eyes showed the presence of soluble TYR enzyme, thus reflecting its toxicity to iris melanocytes and corresponding to its activity in the aqueous humor. Intriguingly, none of these patients developed any clinically appreciable ocular side effects characteristic of BAIT or BADI

  17. The in vivo developmental potential of porcine skin-derived progenitors and neural stem cells.

    Science.gov (United States)

    Zhao, Ming-Tao; Yang, Xiaoyu; Lee, Kiho; Mao, Jiude; Teson, Jennifer M; Whitworth, Kristin M; Samuel, Melissa S; Spate, Lee D; Murphy, Clifton N; Prather, Randall S

    2012-09-20

    Multipotent skin-derived progenitors (SKPs) can be traced back to embryonic neural crest cells and are able to differentiate into both neural and mesodermal progeny in vitro. Neural stem cells (NSCs) are capable of self-renewing and can contribute to neuron and glia in the nervous system. Recently, we derived porcine SKPs and NSCs from the same enhanced green fluorescent protein (EGFP) transgenic fetuses and demonstrated that SKPs could contribute to neural and mesodermal lineages in vivo. However, it remains unclear whether porcine SKPs and NSCs can generate ectoderm and mesoderm lineages or other germ layers in vivo. Embryonic chimeras are a well-established tool for investigating cell lineage determination and cell potency through normal embryonic development. Thus, the purpose of this study was to investigate the in vivo developmental potential of porcine SKPs and fetal brain-derived NSCs by chimera production. Porcine SKPs, NSCs, and fibroblasts were injected into precompact in vitro fertilized embryos (IVF) and then transferred into corresponding surrogates 24 h postinjection. We found that porcine SKPs could incorporate into the early embryos and contribute to various somatic tissues of the 3 germ layers in postnatal chimera, and especially have an endodermal potency. However, this developmental potential is compromised when they differentiate into fibroblasts. In addition, porcine NSCs fail to incorporate into host embryos and contribute to chimeric piglets. Therefore, neural crest-derived SKPs may represent a more primitive state than their counterpart neural stem cells in terms of their contributions to multiple cell lineages.

  18. Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi.

    Science.gov (United States)

    Husain, Ehab A; Mein, Charles; Pozo, Lucia; Blanes, Alfredo; Diaz-Cano, Salvador J

    2011-04-01

    Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

  19. Neural crest cells: from developmental biology to clinical interventions.

    Science.gov (United States)

    Noisa, Parinya; Raivio, Taneli

    2014-09-01

    Neural crest cells are multipotent cells, which are specified in embryonic ectoderm in the border of neural plate and epiderm during early development by interconnection of extrinsic stimuli and intrinsic factors. Neural crest cells are capable of differentiating into various somatic cell types, including melanocytes, craniofacial cartilage and bone, smooth muscle, and peripheral nervous cells, which supports their promise for cell therapy. In this work, we provide a comprehensive review of wide aspects of neural crest cells from their developmental biology to applicability in medical research. We provide a simplified model of neural crest cell development and highlight the key external stimuli and intrinsic regulators that determine the neural crest cell fate. Defects of neural crest cell development leading to several human disorders are also mentioned, with the emphasis of using human induced pluripotent stem cells to model neurocristopathic syndromes. © 2014 Wiley Periodicals, Inc.

  20. Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention.

    Science.gov (United States)

    Heuckeroth, Robert O; Schäfer, Karl-Herbert

    2016-09-15

    Intestinal function is primarily controlled by an intrinsic nervous system of the bowel called the enteric nervous system (ENS). The cells of the ENS are neural crest derivatives that migrate into and through the bowel during early stages of organogenesis before differentiating into a wide variety of neurons and glia. Although genetic factors critically underlie ENS development, it is now clear that many non-genetic factors may influence the number of enteric neurons, types of enteric neurons, and ratio of neurons to glia. These non-genetic influences include dietary nutrients and medicines that may impact ENS structure and function before or after birth. This review summarizes current data about gene-environment interactions that affect ENS development and suggests that these factors may contribute to human intestinal motility disorders like Hirschsprung disease or irritable bowel syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention

    Science.gov (United States)

    Heuckeroth, Robert O.; Schäfer, Karl-Herbert

    2016-01-01

    Intestinal function is primarily controlled by an intrinsic nervous system of the bowel called the enteric nervous system (ENS). The cells of the ENS are neural crest derivatives that migrate into and through the bowel during early stages of organogenesis before differentiating into a wide variety of neurons and glia. Although genetic factors critically underlie ENS development, it is now clear that many non-genetic factors may influence the number of enteric neurons, types of enteric neurons, and ratio of neurons to glia. These non-genetic influences include dietary nutrients and medicines that may impact ENS structure and function before or after birth. This review summarizes current data about gene-environment interactions that affect ENS development and suggests that these factors may contribute to human intestinal motility disorders like Hirschsprung disease or irritable bowel syndrome. PMID:26997034

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

    Science.gov (United States)

    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 skin, although as with all histological features in melanocytic pathology, it requires interpretation within a multifactorial assessment cognizant of potential diagnostic pitfalls.

  3. Trends in Regenerative Medicine: Repigmentation in Vitiligo Through Melanocyte Stem Cell Mobilization.

    Science.gov (United States)

    Birlea, Stanca A; Costin, Gertrude-E; Roop, Dennis R; Norris, David A

    2017-07-01

    Vitiligo is the most frequent human pigmentary disorder, characterized by progressive autoimmune destruction of mature epidermal melanocytes. Of the current treatments offering partial and temporary relief, ultraviolet (UV) light is the most effective, coordinating an intricate network of keratinocyte and melanocyte factors that control numerous cellular and molecular signaling pathways. This UV-activated process is a classic example of regenerative medicine, inducing functional melanocyte stem cell populations in the hair follicle to divide, migrate, and differentiate into mature melanocytes that regenerate the epidermis through a complex process involving melanocytes and other cell lineages in the skin. Using an in-depth correlative analysis of multiple experimental and clinical data sets, we generated a modern molecular research platform that can be used as a working model for further research of vitiligo repigmentation. Our analysis emphasizes the active participation of defined molecular pathways that regulate the balance between stemness and differentiation states of melanocytes and keratinocytes: p53 and its downstream effectors controlling melanogenesis; Wnt/β-catenin with proliferative, migratory, and differentiation roles in different pigmentation systems; integrins, cadherins, tetraspanins, and metalloproteinases, with promigratory effects on melanocytes; TGF-β and its effector PAX3, which control differentiation. Our long-term goal is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and durable repigmentation. © 2016 Wiley Periodicals, Inc.

  4. Giant congenital melanocytic nevus with developmental dysplasia of bilateral hip: A rare association

    Directory of Open Access Journals (Sweden)

    Sutsungkokla Imchen

    2013-01-01

    Full Text Available Giant congenital melanocytic nevi are rare congenital disfiguring benign neoplasms with a risk of transformation to malignant melanoma. They often present with various extra-cutaneous features. Here, we describe a case of giant melanocytic nevus with developmental dysplasia of bilateral hip, a novel association.

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

    Science.gov (United States)

    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.

  6. A review and update on melanocyte stimulating hormone therapy: afamelanotide.

    Science.gov (United States)

    Fabrikant, Jordan; Touloei, Khasha; Brown, Stuart M

    2013-07-01

    Afamelanotide ([Nle4-D-Phe7]-alpha-MSH) is an analog of alpha-melanocyte stimulating hormone given as a subcutaneous injection. Afamelanotide is currently undergoing phase II and III trials in Europe and the US for skin diseases including vitiligo, erythropoietic protoporphyria, polymorphic light eruption and prevention of actinic keratoses in organ transplant recipients. Unregulated analogs and chemicals are being sold online ahead of formal approval. A number of counterfeit chemicals, 'Melanotans' are being sold for tanning purposes. Currently, afamelanotide is already on the market in Italy and Switzerland for patients with erythropoietic protoporphyria. This paper will review the current literature on this promising compound.

  7. Sphere-Derived Multipotent Progenitor Cells Obtained From Human Oral Mucosa Are Enriched in Neural Crest Cells.

    Science.gov (United States)

    Abe, Shigehiro; Yamaguchi, Satoshi; Sato, Yutaka; Harada, Kiyoshi

    2016-01-01

    : Although isolation of oral mucosal stromal stem cells has been previously reported, complex isolation methods are not suitable for clinical application. The neurosphere culture technique is a convenient method for the isolation of neural stem cells and neural crest stem cells (NCSCs); neurosphere generation is a phenotype of NCSCs. However, the molecular details underlying the isolation and characterization of human oral mucosa stromal cells (OMSCs) by neurosphere culture are not understood. The purpose of the present study was to isolate NCSCs from oral mucosa using the neurosphere technique and to establish effective in vivo bone tissue regeneration methods. Human OMSCs were isolated from excised human oral mucosa; these cells formed spheres in neurosphere culture conditions. Oral mucosa sphere-forming cells (OMSFCs) were characterized by biological analyses of stem cells. Additionally, composites of OMSFCs and multiporous polylactic acid scaffolds were implanted subcutaneously into immunocompromised mice. OMSFCs had the capacity for self-renewal and expressed neural crest-related markers (e.g., nestin, CD44, slug, snail, and MSX1). Furthermore, upregulated expression of neural crest-related genes (EDNRA, Hes1, and Sox9) was observed in OMSFCs, which are thought to contain an enriched population of neural crest-derived cells. The expression pattern of α2-integrin (CD49b) in OMSFCs also differed from that in OMSCs. Finally, OMSFCs were capable of differentiating into neural crest lineages in vitro and generating ectopic bone tissues even in the subcutaneous region. The results of the present study suggest that OMSFCs are an ideal source of cells for the neural crest lineage and hard tissue regeneration. The sphere culture technique is a convenient method for isolating stem cells. However, the isolation and characterization of human oral mucosa stromal cells (OMSCs) using the sphere culture system are not fully understood. The present study describes the

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

    Science.gov (United States)

    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.

  9. Diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions.

    Science.gov (United States)

    Rosendahl, Cliff; Tschandl, Philipp; Cameron, Alan; Kittler, Harald

    2011-06-01

    It is unknown whether dermatoscopy improves the diagnostic accuracy for all types of pigmented skin lesions or only for those that are melanocytic. We sought to assess if the addition of dermatoscopy to clinical examination with the unaided eye improves diagnostic accuracy for all types of pigmented lesions. We analyzed 463 consecutively excised pigmented skin lesions collected during a period of 30 months in a primary care skin cancer practice in Queensland, Australia. Of 463 lesions, 217 (46.9%) were nonmelanocytic. Overall 30% (n = 138) were malignant including 29 melanomas, 72 basal cell carcinomas, and 37 squamous cell carcinomas. The diagnostic accuracy for malignant neoplasms measured as area under receiver operating characteristic curves was 0.89 with dermatoscopy and 0.83 without it (P lesions than for melanocytic lesions. A short algorithm based on pattern analysis reached a sensitivity of 98.6% for basal cell carcinoma, 86.5% for pigmented squamous cell carcinoma, and 79.3% for melanoma. Among benign conditions, the highest false-positive rate (90.5%) was observed for lichen planus-like keratosis. Estimates of diagnostic accuracy are influenced by verification bias. Dermatoscopy improves the diagnostic accuracy for nonmelanocytic lesions. A simple algorithm based on pattern analysis is suitable for the detection of melanoma and nonmelanoma skin cancer. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  10. Combined melanocytic nevi: histologic variants and melanoma mimics.

    Science.gov (United States)

    Baran, Johanna L; Duncan, Lyn M

    2011-10-01

    Combined melanocytic nevi are composed of 2 or more distinct populations of nevomelanocytes. Most commonly used to describe the combination of blue nevi with common nevi, it may also be applied to other combinations of benign melanocytic proliferations, including Spitz nevi and nevi with deep dermal pigmented nevomelanocytes. We report the incidence and distribution of these tumors at the Massachusetts General Hospital over the past decade and review guidelines for diagnostic criteria and nomenclature. Between 2000 and 2010 we identified 511 cases of combined nevi, represented by 4 histologically distinct diagnostic categories: (1) blue nevus, (2) nevi with deep dermal pigmented nevomelanocytes (plexiform/deep penetrating, inverted type A/clonal), (3) Spitz or pigmented spindled cell nevus, combined with another type of nevus (usually common or dysplastic), and (4) other combinations including 2 or more nevus types. Nearly one fifth of these tumors displayed atypical features; atypia was observed more often in combined nevi with Spitz or deep pigmented elements (26 of 55, 47%, and 25 of 98, 26%, respectively) than in combined common and blue nevi (37 of 336, 11%). Clinical follow-up data were available for 83% of the patients with atypical combined nevi; none developed recurrence or metastasis with a mean follow-up of over 4 years.

  11. Protective Effect of HemoHIM on Epidermal Melanocytes in Ultraviolet-B irradiated Mice

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hae June [Korea Institute of Radiological and Medical Science, Seoul (Korea, Republic of); Kim, Jong Choon; Moon, Chang Jong; Kim, Sung Ho [Chonnam National University, Gwangju (Korea, Republic of); Jung, U Hee; Park, Hae Ran; Jo, Sung Kee [Jeongeup Campus of Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of); Jang, Jong Sik; Kim, Tae Hwan [Kyungpook National University, Daegu (Korea, Republic of)

    2011-06-15

    We induced the activation of melanocytes in the epidermis of C57BL/6 mice by ultraviolet-B (UV-B) irradiation, and observed the effect of an herbal preparation (HemoHIM, HH) on the formation, and decrease of UV-B-induced epidermal melanocytes. C57BL/6 mice were irradiated by UV-B 80 mJ:cm{sup -2} (0.5 mW:sec{sup -1}) daily for 7 days, and HH was intraperitoneally, orally or topically applied pre- or post-irradiation. For the estimation of change of epidermal melanocytes, light microscopic observation with dihydroxyphenylalanine (DOPA) stain was performed. Split epidermal sheets prepared from the ear of untreated mice exhibited 13∼15 melanocytes:mm{sup -2}, and one week after UV irradiation, the applied areas showed an increased number of strongly DOPA-positive melanocytes with stout dendrites. But intraperitoneal, oral or topical treatment with HH before each irradiation interrupted UV-B-induced pigmentation and resulted in a marked reduction in the number of epidermal melanocytes as compared to the number found in UV-B-irradiated, untreated control skin. The number and size of DOPA-positive epidermal melanocytes were also significantly decreased in intraperitoneally injected or topically applicated group after irradiation with HH at 3rd and 6th weeks after irradiation. The present study suggests the HH as inhibitor of UV-B-induced pigmentation, and depigmenting agent.

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

    Science.gov (United States)

    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.

  13. PREFERENTIAL SECRETION OF INDUCIBLE HSP70 BY VITILIGO MELANOCYTES UNDER STRESS

    Science.gov (United States)

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

    2014-01-01

    SUMMARY 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. PMID:24354861

  14. CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma.

    Science.gov (United States)

    McNeal, Andrew S; Liu, Kevin; Nakhate, Vihang; Natale, Christopher A; Duperret, Elizabeth K; Capell, Brian C; Dentchev, Tzvete; Berger, Shelley L; Herlyn, Meenhard; Seykora, John T; Ridky, Todd W

    2015-10-01

    Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E)-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Furthermore, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma. Although BRAF(V600E) mutations cause melanocytes to initially proliferate into benign moles, mechanisms responsible for their eventual growth arrest are unknown. Using melanocytes from human moles, we show that BRAF activation leads to a CDKN2B induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma. ©2015 American Association for Cancer Research.

  15. YY1 regulates melanocyte development and function by cooperating with MITF.

    Directory of Open Access Journals (Sweden)

    Juying Li

    Full Text Available Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP-seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1 gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF-a general mechanism which may confer tissue-specific gene expression in multiple lineages.

  16. alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes.

    Science.gov (United States)

    Song, Xiuzu; Mosby, Nicole; Yang, Jennifer; Xu, Aie; Abdel-Malek, Zalfa; Kadekaro, Ana Luisa

    2009-12-01

    Exposure of cultured human melanocytes to ultraviolet radiation (UV) results in DNA damage. In melanoma, UV-signature mutations resulting from unrepaired photoproducts are rare, suggesting the possible involvement of oxidative DNA damage in melanocyte malignant transformation. Here we present data demonstrating immediate dose-dependent generation of hydrogen peroxide in UV-irradiated melanocytes, which correlated directly with a decrease in catalase activity. Pretreatment of melanocytes with alpha-melanocortin (alpha-MSH) reduced the UV-induced generation of 7,8-dihydro-8-oxyguanine (8-oxodG), a major form of oxidative DNA damage. Pretreatment with alpha-MSH also increased the protein levels of catalase and ferritin. The effect of alpha-MSH on 8-oxodG induction was mediated by activation of the melanocortin 1 receptor (MC1R), as it was absent in melanocytes expressing loss-of-function MC1R, and blocked by concomitant treatment with an analog of agouti signaling protein (ASIP), ASIP-YY. This study provides unequivocal evidence for induction of oxidative DNA damage by UV in human melanocytes and reduction of this damage by alpha-MSH. Our data unravel some mechanisms by which alpha-MSH protects melanocytes from oxidative DNA damage, which partially explain the strong association of loss-of-function MC1R with melanoma.

  17. Differentiating neurotized melanocytic nevi from neurofibromas using Melan-A (MART-1) immunohistochemical stain.

    Science.gov (United States)

    Chen, Yumei; Klonowski, Paul W; Lind, Anne C; Lu, Dongsi

    2012-07-01

    Neurotized melanocytic nevi and neurofibromas are common, benign cutaneous neoplasms. Usually they are histologically distinct from each other; however, neurotized melanocytic nevi and neurofibromas can be clinically and histologically similar. To determine whether Melan-A (MART-1) immunohistochemical stain is sufficient to differentiate neurotized melanocytic nevi from neurofibromas. Forty-nine consecutive specimens of melanocytic nevi with neurotization and 49 specimens of neurofibromas were selected. We used antibodies against Melan-A, S100, and neurofilament protein. All of the melanocytic nevi showed Melan-A staining within the neurotized areas, with most of the areas staining strongly positive, whereas all the neurofibromas were completely absent of Melan-A stain. All of the nevi, including the neurotized areas, stained strongly and diffusely for S100, whereas all the neurofibromas showed a distinctive, sharp, wavy pattern of S100 staining. Neurofilament protein showed scattered staining of both melanocytic nevi and neurofibromas. Our data indicate that Melan-A immunohistochemical staining is helpful in differentiating neurotized melanocytic nevi from neurofibromas when distinction on histomorphology alone is difficult.

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

    Energy Technology Data Exchange (ETDEWEB)

    Medic, Sandra [School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA (Australia); Rizos, Helen [Westmead Institute for Cancer Research and Melanoma Institute of Australia, University of Sydney at Westmead Millennium Institute, Westmead, NSW (Australia); Ziman, Mel, E-mail: m.ziman@ecu.edu.au [School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA (Australia); School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA (Australia)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chantarawong, Wipa [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Inter Departmental Multidisciplinary Graduate Program in Bioscience, Faculty of Science, Kasetsart University, Bangkok (Thailand); Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Pradermwong, Kantimanee [Department of Zoology, Faculty of Science, Kasetsart University, Bangkok (Thailand); Shibahara, Shigeki, E-mail: shibahar@med.tohoku.ac.jp [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan)

    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.

  20. Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes

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    Tianzhi Chen

    2016-09-01

    Full Text Available 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

  1. alpha-Melanocyte-stimulating-hormone precursors in the pig pituitary

    DEFF Research Database (Denmark)

    Fenger, M

    1986-01-01

    The occurrence of intermediates from the processing of ACTH-(1-39) [adrenocorticotropic hormone-(1-39)] to alpha-melanocyte-stimulating hormone was investigated in normal pig pituitaries by the use of sensitive and specific radioimmunoassays for ACTH-(1-13), ACTH-(1-14), ACTH-(1-13)-NH2 and ACTH-(1......-39). Fractionation by reverse-phase h.p.l.c. revealed ACTH(1-17) and their acetylated analogues. The intermediate lobe contained NO-diacetyl-ACTH-(1-13)-NH2, N-acetyl-ACTH-(1-13)-NH2 and ACTH-(1-13)-NH2. In addition, the corresponding ACTH-(1-14) peptides (the glycine-extended precursor of the amidated peptides...

  2. NEUROFIBROMATOSIS TYPE 1 OR GIANT MELANOCYTIC NEVUS: PROBLEMS OF DIAGNOSTIC

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    A. S. Ol’shanskaya

    2017-01-01

    Full Text Available Neurofibromatosis type 1 (NF-1 is a hereditary disease mainly affecting skin and peripheral nervous system. Individual signs of cutaneous manifestations of NF-1 can imitate or be combined with other neurocutaneous syndromes. At present on the outpatient phase is not always possible to conduct a detailed examination of the patients with NF-1 and to determine the indications for modern diagnostic examination in a specialized hospital. It can be important to verify the diagnosis. The authors presented short review of russian and foreign literature and clinical case of the patient with a specific lesion of the skin against the background of congenital giant melanocytic nevus. Problems of differential diagnosis of NF-1 and congenital giant pigmented nevus were analyzed.

  3. Mast cell - Melanocyte axis mediates pathogenesis in Oral Lichen Planus

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    Komali Rajkumar

    2014-01-01

    Full Text Available Background: Oral Lichen Planus (OLP is a cell-mediated inflammatory condition of the oral cavity with propensity for malignant transformation. Often classified as an autoimmune disorder, the pathogenesis of the lesion is still under debate. The presence of mast cells (MCs and melanocytes (MNs has been identified as an integral part of the cellular reaction in all stages of the disorder. Aims: The present study aims to qualify, localize and quantify MCs and MNs in OLP and normal oral mucosa (NOM using special stains and image analysis software. Computations and correlations between the numbers and localization of the cells in different layers of the tissue were done.Materials and Methods: Thirty cases of OLP and 10 cases of NOM were included. MCs were identified by their metachromasia using Toluidine blue and the MNs by Masson′s Fontana stain. A localization and quantification of the numbers of the two cell groups was done by image analysis and statistically correlated by two sample t-test. Results: The total count of mast cells and melanocytes was more in OLP in comparison to that of NOM. The MCs were present in the deeper tissues in contrast to MNs which were localized only to the basal and sub-basal areas. MNs appeared to proliferate and migrate to the subepithelial areas in OLPs in contrast to their strong localization to the basal layer in NOM. The ratio of MCs/MNs was higher in OLP compared with NOM. Interestingly the toluidine blue stain showed cross-sensitivity in expression of both MCs and MNs in OLP. Conclusion: MCs and MNs are expressed in increased numbers in OLP and probably have a synergistic mode of action in the pathogenesis of the disorder. The spilling out of MNs in OLP to the sub-basal areas is consistent with the clinical observation of pigmentation in healed/under remission OLP cases.

  4. Multiple cranial organ defects after conditionally knocking out Fgf10 in the neural crest

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    Tathyane H.N. Teshima

    2016-10-01

    Full Text Available Fgf10 is necessary for the development of a number of organs that fail to develop or are reduced in size in the null mutant. Here we have knocked out Fgf10 specifically in the neural crest driven by Wnt1cre. The Wnt1creFgf10fl/fl mouse phenocopies many of the null mutant defects, including cleft palate, loss of salivary glands and ocular glands, highlighting the neural crest origin of the Fgf10 expressing mesenchyme surrounding these organs. In contrast tissues such as the limbs and lungs, where Fgf10 is expressed by the surrounding mesoderm, were unaffected, as was the pituitary gland where Fgf10 is expressed by the neuroepithelium. The circumvallate papilla of the tongue formed but was hypoplastic in the conditional and Fgf10 null embryos, suggesting that other sources of FGF can compensate in development of this structure. The tracheal cartilage rings showed normal patterning in the conditional knockout, indicating that the source of Fgf10 for this tissue is mesodermal, which was confirmed using Wnt1cre-dtTom to lineage trace the boundary of the neural crest in this region. The thyroid, thymus and parathyroid glands surrounding the trachea were present but hypoplastic in the conditional mutant, indicating that a neighbouring source of mesodermal Fgf10 might be able to partially compensate for loss of neural crest derived Fgf10.

  5. Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

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    Satoru Morikawa

    2016-01-01

    Full Text Available Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs. The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research.

  6. A structural variant in the 5'-flanking region of the TWIST2 gene affects melanocyte development in belted cattle.

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    Nivedita Awasthi Mishra

    Full Text Available Belted cattle have a circular belt of unpigmented hair and skin around their midsection. The belt is inherited as a monogenic autosomal dominant trait. We mapped the causative variant to a 37 kb segment on bovine chromosome 3. Whole genome sequence data of 2 belted and 130 control cattle yielded only one private genetic variant in the critical interval in the two belted animals. The belt-associated variant was a copy number variant (CNV involving the quadruplication of a 6 kb non-coding sequence located approximately 16 kb upstream of the TWIST2 gene. Increased copy numbers at this CNV were strongly associated with the belt phenotype in a cohort of 333 cases and 1322 controls. We hypothesized that the CNV causes aberrant expression of TWIST2 during neural crest development, which might negatively affect melanoblasts. Functional studies showed that ectopic expression of bovine TWIST2 in neural crest in transgenic zebrafish led to a decrease in melanocyte numbers. Our results thus implicate an unsuspected involvement of TWIST2 in regulating pigmentation and reveal a non-coding CNV underlying a captivating Mendelian character.

  7. Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

    NARCIS (Netherlands)

    Kusters-Vandevelde, Heidi V. N.; van Engen-van Grunsven, Ilse A. C. H.; Kusters, Benno; van Dijk, Marcory R. C. F.; Groenen, Patricia J. T. A.; Wesseling, Pieter; Blokx, Willeke A. M.

    2010-01-01

    The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney

  8. Malignant melanocytic neoplasm of pancreas with liver metastasis: Is it malignant melanoma or clear cell sarcoma?

    Science.gov (United States)

    Kodiatte, Thomas Alex; George, Sam Varghese; Chacko, Raju Titus; Ramakrishna, Banumathi

    2017-01-01

    Malignant melanocytic neoplasm, usually seen in soft tissues, is rare in a visceral location and presents as a diagnostic dilemma. We present a case of pancreatic malignant melanocytic neoplasm with liver metastasis. A 58-year-old man presented with left upper abdominal swelling and loss of appetite. Imaging revealed a large mass arising from the pancreatic tail, and this was diagnosed as malignant neoplasm with melanocytic differentiation on biopsy with the possible differentials of malignant melanoma, clear cell sarcoma (CCS), and perivascular epithelioid cell neoplasm. The patient underwent distal pancreatectomy and splenectomy for the same. Follow-up imaging 6 months later showed a metastatic liver lesion, for which he also underwent a liver resection. BRAF mutational analysis was found to be negative. Both CCS and malignant melanoma have similar morphological features and melanocytic differentiation, but each harbors a distinct genetic background. Differentiation of both has diagnostic and therapeutic implications.

  9. Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors.

    Science.gov (United States)

    Yang, Ruifeng; Zheng, Ying; Li, Ling; Liu, Shujing; Burrows, Michelle; Wei, Zhi; Nace, Arben; Herlyn, Meenhard; Cui, Rutao; Guo, Wei; Cotsarelis, George; Xu, Xiaowei

    2014-12-16

    Direct reprogramming provides a fundamentally new approach for the generation of patient-specific cells. Here, by screening a pool of candidate transcription factors, we identify that a combination of the three factors, MITF, SOX10 and PAX3, directly converts mouse and human fibroblasts to functional melanocytes. Induced melanocytes (iMels) activate melanocyte-specific networks, express components of pigment production and delivery system and produce melanosomes. Human iMels properly integrate into the dermal-epidermal junction and produce and deliver melanin pigment to surrounding keratinocytes in a 3D organotypic skin reconstruct. Human iMels generate pigmented epidermis and hair follicles in skin reconstitution assays in vivo. The generation of iMels has important implications for studies of melanocyte lineage commitment, pigmentation disorders and cell replacement therapies.

  10. EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

    Directory of Open Access Journals (Sweden)

    Makoto Takeo

    2016-05-01

    Full Text Available 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.

  11. Coat-sleeve type giant congenital melanocytic nevus with intraoral blue nevus: A rare case report

    Directory of Open Access Journals (Sweden)

    Lata M Kale

    2017-01-01

    Full Text Available Congenital melanocytic nevi (CMN are visible hyperpigmented (melanocytic, benign, tumor like proliferations in the skin resulting from faulty development of pigment cell precursors in the embryo, and are composed of an abnormal mixture of skin elements. Giant congenital melanocytic nevus (GCMN is usually defined as a melanocytic lesion present at birth that will reach a larger size in adulthood. GCMN is a rare variety of CMN which is characterized by its size (diameter ≥20 cm and the potential for malignant transformation. It is infrequently associated with other findings, which makes the clinical picture complex. In this case, we report a rare association of GCMN with intraoral blue nevus in a 24-year-old male patient.

  12. Congenital Giant Melanocytic Nevus with Malignant Melanoma of the Pleura: Do Primary Pleural Melanomas Exist?

    Directory of Open Access Journals (Sweden)

    Brijesh Sharma

    2017-09-01

    Full Text Available Cases of primary pleural and bronchial melanoma have been described in the literature in the absence of melanocytic cells in the pleura and bronchi. We described a case of congenital giant melanocytic nevus that had a presentation suggestive of primary pleural melanoma. However, biopsy of a chest wall lesion confirmed the presence of another melanoma deposit in a subcutaneous swelling concealed within the congenital giant melanocytic nevus. Histopathology with immunohistochemistry results showed that the pleural and chest wall swelling were similar. The difficult clinical detection of the primary tumor contributes to the fact that 24% of cases of congenital giant melanocytic nevus receive a diagnosis of metastatic melanoma without identification of the primary site. We propose that it is probable that the entity “primary pleural melanoma” may, in fact, not exist. Instead, all such reported tumors in the pleura may actually be metastatic from an unknown, regressed, or missed primary site.

  13. Blood Supply--Susceptible Formation of Melanin Pigment in Hair Bulb Melanocytes of Mice

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    Shogo Maeda, MD

    2015-03-01

    Conclusions: Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

  14. Polycomb group proteins--epigenetic repressors with emerging roles in melanocytes and melanoma.

    Science.gov (United States)

    Huang, Jennifer M; Hornyak, Thomas J

    2015-05-01

    Melanocytes undergo rapid and significant changes in their gene expression programs at regular intervals during development and the hair follicle cycle. In melanoma, the gene expression pattern found in normal melanocytes is disrupted. These gene expression patterns are regulated in part by post-translational histone modifications catalyzed by Polycomb group (PcG) proteins, which play a major role in many developmental processes and are often altered in cancer. In this review, we discuss the role of the PcG proteins in stem cell and cancer biology, in general, as well as in melanocyte development and melanomagenesis. Highlights include the discussion of newly identified treatments that target the activity of PcG proteins as well as new developments in the understanding of the role that these proteins play in melanocyte biology. Published 2014. This is a US Government work and is in the public domain in the USA.

  15. Tyrisonase inhibition and melanin reduction of human melanocytes (HEMn-MP) using Anacardium occidentale L extract.

    Science.gov (United States)

    Abdul Gaffar, R; Abdul Majid, F A; Sarmidi, M R

    2008-07-01

    Cashew (Anacardium occindentale L) leaves extract (CLE) has potential as tyrosinase inhibitor that can be used for therapeutic in pigmentation problem. This study investigates the real potential of CLE to inhibit tyrosinase and melanin reduction using human epidermal melanocytes. The extracts were exposed to the human melanocytes for more than 24 hours. The CLE extract exhibited potential as tyrosinase inhibitor, reduced melanin and high in antioxidant activity relative to commercial extract of Emblica sp.

  16. Reciprocal responses of fibroblasts and melanocytes to α-MSH depending on MC1R polymorphisms.

    Science.gov (United States)

    Stanisz, Hedwig; Seifert, Markus; Tilgen, Wolfgang; Vogt, Thomas; Rass, Knuth

    2011-10-01

    The melanocortin 1-receptor (MC1R) exhibits several variants in form of single nucleotide polymorphisms (SNPs) that are known to differentially regulate melanocyte function. However, whether and how MC1R polymorphisms also affect fibroblast function has not been investigated so far.Therefore we measured intracellular cyclic adenosine monophosphate (cAMP) concentrations and cellular proliferation upon stimulation with alpha-melanocyte stimulating hormone (α-MSH) in eight different human fibroblast and melanocyte cell lines with wild type and different MC1R SNPs.We found that fibroblasts, as well as melanocytes, show differences in MC1R function depending on the MC1R genotype. MC1R stimulation with α-MSH in wild type (MC1R(wt)) melanocytes results in an increase of intracellular cAMP and cellular proliferation. In contrast, MC1R(wt) fibroblasts react with a decrease of intracellular cAMP and proliferation. In MC1R polymorphic fibroblasts (R163Q, R151C and V60L) both effects are significantly alleviated. Similar, but inverse effects could be found in MC1R polymorphic melanocytes (R142H and V92M) with a significantly lower cAMP increase and proliferation rate compared to MC1R(wt) melanocytes.Our results indicate that the MC1R displays reciprocal growth responses in melanocytes and fibroblasts, depending on the MC1R genotype. Thus, the MC1R seems to be not solely important for the skin pigmentary system, but also for the fibroblast function, and might influence different processes of the dermal compartment like wound healing, fibrosis and keloid formation.

  17. Risk of melanoma arising in large congenital melanocytic nevi: a systematic review.

    Science.gov (United States)

    Watt, Andrew J; Kotsis, Sandra V; Chung, Kevin C

    2004-06-01

    Large congenital melanocytic nevi are cutaneous lesions regarded by many as premalignant; estimates of malignancy incidence range from 0 to 42 percent. Given the often complex and extensive nature of large congenital melanocytic nevi resection and reconstruction, the risk of malignant transformation is a crucial factor that surgeons and families must weigh when deciding whether or not to excise the lesion. The authors conducted a systematic analysis of data from the existing literature to critically evaluate the published studies and to establish a crude incidence rate for the risk of malignant melanoma transformation in large congenital melanocytic nevi. After a comprehensive literature search, they analyzed data from eight studies (containing a total of 432 large congenital melanocytic nevi patients) of sufficient scientific quality. Twelve patients (2.8 percent) in this sample developed cutaneous malignant melanoma during the reported follow-up periods. Using a subset of this data and comparing the incidence rates to those of the Surveillance, Epidemiology, and End Results population-based database using a standardized morbidity ratio, the authors found that the large congenital melanocytic nevi patients had an increased risk of melanoma (standardized morbidity ratio, 2599; 95 percent confidence interval, 844 to 6064) compared with the general population. Regarding treatment before developing melanoma in the 12 patients, 50 percent were observed before diagnosis, 17 percent had partial excision, 8.3 percent had dermabrasion, 8.3 percent had a chemical peel, and 17 percent did not have any treatment information. These combined data are clinically useful when consulting with the parents of children with large congenital melanocytic nevi and in the management of older patients with existing lesions. This study shows that there is a significantly increased risk of melanoma in large congenital melanocytic nevi patients. The data also reveal the need for a

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

    Science.gov (United States)

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

    2015-04-01

    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).

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

    OpenAIRE

    Boleira,Manuela; de Almeida Balassiano, Laila Klotz; Jeunon,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).

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

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Yanjun; Cao, Jing; Wang, Haidong; Zhang, Jie; Zhu, Zhiwei; Bai, Rui; Hao, HuanQing; He, Xiaoyan; Fan, Ruiwen [College of Animal Science and Technology, Shanxi Agricultural University, 030801 Taigu, Shanxi (China); Dong, Changsheng, E-mail: cs_dong@sxau.edu.cn [College of Animal Science and Technology, Shanxi Agricultural University, 030801 Taigu, Shanxi (China)

    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.

    Science.gov (United States)

    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. (c) 2010 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa, E-mail: ebuszman@sum.edu.pl

    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.

  4. Substantial Effect of Melanin Influencing Factors on Melanogenesis in Muzzle Melanocytes of Differently Colored Hanwoo

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    Touseef Amna

    2012-07-01

    Full Text Available 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.

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

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    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

  6. Immuno-Histochemical and Quantitative Study of Melanocytes and Melanin Granules in Oral Epithelial Dysplasia.

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    Honwad, Swapna; Ravi, S V; Donoghue, Mandana; Joshi, Manjiri

    2017-07-01

    Oral Epithelial dysplasia (OED) is a potentially malignant disorder that is characterized by the presence of architectural and cytological changes. One of the prime factors responsible for the development of these lesions is the usage of tobacco. A variety of factors provide protective mechanism in order to prevent the effects of chemotoxic agents including tobacco products of which, melanin pigmentation is one of the vital elements. Role of melanocytes in progression of OED has remained unclear, so the present study was done to evaluate density of melanocyte and melanin granules in different grades of epithelial dysplasia and to correlate both findings with different grades of epithelial dysplasia. The study included 60 OED cases, of which three histopathogical sections were prepared from each block. The sections were stained with Hematoxylin and Eosin, Masson Fontana and Human Melanoma Black (HMB-45), an immunohistochemical stain. Quantification of melanin granules was evaluated under 40X magnification using arbitrary scale with micrometer square as, 0= Absence of melanin granules, 1= Rare and scattered melanin granules, 2= Dense but not aggregated melanin granules, 3= Dense and aggregated melanin granules. Density of melanocytes was evaluated under 10X magnification. Five consecutive fields were evaluated for melanocytes and melanin granules starting from the field of highest density. There was an insignificant increase in number of melanocytes and melanin granules in mild and moderate dysplasia compared to normal but significant reduction was observed in severe dysplasia. The decrease in number of melanocytes and melanin granules was proportional to severity of epithelial dysplasia. This could be due to chronic irritation by chemical products leading to death of melanocytes.

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

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    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.

  8. Oral melanocytic nevi: a clinicopathologic study of 100 cases.

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    Ferreira, Leticia; Jham, Bruno; Assi, Rouba; Readinger, Allison; Kessler, Harvey P

    2015-09-01

    The purpose of this study was to evaluate the clinical and histopathologic features of oral melanocytic nevi (OMN). One hundred cases of OMN were retrieved from the files of two oral pathology services, and the data were analyzed with regard to histologic type and clinical features. Intramucosal nevus was the most common type (61%), followed by common blue nevus (23%), compound nevus (7%), and junctional nevus (3%). Combined nevus and cellular blue nevus were rare (2% each). The hard palate was the most commonly affected site (33%), followed by the buccal mucosa (18%), vermilion border of the lip (18%), and gingiva (15%). An interesting case of intramucosal nevus with lipomatosus-like changes and neurotization and two cases of oral dysplastic nevus are also reported. Intramucosal and common blue nevi are the most common types of OMN. Dysplastic nevus, which is recognized as a marker for melanoma in the skin, can rarely involve the oral cavity. Accordingly, dentists, especially oral and maxillofacial pathologists, should become familiar with the clinical and histopathologic features of this entity. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. High-definition optical coherence tomography of melanocytic skin lesions.

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    Gambichler, Thilo; Plura, Iris; Schmid-Wendtner, Monika; Valavanis, Konstantinos; Kulichova, Daniela; Stücker, Markus; Pljakic, Azem; Berking, Carola; Maier, Tanja

    2015-08-01

    High-definition optical coherence tomography (HD-OCT) scanners have recently been developed. We assessed micromorphological HD-OCT correlates of benign naevi (BN) and malignant melanoma (MM). 28 BN and 20 MM were studied using HD-OCT and histology. Epidermal honeycomb/cobblestone pattern, regular junctional cell nests, and edged papillae are more often observed in BN, whereas fusion of rete ridges, pagetoid cells and junctional and/or dermal nests with atypical cells are more frequently seen in MM. A high overlap of HD-OCT features in BN and MM was observed and in 20% of MM we did not find evidence for malignancy in OCT images at all. Using HD-OCT it is possible to visualize architectural and cellular alterations of melanocytic skin lesions. The overlap of HD-OCT features seen in BN and MM and the absence of suspicious HD-OCT features in some MM represents an important limitation of HD-OCT affecting the sensitivity of HD-OCT in diagnosing MM. High-definition optical coherence tomography and the corresponding vertically sectioned histology of a compound naevus. © 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    Science.gov (United States)

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

    2016-01-01

    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. PMID:26315342

  11. Dermoscopic Features in Seborrheic Keratoses; What is the Value of the False Melanocytic Features?

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    Işıl Kılınç Karaarslan

    2009-03-01

    Full Text Available Aim: We aimed to search the dermoscopic features in seborrheic keratoses, especially the false melanocytic ones.Method: Two-hundred and fourteen lesions from 45 patients (27-85 age range, 18 women were included in the study. Dermoscopic images of all lesions were evaluated and histopathological examination was performed when necessary.Results: The dermoscopic features observed were pseudofollicular openings (72%, milia-like cysts (66%, brain-like appearance (32.2 %, vascular structures (23%, “fat fingers” (10.3% and exophytic papillary structures (5.1 %. False melanocytic features were observed in 30 lesions (14 %. These were globule-like structures (9.4%, pigment network-like structures (2.4%, blotch (1.4 %, and blue-white structure (0.9 %. In 7 lesions (3.3%, it was not possible to rule out a melanocytic lesion. Histopathological examination was performed in forty-four lesions. Conclusion: This study indicated that although false melanocytic features may be observed in seborrheic keratoses, the lesions difficult to differentiate from melanocytic lesions are quite rare. In seborrheic keratoses, blotch and blue-white structure have been described for the first time in this study. In addition, “fat fingers”, a recently described feature, has been examined for the first time in this study and found to be in lower incidence compared with the primary report.

  12. Melanocytes: Target Cells of an HLA-C*06:02-Restricted Autoimmune Response in Psoriasis.

    Science.gov (United States)

    Prinz, Jörg Christoph

    2017-10-01

    HLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vβ13S1 T-cell receptor from pathogenic psoriatic CD8+ T cells, we had recently proven that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation in psoriasis and identified ADAMTSL5 as a melanocyte autoantigen. We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. Understanding this pathway, however, requires more detailed explanation. It is based on the fact that an HLA class I-restricted autoreactive CD8+ T-cell response must be directed against a particular target cell type, because HLA class I molecules present peptide antigens generated from cytoplasmic (i.e., intracellular) proteins. This review summarizes the findings on the melanocyte-specific autoimmune response in the context of the immune mechanisms related to HLA function and T-cell receptor-antigen recognition. Identifying melanocytes as target cells of the psoriatic immune response now explains psoriasis as a primary autoimmune skin disease. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  14. Cyclic stretch up-regulates proliferation and heat shock protein 90 expression in human melanocytes.

    Science.gov (United States)

    Kippenberger, S; Bernd, A; Loitsch, S; Müller, J; Guschel, M; Kaufmann, R

    1999-08-01

    Human skin is repeatedly exposed to mechanical stretching in vivo, but in an ordinary culture of skin cells this prominent feature has been neglected. In order to study whether mechanical stretching plays a role for human melanocytes, we have established a culture technique to mimic this physical stretching: primary cultures of human melanocytes were plated on silicon supports, which undergo a stretching of about 10% of the initial length. After application of repeated stretching and relaxation for 4 days, cell count was significantly (about 40%) enhanced. In addition, we found approximately 2-fold increase in heat shock protein (HSP) 90, both at the protein and mRNA level. HSP 90 is known to bind to Raf-1 and, therefore, may contribute to the Raf-1-MEK (mitogen-activated protein-kinase kinase)-MAPK (mitogen-activated protein-kinase) signaling pathway. Disruption of the Raf-1-HSP 90 multimolecular complex by geldanamycin lead to a considerable decrease in melanocyte cell count. However, geldanamycin did not reverse the stretch-induced growth stimulation. Therefore, the stretch-mediated up-regulation of HSP 90 expression in melanocytes appears to be independent of stretch-mediated growth stimulation. These findings have strong implications for the in vitro cultivation of melanocytes for transplantation purposes.

  15. Expert review remains important in the histopathological diagnosis of cutaneous melanocytic lesions.

    Science.gov (United States)

    van Dijk, M C R F; Aben, K K H; van Hees, F; Klaasen, A; Blokx, W A M; Kiemeney, L A L M; Ruiter, D J

    2008-01-01

    To assess the type of problems encountered in diagnosing melanocytic lesions and to evaluate the contribution of expert review. Data from 1887 lesions submitted for consultation to one of the expert pathologists of the Dutch Melanoma Working Group Pathology Panel between 1991 and 2004 were analysed. Referring pathologists can voluntarily submit lesions which are difficult to classify to the panel. Most cutaneous melanocytic lesions (n = 1217) were submitted with a presumed diagnosis by the referring pathologists. Relevant underdiagnoses of melanoma (in situ) and overdiagnoses of naevi were prevented in 12% (144/1217) and 15% (178/1217) of cases, respectively. Problematic melanocytic lesions were (i) spitzoid and dysplastic lesions, (ii) lesions with histological features that hampered the diagnosis such as regression, lymphocytic infiltrate, or a combination with other melanocytic lesions, and (iii) lesions with unusual clinical features, e.g. childhood melanoma. Remarkably, the features of the lesions that were submitted and the types of over- and under-diagnosis remained consistent from 1991 to 2004. A second opinion from an expert pathologist on problem-prone melanocytic lesions improves patient care, in our series in 27% of cases.

  16. Post-transcriptional regulation of neurofibromin level in cultured human melanocytes in response to growth factors.

    Science.gov (United States)

    Griesser, J; Kaufmann, D; Maier, B; Mailhammer, R; Kuehl, P; Krone, W

    1997-03-01

    Among the symptoms that characterize neurofibromatosis type 1 (NF1) are pigmentation anomalies such as cafe au lait spots. It has been suggested that the reduction of the neurofibromin level in the epidermis of NF1 patients is responsible for the observed signs such as altered melanogenesis and altered density of melanocytes. Our studies show that in cultured normal human melanocytes, the neurofibromin level can be varied in vitro over a wide range by using different culture conditions. The influence of factors that control differentiation and proliferation of melanocytes on neurofibromin levels was studied. Immunoprecipitation followed by western blotting showed a 3- to 4-fold increase of neurofibromin after stimulation by PMA or bFGF, respectively, and a 1.5-fold increase in cells stimulated with steel factor. The increase of neurofibromin was not paralleled by a higher NF1 mRNA level as proved by northern blotting. Pulse-chase experiments with 35S-labeled melanocytes revealed an approximately 3-fold increase in the half-life of neurofibromin in bFGF- or PMA-stimulated cells compared to controls. These results indicate that the neurofibromin level of cultured melanocytes can be regulated by a mechanism independent of NF1 gene transcription and translation, which might influence the degradation rate of the protein.

  17. Differential Clinicopathological Features in Spontaneous Regression of Melanomas and Melanocytic Naevi

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    José M. Martín

    2017-03-01

    Full Text Available The aim of this study was to determine the clinical, histological and/or immunohistochemical features that enable differential diagnosis of regression of melanocytic naevi from regression of melanomas. All melanocytic neoplasms with histologically-confirmed regression diagnosed in our hospital between 2002 and 2009 were reviewed retrospectively. Lamellar and delicate fibrosis were associated with melanocytic naevi (p < 0.0001 and p = 0.021, respectively. Compact fibrosis, high vessel density and higher number of granzyme B+ lymphocytes were associated with malignant melanoma (p = 0.011, p = 0.005 and p = 0.013, respectively. Density of inflammatory infiltrate (p = 0.016, vascular proliferation (p = 0.005, epidermal atrophy (p = 0.009, rate of apoptosis (p = 0.046 and granzyme B immunoreactivity (p = 0.013 was more common in severe–dysplastic naevi and melanomas than in the remaining melanocytic naevi. Logistic regression demonstrates that 5 variables (age, lamellar fibrosis, melanophages, vessel density, and granzyme B immunostaining would serve to classify appropriately 87% of melanomas among melanocytic lesions with complete regression.

  18. [The intervention of nicotinamide on skin melanocyte's cell proliferation after UVA (365 nm) exposed.].

    Science.gov (United States)

    Patam, Muhammad; Jin, Xi-peng; Pan, Jian-ying; Shen, Guang-zu; Jin, Tai-Yi

    2005-02-01

    To investigate the interference effect of nicotinamide on UVA-induced cell proliferation in human skin melanocyte. To apply the optimum UVA dose expected to cause cell proliferation: 0.2 cm2, nicotinamide was added after the 0.2 cm2 UVA exposure immediately or 48 h later, then the rate of cell proliferation, calcium concentration and the activities of Na+-K+, Ca2+-ATP enzymes of melanocytes were measured respectively. After treatment with 1.000 mg/ml nicotinamide following UVA exposure, the rate of cell proliferation was decreased significantly 24 hours later. Treatment with 0.125 mg/ml nicotinamide 48 hours after UVA exposure also significantly inhibited the cell proliferation; 1.25 mg/ml nicotinamide increased calcium concentration in cells; 0.250 mg/ml nicotinamide increased the activities of Na+-K+, Ca2+-ATP enzymes in melanocytes (P Nicotinamide has more obvious effect on inhibiting melanocyte's proliferation if added immediately following UVA exposure. Our discovery indicated that nicotinamide may affect the melanocyte through modulating the calcium concentration. It is possible to consider nicotinamide as an efficient and safe sun screen to provide a certain level of protection for UVA exposed skin.

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

    Science.gov (United States)

    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. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2017-07-01

    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 (κ w ) or kappa (κ) analysis (original cytology vs cytology review κ w = 0.24; original cytology vs original histopathology κ w = 0.007; original cytology vs histopathology review κ w = 0.23; cytology review vs original histopathology κ w = 0.008; cytology review vs histopathology review κ w = 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.

  1. Lacunarity analysis: a promising method for the automated assessment of melanocytic naevi and melanoma.

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    Stephen Gilmore

    Full Text Available The early diagnosis of melanoma is critical to achieving reduced mortality and increased survival. Although clinical examination is currently the method of choice for melanocytic lesion assessment, there is a growing interest among clinicians regarding the potential diagnostic utility of computerised image analysis. Recognising that there exist significant shortcomings in currently available algorithms, we are motivated to investigate the utility of lacunarity, a simple statistical measure previously used in geology and other fields for the analysis of fractal and multi-scaled images, in the automated assessment of melanocytic naevi and melanoma. Digitised dermoscopic images of 111 benign melanocytic naevi, 99 dysplastic naevi and 102 melanomas were obtained over the period 2003 to 2008, and subject to lacunarity analysis. We found the lacunarity algorithm could accurately distinguish melanoma from benign melanocytic naevi or non-melanoma without introducing many of the limitations associated with other previously reported diagnostic algorithms. Lacunarity analysis suggests an ordering of irregularity in melanocytic lesions, and we suggest the clinical application of this ordering may have utility in the naked-eye dermoscopic diagnosis of early melanoma.

  2. Skin melanocytes and fibroblasts show different changes in choline metabolism during cellular senescence.

    Science.gov (United States)

    Windler, Cordula; Gey, Claudia; Seeger, Karsten

    2017-06-01

    Unmodified cells undergo only a limited number of cell divisions until they enter a state termed cellular senescence. Other triggers like cytotoxic compounds can also induce cell senescence. Since cell senescence represents a major mechanism of tumor suppression this cellular state has attracted increasing attention. Different markers like senescence-associated β-galactosidase (SAβGal), senescence-associated heterochromatic foci (SAHF) or certain metabolic changes have been identified to be characteristic for senescent cells; however, data is often limited to fibroblasts - the cardinal model system for cellular senescence. In order to investigate whether metabolic changes during senescence are cell type independent, skin fibroblasts and skin melanocytes have been examined. Expression of the senescence marker p16 could be detected in skin fibroblasts but not in melanocytes of this specific donor, rendering the senescent phenotype not fully ascertained for the melanocytes. Metabolic profiles of senescent cells and controls have been determined using NMR spectroscopy. Changes in metabolism are different for fibroblasts and melanocytes. Senescent melanocytes showed lower levels of phosphocholine whereas for fibroblasts in accordance with literature, levels of glycerophosphocholine were increased during senescence. Although no general metabolic marker for cellular senescence exists, the same metabolic pathway seems to be affected for both cell types. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Prevention of hair graying by factors that promote the growth and differentiation of melanocytes.

    Science.gov (United States)

    Endou, Mariko; Aoki, Hitomi; Kobayashi, Tatsushi; Kunisada, Takahiro

    2014-08-01

    Epidermal melanocyte precursors migrate into developing hair follicles to form the melanocyte stem cell system required to supply pigmented melanocytes necessary for hair pigmentation in repetitive hair cycles. Hair graying is caused by irreversible defects in the self-renewal and/or development of follicular melanocyte stem cells in the hair follicles. To investigate the mechanism(s) of hair graying during the normal aging process, we established a hair graying model in mice by repeatedly plucking or shaving trunk hairs. We repeatedly plucked or shaved trunk hairs to induce and accelerate the hair graying and counted the gray hairs. By using this functional model of hair graying in mice, we assessed the effects of genes known to affect melanocyte development, such as Kitl, hepatocyte growth factor (HGF) and endotheline 3 (ET3). After increasing the total numbers of cumulative hair cycles by plucking or shaving, we observed a significant increase in the gray hair of C57BL/6 mice. Kitl expression in the skin was the most effective for preventing hair graying and a significant effect was also confirmed for HGF and ET3 expression. The repeated hair plucking or shaving led to hair graying without any genetic lesion. Kitl is a more effective factor for prevention of hair graying than HGF or ET3. Our simple model of hair graying may provide a basic tool for screening the molecules or reagents preventing the progression of hair graying. © 2014 Japanese Dermatological Association.

  4. Clinical, dermoscopic and histopathological features of melanocytic nevi in dystrophic epidermolysis bullosa.

    Science.gov (United States)

    Fernandes, Juliana Dumêt; Rivitti-Machado, Maria Cecilia; Nakano, Juliana; de Oliveira Rocha, Bruno; Oliveira, Zilda Najjar P

    2014-03-01

    Epidermolysis bullosa (EB) nevi are acquired pigmented melanocytic lesions which may have clinical and dermoscopic features quite similar to those found in melanoma. More detailed information on this phenomenon is still lacking. To evaluate clinical, dermoscopic, and histopathological features of melanocytic lesions in 13 patients with dystrophic EB (DEB). Patients underwent clinical and dermoscopic evaluation. Suspicious lesions were excised and examined microscopically. There were 12 cases of recessive DEB and one of dominant DEB. Five patients were men; 8 were women; the ages ranged from 2 to 27 years old. All patients had at least 2 atypical melanocytic lesions. Two of the 5 biopsied patients showed an atypical nevus or lentigo on histopathological examination. We observed a high incidence of large and atypical melanocytic lesions in DEB patients. Although the exact explanation for this is still unclear, it seems that re-epithelization and the chronic inflammatory process may stimulate the proliferation of melanocytes, as well as the emergence of lesions with atypical clinical and dermoscopic features. As an unequivocal discrimination from malignant melanoma in vivo is not always possible, regular clinical follow-up and histopathological evaluation of suspicious lesions in EB patients are mandatory. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  5. Methods for Derivation of Multipotent Neural Crest Cells Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Avery, John; Dalton, Stephen

    2016-01-01

    Multipotent, neural crest cells (NCCs) produce a wide range of cell types during embryonic development. This includes melanocytes, peripheral neurons, smooth muscle cells, osteocytes, chondrocytes, and adipocytes. The protocol described here allows for highly efficient differentiation of human pluripotent stem cells to a neural crest fate within 15 days. This is accomplished under feeder-free conditions, using chemically defined medium supplemented with two small molecule inhibitors that block glycogen synthase kinase 3 (GSK3) and bone morphogenic protein (BMP) signaling. This technology is well suited as a platform to understand in greater detail the pathogenesis of human disease associated with impaired neural crest development/migration.

  6. Human skin melanocyte migration towards stromal cell-derived factor-1α demonstrated by optical real-time cell mobility assay: modulation of their chemotactic ability by α-melanocyte-stimulating hormone.

    Science.gov (United States)

    Yamauchi, Akira; Hadjur, Christophe; Takahashi, Tadahito; Suzuki, Itaru; Hirose, Kunitaka; Mahe, Yann F

    2013-10-01

    To identify potential regulators of normal human melanocyte behaviour, we have developed an in vitro human melanocyte migration assay, using the optically accessible, real-time cell motility assay device TAXIScan. Coating of the glass surface with an extracellular matrix that served as scaffolding molecule was essential to demonstrate efficient melanocyte migration. Among several chemokines tested, stromal cell-derived factor (SDF)-1α/CXCL12 was the most effective driver of human normal skin melanocytes. Incubation of melanocytes with α-melanocyte-stimulating hormone (MSH) before the assay specifically enhanced CXCR4 expression and consequently chemotaxis towards SDF-1α/CXCL12. These results suggest that α-MSH acts on melanocytes to produce melanin as well as stimulates the cells to migrate to the site where they work through CXCR4 up-regulation, which is a new dynamic mode of action of α-MSH on melanocyte physiology. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant response promotes melanocyte viability and reduces toxicity of the vitiligo-inducing phenol monobenzone.

    Science.gov (United States)

    Arowojolu, Omotayo A; Orlow, Seth J; Elbuluk, Nada; Manga, Prashiela

    2017-07-01

    Vitiligo, characterised by progressive melanocyte death, can be initiated by exposure to vitiligo-inducing phenols (VIPs). VIPs generate oxidative stress in melanocytes and activate the master antioxidant regulator NRF2. While NRF2-regulated antioxidants are reported to protect melanocytes from oxidative stress, the role of NRF2 in the melanocyte response to monobenzone, a clinically relevant VIP, has not been characterised. We hypothesised that activation of NRF2 may protect melanocytes from monobenzone-induced toxicity. We observed that knockdown of NRF2 or NRF2-regulated antioxidants NQO1 and PRDX6 reduced melanocyte viability, but not viability of keratinocytes and fibroblasts, suggesting that melanocytes were preferentially dependent upon NRF2 activity for growth compared to other cutaneous cells. Furthermore, melanocytes activated the NRF2 response following monobenzone exposure and constitutive NRF2 activation reduced monobenzone toxicity, supporting NRF2's role in the melanocyte stress response. In contrast, melanocytes from individuals with vitiligo (vitiligo melanocytes) did not activate the NRF2 response as efficiently. Dimethyl fumarate-mediated NRF2 activation protected normal and vitiligo melanocytes against monobenzone-induced toxicity. Given the contribution of oxidant-antioxidant imbalance in vitiligo, modulation of this pathway may be of therapeutic interest. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Immunopolarization of CD4(+) and CD8(+) T cells to type-1-like is associated with melanocyte loss in human vitiligo

    NARCIS (Netherlands)

    Wańkowicz-Kalińska, Anna; van den Wijngaard, René M. J. G. J.; Tigges, Bert J.; Westerhof, Wiete; Ogg, Graham S.; Cerundolo, Vincenzo; Storkus, Walter J.; Das, Pranab K.

    2003-01-01

    Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. High frequencies of melanocyte-reactive cytotoxic T cells in the peripheral blood of vitiligo patients and the observed correlation between perilesional T-cell infiltration and melanocyte loss in situ suggest the

  9. Identification of the minimal melanocyte-specific promoter in the melanocortin receptor 1 gene

    Directory of Open Access Journals (Sweden)

    Natali Pier

    2008-11-01

    Full Text Available Abstract Background The understanding of cutaneous pigmentation biology is relevant from the biologic and clinical point of view. The binding of α-melanocortin and its specific receptor, on the plasma membrane of melanin synthesising cells, plays a crucial role in melanins biosynthesis. Furthermore, loss of MC1R function is associated with an increased incidence of melanoma and non-melanoma skin cancer. The expression of the α-melanocortin receptor gene is highly controlled but, at the present, region responsible for tissue-specific activity of the gene promoter has not been identified. Methods We have cloned the genomic sequences upstream the human MC1R coding gene. A DNA fragment of 5 kilobases upstream the human MC1R encoding sequence was placed in front of a reporter gene and several deletion mutants of such fragment have been prepared. These constructs have been tested for the ability to drive the melanocyte-specific gene expression of the reporter gene using transfection experiments in melanocyte and non-melanocyte cell lines. From these experiments we identified a DNA fragment with the ability to drive the gene transcription in a tissue-specific way and we used this small DNA fragment in DNA-protein interaction assays. Results We show that the 150 base pairs upstream the MC1R gene initiation codon are able to drive the melanocyte-specific gene transcription. Furthermore, we provide experimental evidences suggesting that on such minimal melanocyte-specific gene promoter can assemble tissue-specific complexes. Conclusion The present results strongly imply that the transcriptional regulation of the melanocyte-specific MC1R gene requires an internal promoter located in the 150 base pairs upstream the initiation codon.

  10. Increasing epidermal growth factor receptor expression in human melanocytic tumor progression.

    Science.gov (United States)

    de Wit, P E; Moretti, S; Koenders, P G; Weterman, M A; van Muijen, G N; Gianotti, B; Ruiter, D J

    1992-08-01

    Different results have been reported on the expression of epidermal growth factor receptor (EGFR) in human melanocytic lesions, which may be due to different methodologic approaches. Therefore, we compared EGFR expression in six human melanoma cell lines by utilizing the monoclonal antibodies 2E9, 425, and 225, applying four immunocytochemical staining procedures. The results were compared with those obtained by a multiple point ligand binding assay. In addition, Northern blot analysis was performed. A three-step immunoperoxidase method using the monoclonal antibody 2E9 proved most sensitive. Staining intensities, estimated semiquantitatively, correlated well with the quantitative data obtained by the ligand-binding assay. Expression on the mRNA level was also in agreement with these results. Immunohistochemical staining of a large series of human cutaneous melanocytic lesions using the method selected showed differential EGFR expression in various stages of melanocytic tumor progression: 19% of common nevocellular nevi; 61% of dysplastic nevi, 89% of primary cutaneous melanomas, and 91% of melanoma metastases showed staining of the melanocytic cells. Intralesional heterogeneity of EGFR expression was present. Although the mean percentage of positive melanocytic cells in positive lesions did not increase with progression, mean staining intensity was stronger in malignant lesions compared to benign lesions. Ligand binding assays showed that EGFR expression in the highly metastasizing cell lines MV3 and BLM was at least 40 times higher than in the cell lines IF6, 530, M14, and Mel57, which do not or only sporadically metastasize after subcutaneous inoculation in nude mice. Although the differences between the various stages of progression are not absolute, we provide further evidence that EGFR expression increases in human melanocytic tumor progression.

  11. Rapidly lethal metastatic melanoma arising from a large congenital melanocytic naevus

    OpenAIRE

    Wei, Christina Hsiao; Shoo, Brenda A.; Zedek, Daniel C.; Kashani-Sabet, Mohammed; Sagebiel, Richard W.; Leong, Stanley P L

    2009-01-01

    A case of fatal metastatic melanoma arising from a very large congenital melanocytic naevus (VLCMN) is reported. Large congenital naevi (LCMN) are naevi >20 cm in diameter. VLCMN is used in this report to mean an extensive LCMN involving a large percentage of the body, including smaller so-called satellite naevi. A 19-year-old man with a large congenital melanocytic naevus (LCMN) presented with a new nodule on the left chest wall, which was diagnosed as a thick melanoma with synchronous axill...

  12. Imaging pigment chemistry in melanocytic conjunctival lesions with pump-probe microscopy

    Science.gov (United States)

    Wilson, Jesse W.; Vajzovic, Lejla; Robles, Francisco E.; Cummings, Thomas J.; Mruthyunjaya, Prithvi; Warren, Warren S.

    2013-03-01

    We extend nonlinear pump-probe microscopy, recently demonstrated to image the microscopic distribution of eumelanin and pheomelanin in unstained skin biopsy sections, to the case of melanocytic conjunctival lesions. The microscopic distribution of pigmentation chemistry serves as a functional indicator of melanocyte activity. In these conjunctival specimens (benign nevi, primary acquired melanoses, and conjunctival melanoma), we have observed pump-probe spectroscopic signatures of eumelanin, pheomelanin, hemoglobin, and surgical ink, in addition to important structural features that differentiate benign from malignant lesions. We will also discuss prospects for an in vivo `optical biopsy' to provide additional information before having to perform invasive procedures.

  13. Oral Melanocytic nevi : review of literature and report of a case

    Directory of Open Access Journals (Sweden)

    Cyril Pandarakalam

    2007-01-01

    Full Text Available Melanocytic nevi are uncommon lesions of the oral cavity. Most reports are of isolated cases or of a small series of cases. The purpose of this article is to report a case of oral melanocytic nevi and to review the literature. Review of literature revealed that about one third of patients with malignant melanoma had preexisting macular pigmentation present. Therefore, removal of all lesions suspected to be nevi is recommended. Oral lesions are uncommon and usually small that excision seems advisable.

  14. Growth and hormone profiling in children with congenital melanocytic naevi.

    Science.gov (United States)

    Waelchli, R; Williams, J; Cole, T; Dattani, M; Hindmarsh, P; Kennedy, H; Martinez, A; Khan, S; Semple, R K; White, A; Sebire, N; Healy, E; Moore, G; Kinsler, V A

    2015-12-01

    Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN. To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group). Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition. Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one. Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually

  15. Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis.

    Science.gov (United States)

    Sedykh, Irina; Yoon, Baul; Roberson, Laura; Moskvin, Oleg; Dewey, Colin N; Grinblat, Yevgenya

    2017-09-01

    The vertebrate retina develops in close proximity to the forebrain and neural crest-derived cartilages of the face and jaw. Coloboma, a congenital eye malformation, is associated with aberrant forebrain development (holoprosencephaly) and with craniofacial defects (frontonasal dysplasia) in humans, suggesting a critical role for cross-lineage interactions during retinal morphogenesis. ZIC2, a zinc-finger transcription factor, is linked to human holoprosencephaly. We have previously used morpholino assays to show zebrafish zic2 functions in the developing forebrain, retina and craniofacial cartilage. We now report that zebrafish with genetic lesions in zebrafish zic2 orthologs, zic2a and zic2b, develop with retinal coloboma and craniofacial anomalies. We demonstrate a requirement for zic2 in restricting pax2a expression and show evidence that zic2 function limits Hh signaling. RNA-seq transcriptome analysis identified an early requirement for zic2 in periocular neural crest as an activator of alx1, a transcription factor with essential roles in craniofacial and ocular morphogenesis in human and zebrafish. Collectively, these data establish zic2 mutant zebrafish as a powerful new genetic model for in-depth dissection of cell interactions and genetic controls during craniofacial complex development. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human epidermal keratinocytes and melanocytes modulated by alpha-melanocyte-stimulating hormone [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Markus Böhm

    2016-05-01

    Full Text Available 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.

  17. Development of a three-dimensional surface imaging system for melanocytic skin lesion evaluation.

    Science.gov (United States)

    Tosca, Androniki; Kokolakis, Athanasios; Lasithiotakis, Konstantinos; Zacharopoulos, Athanasios; Zabulis, Xenophon; Marnelakis, Ioannis; Ripoll, Jorge; Stephanidis, Constantine

    2013-01-01

    Even though surface morphology is always taken into account when assessing clinically pigmented skin lesions, it is not captured by most modern imaging systems using digital imaging. Our aim is to develop a novel three-dimensional (3D) imaging technique to record detailed information of the surface anatomy of melanocytic lesions that will enable improved classification through digital imaging. The apparatus consists of three high-resolution cameras, a light source, and accompanying software. Volume measurements of specific phantoms using volumetric tubes render slightly lower values than those obtained by our 3D imaging system (mean%± SD, 3.8%± 0.98, Pimaging of melanocytic lesions is carried out. The mean%± SD differences of area, major axis length, volume, and maximum height are 2.1%± 1.1, 0.9%± 0.8, 3.8%± 2.9, and 2.5%± 3.5, respectively. Thirty melanocytic lesions are assessed, including common and dysplastic nevi and melanomas. There is a significant difference between nevi and melanomas in terms of variance in height and boundary asymmetry (P<0.001). Moreover, dysplastic nevi have significantly higher variances in pigment density values than common nevi (P<0.001). Preliminary data suggest that our instrument has great potential in the evaluation of the melanocytic lesions. However, these findings should be confirmed in larger-scale studies.

  18. Grafting of in vitro cultured melanocytes onto laser-ablated lesions in vitiligo.

    Science.gov (United States)

    Kaufmann, R; Greiner, D; Kippenberger, S; Bernd, A

    1998-03-01

    A variety of grafting procedures using autologous melanocytes have achieved promising results in the treatment of vitiligo. We here report on the preparation of an adequate graft recipient bed by pulsed Erbium-YAG laser skin ablation. In particular, for irregular lesions on delicate sites, which cannot be approached by utilization of suction blisters or dermabrasion, this technique may offer a distinct advantage.

  19. Behandling og håndtering af kongenitte melanocytære naevi

    DEFF Research Database (Denmark)

    Bahn, Kamille-Amalie; Hædersdal, Merete; Schmidt, Grethe

    2016-01-01

    Congenital melanocytic naevi (CMN) appear in approximately 2.6% of Caucasians. There is a major demand for treatment but no vital indication. Laser therapy, curettage and excision are available treatment modalities, but there is no ideal treatment with documented long-term effect and without side...

  20. Vesicular Stomatitis Virus Variants Selectively Infect and Kill Human Melanomas but Not Normal Melanocytes

    Science.gov (United States)

    Wollmann, Guido; Davis, John N.; Bosenberg, Marcus W.

    2013-01-01

    Metastatic malignant melanoma remains one of the most therapeutically challenging forms of cancer. Here we test replication-competent vesicular stomatitis viruses (VSV) on 19 primary human melanoma samples and compare these infections with those of normal human melanocyte control cells. Even at a low viral concentration, we found a strong susceptibility to viral oncolysis in over 70% of melanomas. In contrast, melanocytes displayed strong resistance to virus infection and showed complete protection by interferon. Several recombinant VSVs were compared, and all infected and killed most melanomas with differences in the time course with increasing rates of melanoma infection, as follows: VSV-CT9-M51 VSV-M51 VSV-G/GFP VSV-rp30. VSV-rp30 sequencing revealed 2 nonsynonymous mutations at codon positions P126 and L223, both of which appear to be required for the enhanced phenotype. VSV-rp30 showed effective targeting and infection of multiple subcutaneous and intracranial melanoma xenografts in SCID mice after tail vein virus application. Sequence analysis of mutations in the melanomas used revealed that BRAF but not NRAS gene mutation status was predictive for enhanced susceptibility to infection. In mouse melanoma models with specific induced gene mutations including mutations of the Braf, Pten, and Cdkn2a genes, viral infection correlated with the extent of malignant transformation. Similar to human melanocytes, mouse melanocytes resisted VSV-rp30 infection. This study confirms the general susceptibility of the majority of human melanoma types for VSV-mediated oncolysis. PMID:23552414

  1. Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes.

    Science.gov (United States)

    Wollmann, Guido; Davis, John N; Bosenberg, Marcus W; van den Pol, Anthony N

    2013-06-01

    Metastatic malignant melanoma remains one of the most therapeutically challenging forms of cancer. Here we test replication-competent vesicular stomatitis viruses (VSV) on 19 primary human melanoma samples and compare these infections with those of normal human melanocyte control cells. Even at a low viral concentration, we found a strong susceptibility to viral oncolysis in over 70% of melanomas. In contrast, melanocytes displayed strong resistance to virus infection and showed complete protection by interferon. Several recombinant VSVs were compared, and all infected and killed most melanomas with differences in the time course with increasing rates of melanoma infection, as follows: VSV-CT9-M51 VSV-M51 VSV-G/GFP VSV-rp30. VSV-rp30 sequencing revealed 2 nonsynonymous mutations at codon positions P126 and L223, both of which appear to be required for the enhanced phenotype. VSV-rp30 showed effective targeting and infection of multiple subcutaneous and intracranial melanoma xenografts in SCID mice after tail vein virus application. Sequence analysis of mutations in the melanomas used revealed that BRAF but not NRAS gene mutation status was predictive for enhanced susceptibility to infection. In mouse melanoma models with specific induced gene mutations including mutations of the Braf, Pten, and Cdkn2a genes, viral infection correlated with the extent of malignant transformation. Similar to human melanocytes, mouse melanocytes resisted VSV-rp30 infection. This study confirms the general susceptibility of the majority of human melanoma types for VSV-mediated oncolysis.

  2. Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes.

    Science.gov (United States)

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling.

    Science.gov (United States)

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

    2016-05-10

    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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Progressive Increase in Telomerase Activity From Benign Melanocytic Conditions to Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Ruben D. Ramirez

    1999-04-01

    Full Text Available The expression of telomerase activity and the in situ localization of the human telomerase RNA component (hTR in melanocytic skin lesions was evaluated in specimens from sixty-three patients. Specimens of melanocytic nevi, primary melanomas and subcutaneous metastases of melanoma were obtained from fifty-eight patients, whereas metastasized lymph nodes were obtained from five patients. Telomerase activity was determined in these specimens by using a Polymerase Chain Reaction—based assay (TRAP. High relative mean telomerase activity levels were detected in metastatic melanoma (subcutaneous metastasess = 54.5, lymph node metastasess = 56.5. Much lower levels were detected in primary melanomas, which increased with advancing levels of tumor cell penetration (Clark II = 0.02, Clark III = 1.1, and Clark IV = 1.9. Twenty-six formalin-fixed, paraffin-embedded melanocytic lesions were sectioned and analyzed for telomerase RNA with a radioactive in situ hybridization assay. In situ hybridization studies with a probe to the template RNA component of telomerase confirmed that expression was almost exclusively confined to tumor cells and not infiltrating lymphocytes. These results indicate that levels of telomerase activity and telomerase RNA in melanocytic lesions correlate well with clinical stage and could potentially assist in the diagnosis of borderline lesions.

  5. Reciprocal responses of fibroblasts and melanocytes to α-MSH depending on MC1R polymorphisms

    OpenAIRE

    Stanisz, Hedwig; Seifert, Markus; Tilgen, Wolfgang; Vogt, Thomas; Rass, Knuth

    2011-01-01

    The melanocortin 1-receptor (MC1R) exhibits several variants in form of single nucleotide polymorphisms (SNPs) that are known to differentially regulate melanocyte function. However, whether and how MC1R polymorphisms also affect fibroblast function has not been investigated so far.

  6. Increasing epidermal growth factor receptor expression in human melanocytic tumor progression

    NARCIS (Netherlands)

    de Wit, P. E.; Moretti, S.; Koenders, P. G.; Weterman, M. A.; van Muijen, G. N.; Gianotti, B.; Ruiter, D. J.

    1992-01-01

    Different results have been reported on the expression of epidermal growth factor receptor (EGFR) in human melanocytic lesions, which may be due to different methodologic approaches. Therefore, we compared EGFR expression in six human melanoma cell lines by utilizing the monoclonal antibodies 2E9,

  7. Clinical and histological responses of congenital melanocytic nevi after single treatment with Q-switched lasers

    NARCIS (Netherlands)

    Grevelink, JM; vanLeeuwen, RL; Anderson, RR; Byers, HR

    Background: Laser irradiation of congenital melanocytic nevi is a controversial treatment. Recurrence of lesions after laser treatment appears to be the rule, and the effects of laser irradiation on cellular biological behavior and the possible mutagenic responses of nevomelanocytes that have

  8. Giant congenital melanocytic nevus (bathing trunk nevus associated with lipoma and neurofibroma: Report of two cases

    Directory of Open Access Journals (Sweden)

    Bhagwat P

    2009-01-01

    Full Text Available Giant congenital melanocytic nevi are rare and occur in about one out of every 2,00,000 to 5,00,000 births. There is a significant association between bathing trunk nevus and neurofibromatosis and lipomatosis. Apart from this, association of bathing trunk nevus with abnormalities like spina bifida occulta, meningocele, club foot and hypertrophy or atrophy of deeper structures of a limb, have been described. We are herewith reporting two cases of bathing trunk nevi. In our first case, an eight-year-old girl presented with a bathing trunk nevus studded with multiple, large nodules. Histopathological examination of the biopsy taken from one nodule revealed features of both neurofibroma and lipoma. To the best of our knowledge, features of both these hamartomas in one nodule of a single patient are probably not reported in the literature. In our second case, a 12-year-old girl presented with bathing trunk nevus and she had spina bifida occulta. She also had lipoma in the lesion of bathing trunk nevus. Both of our patients had satellite melanocytic nevi over the face, forearm, upper back and legs. Our second patient, in addition, had small melanocytic nevi over the medial canthus and sclerocorneal junction of the right eye. By the time this girl presented to us, the melanocytic nevus started fading in color and it had become brownish. We are reporting these cases for their peculiarities and for their rare features.

  9. Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms

    NARCIS (Netherlands)

    Kusters-vandevelde, H.V.; Engen-van Grunsven, A.C.H. van; Coupland, S.E.; Lake, S.L.; Rijntjes, J.; Pfundt, R.P.; Kusters, B.; Wesseling, P.; Blokx, W.A.M.; Groenen, P.J.T.A.

    2015-01-01

    Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal

  10. Mutations in G Protein Encoding Genes and Chromosomal Alterations in Primary Leptomeningeal Melanocytic Neoplasms

    NARCIS (Netherlands)

    Küsters-Vandevelde, Heidi V N; van Engen- van Grunsven, Ilse A C H; Coupland, Sarah E.; Lake, Sarah L.; Rijntjes, Jos; Pfundt, Rolph; Küsters, Benno; Wesseling, Pieter; Blokx, Willeke A M; Groenen, Patricia J T A

    2015-01-01

    Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal

  11. Expression of heat shock protein 105 and 70 in malignant melanoma and benign melanocytic nevi.

    Science.gov (United States)

    Park, Hye-Sang; Park, Chan-Hyuk; Choi, Bo-Ra; Lim, Mi-Sun; Heo, Su-Hak; Kim, Cheol-Hann; Kang, Sang-Gue; Whang, Kyu U; Cho, Moon K

    2009-05-01

    Heat shock proteins (HSPs) restore immature proteins or denatured proteins, thus protecting cells. Also, the expression of some HSPs is elevated substantially in malignant tumors, but the expression of HSPs in association with melanoma has yet to be studied. Therefore, we examined the expression patterns of HSP 70 and 105 in melanoma, benign melanocytic nevi and normal human skin. Two specimens of malignant melanoma, two of benign melanocytic nevi and six of normal human skin were analyzed using Western blot analysis for expression of HSP 70 and 105. In another set, 16 specimens of malignant melanoma, 24 of benign melanocytic nevi and eight of normal human skin were analyzed for the expression of HSP 105 using immunohistochemical studies. The Western blot analysis showed that HSP 70 was overexpressed in all three types. But, the HSP 105 was hardly expressed in normal human skin and benign melanocytic nevi. However, in malignant melanoma, the HSP 105 was overexpressed, and immunohistochemical examination of HSP 105 showed a result similar to that of Western blot analysis. In our study, HSP 105 is thought to be a more relevant tumor-associated antigen in malignant melanoma than is HSP 70.

  12. (Pheo)melanin photosensitizes UVA-induced DNA damage in cultured human melanocytes

    NARCIS (Netherlands)

    Wenczl, E.; Schans, G.P. van der; Roza, L.; Kolb, R.M.; Timmerman, A.J.; Smit, N.P.M.; Pavel, S.; Schothorst, A.A.

    1998-01-01

    The question of whether melanins are photoprotecting and/or photosensitizing in human skin cells continues to be debated. To evaluate the role of melanin upon UVA irradiation, DNA single-strand breaks (ssb) were measured in human melanocytes differing only in the amount of pigment produced by

  13. Giant congenital melanocytic nevus - Reconstruction using multiple modalities: A case report

    Directory of Open Access Journals (Sweden)

    Mohammed Mesfer Alkahtani

    2017-01-01

    Full Text Available Congenital melanocytic naevi are neuroectodermal lesions that are mainly composed of melanocytes. They are present in 1% to 6% of all newborns. These lesions carry the risk of transforming into melanomas; however, the psychological effect of such disfiguring naevi is potentially of greater concern to both the child and parent. Several classifications for congenital melanocytic naevi have been proposed, the most common of which is the sub-classification according to their size as this affects the choice of treatment. Many treatment modalities have been utilized including surgical excision followed by reconstruction, curettage, dermabrasion, laser therapy and chemical peels. In this report, we present a case of an otherwise healthy eight-year-old girl with a giant congenital melanocytic naevus on the central face. The lesion was mostly excised with remaining satellite lesions dermabraded. The defect was then reconstructed with a full thickness skin graft harvested from the expanded supraclavicular skin, in addition to the ReCell (non-cultured epithelial autograft technique. Within six months post-operation, excellent skin pigmentation and texture was achieved.

  14. Helium-neon laser irradiation stimulates migration and proliferation in melanocytes and induces repigmentation in segmental-type vitiligo.

    Science.gov (United States)

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

    Directory of Open Access Journals (Sweden)

    Zhuhui Qiao

    2016-01-01

    Full Text Available 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.

  16. LASP1, a Newly Identified Melanocytic Protein with a Possible Role in Melanin Release, but Not in Melanoma Progression.

    Directory of Open Access Journals (Sweden)

    Anjana Vaman V S

    Full Text Available The LIM and SH3 protein 1 (LASP1 is a focal adhesion protein. Its expression is increased in many malignant tumors. However, little is known about the physiological role of the protein. In the present study, we investigated the expression and function of LASP1 in normal skin, melanocytic nevi and malignant melanoma. In normal skin, a distinct LASP1 expression is visible only in the basal epidermal layer while in nevi LASP1 protein is detected in all melanocytes. Melanoma exhibit no increase in LASP1 mRNA compared to normal skin. In melanocytes, the protein is bound to dynamin and mainly localized at late melanosomes along the edges and at the tips of the cell. Knockdown of LASP1 results in increased melanin concentration in the cells. Collectively, we identified LASP1 as a hitherto unknown protein in melanocytes and as novel partner of dynamin in the physiological process of membrane constriction and melanosome vesicle release.

  17. Appearance of New Vemurafenib-associated Melanocytic Nevi on Normal-appearing Skin

    Science.gov (United States)

    Bedikian, Agop Y.; Kim, Kevin B.

    2013-01-01

    Background: Vemurafenib, a selective BRAF inhibitor that has antineoplastic activity in patients with unresectable or metastatic malignant melanoma whose tumor harbors a BRAF V600E mutation, has multiple drug-associated cutaneous adverse effects. Purpose: To provide a detailed and comprehensive review of reported changing or new pigmented lesions in oncology patients who have been treated with vemurafenib. Methods: The new appearance of melanocytic nevi on normal-appearing skin after initiating treatment with vemurafenib is described in two men with metastatic malignant melanoma whose tumors demonstrated a BRAF V600E mutation. Using the PubMed database, an extensive literature search was performed for the following topics: vermurafenib, nevus, nevi, melanoma, pigmented lesion, cutaneous, adverse effect, side effect. The results of the search were used to secure all reports of new or changing pigmented lesions after initiating treatment with vemurafenib. Results: Vemurafenib is associated with both changes in existing pigmented lesions (including involution, alteration of color and size, and progression to melanoma) and the onset of new melanocytic lesions—nevi (in 5 patients) and primary melanomas (in 2 patients). Visual examination, dermoscopic evaluation, and reflectance confocal microscopy have been used to document the changes in existing or new melanocytic lesions subsequent to initiating treatment with vermurafenib. Histopathology analysis has shown these lesions to usually be either dysplastic nevi or new primary melanomas. Conclusion: Vemurafenib-treated patients can develop new pigmented lesions (such as nevi) and/or morphological changes in their existing melanocytic lesions (such as involution, increase in size, or alternation of color). In addition, they can develop new primary malignant melanomas that either occur de novo on normal-appearing skin or develop in pre-existing melanocytic lesions. Therefore, total body skin examination should be

  18. Deep shave excision of macular melanocytic nevi with the razor blade biopsy technique.

    Science.gov (United States)

    Gambichler, T; Senger, E; Rapp, S; Alamouti, D; Altmeyer, P; Hoffmann, K

    2000-07-01

    Shave excision is an established surgical method for removing benign skin lesions for cosmetic and functional reasons. Usually superficial shave excision is performed with a common scalpel blade for the removal of papular nevi. However, there is little known about deep shave excision of macular melanocytic nevi with the razor blade technique. The present study was undertaken to evaluate the cosmetic outcome of deep shave excision of macular melanocytic nevi with the razor blade technique. Moreover, its potency for sufficient removal of these lesions was investigated. Within routine skin cancer screening 45 outpatients with a total of 77 macular melanocytic nevi were prospectively recruited. Deep shave excisions of these lesions were performed with a double-edged razor blade followed by chemical hemostasis. Histologically all specimens were processed and evaluated in a routine manner. After 6 months the physician and patients evaluated the shave sites for cosmetic outcome with a score graded from 1 to 4 (1 = excellent; 2 = good; 3 = moderate; 4 = poor). Histologically 88% (68 of 77) of the melanocytic lesions were described as completely excised and 60% (46 of 77) were diagnosed as atypical melanocytic nevi; 12% (9 of 77) of the nevi were incompletely excised on the depth. On average, the deep margin of the specimens (n = 77) was 0.5 mm (range 0-1.8 mm) and the lateral margin was 2 mm (range 0.3-8.2 mm). After 6 months 56 shave sites could be reassessed. We observed mild hypopigmentation in 52% (29 of 56), hyperpigmentation in 32% (18 of 56), and erythema in 23% (13 of 56). Recurrent nevi occurred in 13% (7 of 56). The evaluation of the cosmetic outcome by the patients (mean score 1.7) achieved better results than the evaluation by the physician (mean score 2.5). The cosmetic results showed no significant (P >.05) differences in various anatomic sites. Our data confirm that deep razor blade excision presents a highly useful and inexpensive method for the removal of

  19. Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma.

    Science.gov (United States)

    Takata, Minoru; Murata, Hiroshi; Saida, Toshiaki

    2010-02-01

    The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark's multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking 'field melanocytes', which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.

  20. Loss of heterozygosity and microsatellite instability in acquired melanocytic nevi: towards a molecular definition of the dysplastic nevus.

    Science.gov (United States)

    Rübben, Albert; Bogdan, Inja; Grussendorf-Conen, Elke-Ingrid; Burg, Günter; Böni, Roland

    2002-01-01

    Acquired melanocytic nevi may show signs of histological dysplasia, and epidemiological studies have demonstrated that dysplastic melanocytic nevi (DMN) are associated with an elevated melanoma risk. Nevertheless, the concept of DMN as precursors of melanoma has remained a concept, in view of the difficulty of establishing unambiguous cytological and histological criteria for DMN. Recent molecular data suggest that genetic instability is more frequent in DMN than in benign acquired melanocytic nevi. We have analyzed 54 benign melanocytic nevi and 6 DMN for loss of heterozygosity (LOH) at microsatellite markers D9S171, IFNA, D9S270, D9S265. LOH at one or more loci was detected in 17 out of 54 benign nevi and in 4 out of 6 DMN. LOH was demonstrated at 26 out of 103 amplified and informative microsatellites in benign nevi and at 6 out of 11 microsatellites in DMN. In addition, 6 benign nevi and 6 DMN were microdissected in 4-15 regions per lesion and analyzed for LOH and microsatellite instability (MSI) at D9S162 and D14S53. Both LOH and MSI were detected more frequently in dysplastic nevi (LOH frequency 0.61 vs 0.18; MSI frequency 0.27 vs 0.05). These results confirm that genetic instability is more prevalent in DMN than in benign acquired melanocytic nevi. Therefore, DMN might be defined as a monoclonal and genetically unstable, but limited, melanocytic proliferation that distinguishes this entity from the benign nevus and from malignant melanoma.

  1. Substantial Effect of Melanin Influencing Factors on In vitro Melanogenesis in Muzzle Melanocytes of Differently Colored Hanwoo

    Science.gov (United States)

    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

  2. Raman Spectroscopic Characterization of Melanoma and Benign Melanocytic Lesions Suspected of Melanoma Using High-Wavenumber Raman Spectroscopy.

    Science.gov (United States)

    Santos, Inês P; Caspers, Peter J; Bakker Schut, Tom C; van Doorn, Remco; Noordhoek Hegt, Vincent; Koljenović, Senada; Puppels, Gerwin J

    2016-08-02

    Melanoma is a pigmented type of skin cancer, which has the highest mortality of all skin cancers. Because of the low clinical diagnostic accuracy for melanoma, an objective tool is needed to assist clinical assessment of skin lesions that are suspected of (early) melanoma. The aim of this study was to identify spectral differences in the CH region of HWVN (high-wavenumber) Raman spectra between melanoma and benign melanocytic lesions clinically suspected of melanoma. We used these spectral differences to explore preliminary classification models to distinguish melanoma from benign melanocytic lesions. Data from 82 freshly excised melanocytic lesions clinically suspected of melanoma were measured using an in-house built Raman spectrometer, which has been optimized for measurements on pigmented skin lesions (excitation wavelength 976 nm and a wavelength range of the Raman signal 1340-1540 nm). Clear spectral differences were observed between melanoma and benign melanocytic lesions. These differences can be assigned mainly to the symmetric CH2 stretching vibrations of lipids. Our results show that the Raman bands between 2840 and 2930 cm(-1) have increased intensity for melanoma when compared to benign melanocytic lesions, suggesting an increase in lipid content in melanoma. These results demonstrate that spectroscopic information in the CH-stretching region of HWVN Raman spectra can discriminate melanoma from benign melanocytic lesions that are often clinically misdiagnosed as melanoma and that Raman spectroscopy has the potential to provide an objective clinical tool to improve the clinical diagnostic accuracy of skin lesions suspected of melanoma.

  3. Immunohistochemical expression of the glucose transporters Glut-1 and Glut-3 in human malignant melanomas and benign melanocytic lesions

    Directory of Open Access Journals (Sweden)

    Parente Paola

    2008-09-01

    Full Text Available Abstract Background Reported data indicate that cancer cells have increased rates of glucose metabolism, as determined by 18FDG-PET imaging in patients with malignancies. The results of many studies have demonstrated that the expression of glucose transporters, especially Glut-1, is increased in a variety of malignancies. This study was undertaken to assess the differential expression of Glut-1 and Glut-3 by benign and malignant melanocytic lesions. Methods Immunohistochemical staining for Glut-1 and Glut-3 was performed on paraffin-embedded tissue sections prepared from melanocytic nevi (12 cases, Spitz nevi (12 cases and primary cutaneous malignant melanomas (20 cases. Results We observed immunoreactivity for Glut-1 in all melanocytic nevi, 9 of the 12 Spitz nevi and in 9 of the 20 malignant melanomas, whereas Glut-3 was expressed in all the melanocytic lesions, both benign and malignant. Conclusion These findings indicate that the glucose transporters Glut-1 and Glut-3 play a role in the glucose metabolism of melanocytic cells. Glut-1 was present in the majority of benign nevi, whereas its expression was downregulated in 55% of malignant melanomas. Our results suggest that glucose transporter Glut-1 expression can significantly discriminate between human malignant melanoma and benign melanocytic nevi, and support the idea that additional mechanisms other than Glut-1 may contribute to glucose uptake in melanomas.

  4. Reflectance Confocal Microscopy: A Promising Tool to Identify Malignancy in Melanocytic Lesions Exhibiting a Dermoscopic Island.

    Science.gov (United States)

    Elosua-González, M; Gamo-Villegas, R; Floristán-Muruzábal, U; Pinedo-Moraleda, F; López-Estebaranz, J L

    2017-11-22

    The dermoscopic island is described as a well-defined area in a melanocytic lesion, with a different dermoscopic pattern from the rest of the lesion. It is predictive of melanoma, particularly when the pattern of the island is atypical. We present the reflectance confocal microscopy (RCM) findings in 3 lesions with dermoscopic islands: nevus-associated melanoma, melanocytic nevus, and in situ melanoma. The nevus-associated melanoma and in situ melanoma presented cellular atypia (atypical cells in isolation or forming nests) and architectural distortion on RCM. The nevus presented an island sign with a typical globular pattern with dense nests and no atypia on RCM. The island sign is mainly associated with in situ and nevus-associated melanomas. RCM offers good cellular resolution to the depth of the reticular dermis and is useful for diagnosing of melanomas presenting a dermoscopic island. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. "Sky Full of Stars" Pattern: Dermoscopic Findings in a Desmoplastic Giant Congenital Melanocytic Nevus.

    Science.gov (United States)

    Martín-Carrasco, Pablo; Bernabeu-Wittel, José; Dominguez-Cruz, Javier; Zulueta Dorado, Teresa; Conejo-Mir Sanchez, Julian

    2017-05-01

    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. © 2017 Wiley Periodicals, Inc.

  6. Melanocyte response to gravitational stress: an overview with a focus on the role of cyclic nucleotides

    Science.gov (United States)

    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

  7. Stereological estimation of nuclear volume in benign melanocytic lesions and cutaneous malignant melanomas

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt

    1989-01-01

    noninvasive melanocytic cutaneous tumors were investigated retrospectively. vV clearly distinguished between noninvasive (average vV = 122 microns 3) and invasive lesions (average vV = 246 microns 3). Most of the patients with malignant melanomas showing an overlap of nuclear vV with benign lesions had......V in melanocytic cutaneous tumors and to compare these with estimates of nuclear volume fraction and with traditional two-dimensional morphometric estimates of nuclear profile area, nuclear density, and mitotic index. Routinely processed, paraffin embedded tissue specimens from 47 malignant melanomas and 76...... a favorable prognosis. No significant differences in vV could be demonstrated among different noninvasive tumor types. Two-dimensional estimates only distinguished benign from malignant tumors with considerable overlap and with significantly varying influence from other factors among different benign lesional...

  8. Malignant melanoma arising in congenital melanocytic nevi: clinical and dermoscopic challenges

    Directory of Open Access Journals (Sweden)

    Fatma Pelin Cengiz

    2017-01-01

    Full Text Available Congenital melanocytic nevi (CMN are visible pigmented lesions in the skin that are present at birth. CMN are benign malformations resulting from defective development of melanocyte precursors in the embryo. Six MMs from six patients were analyzed by clinical and dermoscopic examination. Of the patients, 33.3% were female (N = 2 and 66.6% were male (N = 4. Of the MMs, four (66.6% were superficial spreading MM and two (33.3 % were in situ MM. A reticular pattern was present in the MMs of three patients (50%, a homogeneous pattern was present in the other patients (50% at the base of the MMs. Superficial spreading melanomas and in situ melanomas with atypical dots and globules and a blue-white veil were the most common dermoscopic features of MMs found in CMN.

  9. Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality

    Directory of Open Access Journals (Sweden)

    Thomas D. Arnold

    2013-09-01

    Neural crest cells (NCCs participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Integrin-linked kinase (ILK is a serine/threonine kinase and a major regulator of integrin signaling. It links integrins to the actin cytoskeleton and recruits other adaptor molecules into a large complex to regulate actin dynamics and integrin function. Using the Cre-lox system, we deleted Ilk from NCCs of mice to investigate its role in NCC morphogenesis. The resulting mutants developed a severe aneurysmal arterial trunk that resulted in embryonic lethality during late gestation. Ilk mutants showed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and the outflow tract. Within the conotruncal cushions, Ilk-deficient NCCs exhibited disorganization of F-actin stress fibers and a significantly rounder morphology, with shorter cellular projections. Additionally, absence of ILK resulted in reduced in vivo phosphorylation of Smad3 in NCCs, which correlated with reduced αSMA levels. Our findings resemble those seen in Pinch1 and β1 integrin conditional mutant mice, and therefore support that, in neural crest-derived cells, ILK and Pinch1 act as cytoplasmic effectors of β1 integrin in a pathway that protects against aneurysms. In addition, our conditional Ilk mutant mice might prove useful as a model to study aortic aneurysms caused by reduced Smad3 signaling, as occurs in the newly described aneurysms-osteoarthritis syndrome, for example.

  10. Comparison of visual effects of immersion fluids for dermoscopic examination of acral volar melanocytic lesions

    Directory of Open Access Journals (Sweden)

    Tzu-Hsiu Chen

    2014-06-01

    Conclusion: The use of either mineral oil or ultrasound jelly as interface provides acceptable visual effects for the dermoscopic examination of acral volar melanocytic lesions. The use of the polarized light mode reduced the reflection and scattering of light, resulting in better visual effect than that achieved using the nonpolarized light mode. In the early diagnosis of acral melanoma, choosing the appropriate application of immersion fluid and observation mode yields the optimal visual effect.

  11. Resolution of vitiligo following excision of halo congenital melanocytic nevus: a rare case report.

    Science.gov (United States)

    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. © 2015 Wiley Periodicals, Inc.

  12. Interferon-γ links UV to melanocyte activation and promotes melanomagenesis

    Science.gov (United States)

    Zaidi, M. Raza; Davis, Sean; Noonan, Frances P.; Graff-Cherry, Cari; Hawley, Teresa S.; Walker, Robert L.; Feigenbaum, Lionel; Fuchs, Elaine; Lyakh, Lyudmila; Young, Howard A.; Hornyak, Thomas J.; Arnheiter, Heinz; Trinchieri, Giorgio; Meltzer, Paul S.; De Fabo, Edward C.; Merlino, Glenn

    2010-01-01

    Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, whose incidence continues to rise. Epidemiological studies reveal that the major etiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood1,2. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor (HGF/SF) transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and etiologic criteria, but only when irradiated as neonatal pups with UVB, not UVA3,4. However, mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, and suggest that IFN-γ-R signaling represents a novel therapeutic melanoma target. PMID:21248750

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

    OpenAIRE

    Nasti, Tahseen H.; Cochran, J. Barry; Tsuruta, Yuko; Yusuf, Nabiha; McKay, Kristopher M.; Athar, Mohammad; Timares, Laura; 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 lesio...

  14. Histopathologic Findings of Cutaneous Hyperpigmentation in Addison Disease and Immunostain of the Melanocytic Population.

    Science.gov (United States)

    Fernandez-Flores, Angel; Cassarino, David S

    2017-05-31

    The histopathological features of cutaneous hyperpigmentation in Addison disease have very occasionally been reported, and they include acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin hyperpigmentation, and superficial dermal melanophages. We present a study on 2 biopsies from the arm and the thigh in a 77-year-old woman with a long clinical history of Addison disease as well as senile purpura and alopecia of female pattern. The patient presented diffuse hyperpigmentation of the skin, more pronounced on her face, and left upper forehead. The skin biopsies showed no remarkable dermal inflammatory infiltrate with melanocytic hyperpigmentation of the basal layer of the epidermis as well as a mild amount of melanophages in the papillary dermis. In addition, we found lipofuscin in the luminal pole of the secretory epithelium of the eccrine glands. In the perieccrine areas, there was Perls-positive pigment in the cytoplasm of macrophages most likely related to the senile purpura. An immunohistochemical study with Melan-A showed a melanocyte/keratinocyte ratio of 1:20 (5%) in the arm and of less than 1:50 (only 2 melanocytes in the whole section; <2%) in the thigh.

  15. Human telomerase RNA component expression in Spitz nevi, common melanocytic nevi, and malignant melanomas.

    Science.gov (United States)

    Guttman-Yassky, Emma; Bergman, Reuven; Manov, Lena; Sprecher, Eli; Shaefer, Yan; Kerner, Hedviga

    2002-07-01

    Telomerase is a ribonucleoprotein DNA polymerase that is capable of synthesizing telomeres onto the ends of chromosomes. The cumulative loss of telomerase activity is believed to be associated with cell senescence. Telomerase activity has been shown to be higher in malignant melanomas than in common melanocytic nevi. The aim of the present study was to elucidate the pattern of expression of the human telomerase RNA (hTER) component in routinely processed specimens of Spitz nevi, malignant melanomas, and ordinary melanocytic nevi. Ten specimens of each type of tumor were studied, using an in situ hybridization technique. All three types of tumors demonstrated moderate to high intensities of hTER expression, usually in more than half of the tumor cells, and the majority of the studied lesions in each group did not show stratification of staining. The hTER component was also detected in the epidermis, sweat glands, and pilosebaceous units. hTER levels do not necessarily correlate with the level of telomerase activity, and the level and pattern of hTER expression are not useful as an adjunct to the histologic differential diagnosis of Spitz nevi from melanocytic nevi and malignant melanomas.

  16. C-fos protein expression in Spitz nevi, common melanocytic nevi, and malignant melanomas.

    Science.gov (United States)

    Bergman, R; Kerner, H; Manov, L; Friedman-Birnbaum, R

    1998-06-01

    The expression of c-fos protein was studied in formalin-fixed, paraffin-embedded sections of 11 compound Spitz nevi (SNs), 16 ordinary compound melanocytic nevi (MNs), and 17 malignant melanomas (MMs) using monoclonal antibody MAB1283 and an immunoperoxidase technique. Eleven (100%) SNs, 15 (94%) MNs, and 16 (94%) MMs showed positive reactions in some of the tumor cells (p = nonsignificant). In the majority of the tumors the staining was located in nuclei and graded as moderate to strong in intensity. The percentages of positively stained cells did not differentiate the three types of tumor, although they were higher in the melanocytic nevi. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Positive staining for c-fos was also frequently found in the normal skin constituents within and adjacent to the melanocytic tumors. In conclusion, the pattern of expression of c-fos in routinely processed specimens does not differentiate between SNs, MNs, and MMs.

  17. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus

    Science.gov (United States)

    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.

  18. A histopathological study of melanocytic and pigmented skin lesions in patients with albinism.

    Science.gov (United States)

    van der Westhuizen, Gerhard; Beukes, Catherine A; Green, Brent; Sinclair, Werner; Goedhals, Jacqueline

    2015-11-01

    Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by diminished pigmentation of the skin, hair and eyes. Individuals with OCA are at increased risk to develop sun-induced skin malignancies. The incidence of malignant melanoma in OCA individuals is, however, very low. The aim of this study was to document pigmented and melanocytic skin lesions occurring in patients with OCA. A prospective study was performed. Sixteen patients with OCA presenting at the Oncology and Dermatology Departments at Universitas Academic Hospital Annex in Bloemfontein, South Africa, were included. Selected clinically pigmented and/or melanocytic lesions were biopsied and studied by light microscopy. Twenty-four punch biopsies were taken. Ten dendritic freckles and 10 melanocytic nevi were confirmed histologically. The nevi, which occurred in eight patients, were found on sun-protected skin. All the freckles occurred on sun-exposed skin. Twelve patients had current or previous skin malignancies. No melanomas were present in the study population. Other skin lesions ranged from solar keratoses to squamous cell carcinomas. The majority of pigmented lesions were dendritic freckles that occurred on sun-exposed skin. None of the patients had a current or previous diagnosis of malignant melanoma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Study of transplantation of melanocyte keratinocyte suspension in treatment of vitiligo

    Directory of Open Access Journals (Sweden)

    Rastogi Swati

    2006-01-01

    Full Text Available Background: Vitiligo is a common skin disease; however it still remains a difficult disease to treat. Not all patients respond to current forms of treatment. Surgical techniques offer a potential solution for patients with vitiligo who fail to respond to medical treatments. Aims: Aims of the study were to evaluate response of transplantation of melanocyte keratinocyte cell suspension in patients of stable vitiligo. Materials and Methods: Total 10 patients of stable localized vitiligo were included in the study and were treated with transplantation of autologous melanocyte keratinocyte suspension after motor/manual dermabrasion. Results: Out of total 10 patients, 40% [4 patients] had excellent [95 to 100%] response, 30% [3 patients] had good [65 to 94%] response, 20% [2 patients] had fair [20 to 64%] response and 10% [1 patient] had poor response [0 to 19%]. Age and sex of the patients and size and location of lesions, did not show significant influence on results of transplantation. Conclusion: Autologus melanocyte keratinocyte suspension combined with motor/manual dermabrasion is an effective affordable treatment for patients with stable vitiligo who fail to respond to medical treatments.

  20. Normal and tumoral melanocytes exhibit q-Gaussian random search patterns.

    Directory of Open Access Journals (Sweden)

    Priscila C A da Silva

    Full Text Available In multicellular organisms, cell motility is central in all morphogenetic processes, tissue maintenance, wound healing and immune surveillance. Hence, failures in its regulation potentiates numerous diseases. Here, cell migration assays on plastic 2D surfaces were performed using normal (Melan A and tumoral (B16F10 murine melanocytes in random motility conditions. The trajectories of the centroids of the cell perimeters were tracked through time-lapse microscopy. The statistics of these trajectories was analyzed by building velocity and turn angle distributions, as well as velocity autocorrelations and the scaling of mean-squared displacements. We find that these cells exhibit a crossover from a normal to a super-diffusive motion without angular persistence at long time scales. Moreover, these melanocytes move with non-Gaussian velocity distributions. This major finding indicates that amongst those animal cells supposedly migrating through Lévy walks, some of them can instead perform q-Gaussian walks. Furthermore, our results reveal that B16F10 cells infected by mycoplasmas exhibit essentially the same diffusivity than their healthy counterparts. Finally, a q-Gaussian random walk model was proposed to account for these melanocytic migratory traits. Simulations based on this model correctly describe the crossover to super-diffusivity in the cell migration tracks.

  1. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

    Directory of Open Access Journals (Sweden)

    Hyunjung Choi

    Full Text Available 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.

  2. α-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes

    Science.gov (United States)

    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

  3. UV light activates a Gαq/11-coupled phototransduction pathway in human melanocytes

    Science.gov (United States)

    Bellono, Nicholas W.; Najera, Julia A.

    2014-01-01

    While short exposure to solar ultraviolet radiation (UVR) can elicit increased skin pigmentation, a protective response mediated by epidermal melanocytes, chronic exposure can lead to skin cancer and photoaging. However, the molecular mechanisms that allow human skin to detect and respond to UVR remain incompletely understood. UVR stimulates a retinal-dependent signaling cascade in human melanocytes that requires GTP hydrolysis and phospholipase C β (PLCβ) activity. This pathway involves the activation of transient receptor potential A1 (TRPA1) ion channels, an increase in intracellular Ca2+, and an increase in cellular melanin content. Here, we investigated the identity of the G protein and downstream elements of the signaling cascade and found that UVR phototransduction is Gαq/11 dependent. Activation of Gαq/11/PLCβ signaling leads to hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate diacylglycerol (DAG) and inositol 1, 4, 5-trisphosphate (IP3). We found that PIP2 regulated TRPA1-mediated photocurrents, and IP3 stimulated intracellular Ca2+ release. The UVR-elicited Ca2+ response appears to involve both IP3-mediated release from intracellular stores and Ca2+ influx through TRPA1 channels, showing the fast rising phase of the former and the slow decay of the latter. We propose that melanocytes use a UVR phototransduction mechanism that involves the activation of a Gαq/11-dependent phosphoinositide cascade, and resembles light phototransduction cascades of the eye. PMID:24470488

  4. FGF21 regulates melanogenesis in alpaca melanocytes via ERK1/2-mediated MITF downregulation.

    Science.gov (United States)

    Wang, Ruiwei; Chen, Tianzhi; Zhao, Bingling; Fan, Ruiwen; Ji, Kaiyuan; Yu, Xiuju; Wang, Xianjun; Dong, Changsheng

    2017-08-19

    Fibroblast growth factor 21 (FGF21) is known as a metabolic regulator to regulate the metabolism of glucose and lipids. However, the underlying mechanism of FGF21 on melanin synthesis remains unknown. Therefore, the current study investigates the effect of FGF21 on melanogenesis in alpaca melanocytes. We transfected the FGF21 into alpaca melanocytes, then detected the melanin contents, protein and mRNA levels of pigmentation-related genes in order to determine the melanogenesis-regulating pathway of FGF21. The results showed that FGF21 overexpression suppressed melanogenesis and decreased the expression of the major target genes termed microphthalmia-associated transcription factor (MITF) and its downstream genes, including tyrosinase (TYR) and tyrosinase-related protein 2 (TRP2). However FGF21 increased the expression of phospho-extracellular signal-regulated kinase (p-Erk1/2). In contrast, FGF21-siRNA, a small interference RNA mediating FGF21 silencing, abolished the inhibition of melanogenesis. Altogether, FGF21 may decrease melanogenesis in alpaca melanocytes via ERK activation and subsequent MITF downregulation, which is then followed by the suppression of melanogenic enzymes and melanin production. Copyright © 2017. Published by Elsevier Inc.

  5. Normal and tumoral melanocytes exhibit q-Gaussian random search patterns.

    Science.gov (United States)

    da Silva, Priscila C A; Rosembach, Tiago V; Santos, Anésia A; Rocha, Márcio S; Martins, Marcelo L

    2014-01-01

    In multicellular organisms, cell motility is central in all morphogenetic processes, tissue maintenance, wound healing and immune surveillance. Hence, failures in its regulation potentiates numerous diseases. Here, cell migration assays on plastic 2D surfaces were performed using normal (Melan A) and tumoral (B16F10) murine melanocytes in random motility conditions. The trajectories of the centroids of the cell perimeters were tracked through time-lapse microscopy. The statistics of these trajectories was analyzed by building velocity and turn angle distributions, as well as velocity autocorrelations and the scaling of mean-squared displacements. We find that these cells exhibit a crossover from a normal to a super-diffusive motion without angular persistence at long time scales. Moreover, these melanocytes move with non-Gaussian velocity distributions. This major finding indicates that amongst those animal cells supposedly migrating through Lévy walks, some of them can instead perform q-Gaussian walks. Furthermore, our results reveal that B16F10 cells infected by mycoplasmas exhibit essentially the same diffusivity than their healthy counterparts. Finally, a q-Gaussian random walk model was proposed to account for these melanocytic migratory traits. Simulations based on this model correctly describe the crossover to super-diffusivity in the cell migration tracks.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Clarke, Loren E; 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

    2017-02-15

    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. 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. The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. 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. © 2016 Myriad Genetics, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  8. [Management of benign melanocytic lesions as a melanoma prevention. Systematic review].

    Science.gov (United States)

    Linertová, Renata; Valcárcel-Nazco, Cristina; Lacalle-Remigio, Juan Ramón

    2016-08-19

    There is a growing concern and awareness of skin cancer. As a result, possibly unnecessary surgeries of melanocytic lesions are carried out as a prophylactic measure. We performed a systematic review of the medical literature to identify primary studies on the effectiveness and cost-effectiveness of surgery treatment of benign melanocytic lesions for melanoma prevention. We included 19 primary studies on surgical treatment of acquired melanocytic lesions and one economic evaluation. Indicators, such as number needed to treat and the malignancy ratio, depend on several factors such as specialty and experience of the physician, pressure from the patient or patient characteristics. Early diagnosis of melanoma is critical in preventing skin cancer. However, primary studies show through several indicators that there are factors that increase the proportion of lesions treated unnecessarily. Effectiveness can be improved by careful use of techniques to identify suspicious lesions and educational programs for physicians, especially in primary care. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  9. Premature graying as a consequence of compromised antioxidant activity in hair bulb melanocytes and their precursors.

    Science.gov (United States)

    Shi, Ying; Luo, Long-Fei; Liu, Xiao-Ming; Zhou, Qiong; Xu, Shi-Zheng; Lei, Tie-Chi

    2014-01-01

    Intricate coordinated mechanisms that govern the synchrony of hair growth and melanin synthesis remain largely unclear. These two events can be uncoupled in prematurely gray hair, probably due to oxidative insults that lead to the death of oxidative stress-sensitive melanocytes. In this study, we examined the gene expression profiles of middle (bulge) and lower (hair bulb) segments that had been micro-dissected from unpigmented and from normally pigmented hair follicles from the same donors using quantitative real-time RT-PCR (qPCR) arrays. We found a significant down-regulation of melanogenesis-related genes (TYR, TYRP1, MITF, PAX3, POMC) in unpigmented hair bulbs and of marker genes typical for melanocyte precursor cells (PAX3, SOX10, DCT) in unpigmented mid-segments compared with their pigmented analogues. qPCR, western blotting and spin trapping assays revealed that catalase protein expression and hydroxyl radical scavenging activities are strongly repressed in unpigmented hair follicles. These data provide the first clear evidence that compromised antioxidant activity in gray hair follicles simultaneously affects mature hair bulb melanocytes and their immature precursor cells in the bulge region.

  10. Premature graying as a consequence of compromised antioxidant activity in hair bulb melanocytes and their precursors.

    Directory of Open Access Journals (Sweden)

    Ying Shi

    Full Text Available Intricate coordinated mechanisms that govern the synchrony of hair growth and melanin synthesis remain largely unclear. These two events can be uncoupled in prematurely gray hair, probably due to oxidative insults that lead to the death of oxidative stress-sensitive melanocytes. In this study, we examined the gene expression profiles of middle (bulge and lower (hair bulb segments that had been micro-dissected from unpigmented and from normally pigmented hair follicles from the same donors using quantitative real-time RT-PCR (qPCR arrays. We found a significant down-regulation of melanogenesis-related genes (TYR, TYRP1, MITF, PAX3, POMC in unpigmented hair bulbs and of marker genes typical for melanocyte precursor cells (PAX3, SOX10, DCT in unpigmented mid-segments compared with their pigmented analogues. qPCR, western blotting and spin trapping assays revealed that catalase protein expression and hydroxyl radical scavenging activities are strongly repressed in unpigmented hair follicles. These data provide the first clear evidence that compromised antioxidant activity in gray hair follicles simultaneously affects mature hair bulb melanocytes and their immature precursor cells in the bulge region.

  11. Expression of Glut-1 in Malignant Melanoma and Melanocytic Nevi: an Immunohistochemical Study of 400 Cases.

    Science.gov (United States)

    Důra, Miroslav; Němejcová, Kristýna; Jakša, Radek; Bártů, Michaela; Kodet, Ondřej; Tichá, Ivana; Michálková, Romana; Dundr, Pavel

    2017-11-11

    The glucose transporter-1 (Glut-1) is a cell membrane glycoprotein involved in glucose uptake. An increased expression of Glut-1 is an important cell adaptation mechanism against hypoxia. An upregulation of Glut-1 can be found in several types of malignant tumors, which are able to reprogram their metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect). However, the data regarding melanocytic lesions is equivocal. We performed comprehensive immunohistochemical analysis of the Glut-1 expression in 225 malignant melanomas (MM) and 175 benign nevi. Only the membranous expression of Glut-1 was regarded as positive. The expression of Glut-1 (the cut-off for positivity was determined as H-score 15) was found in 69/225 malignant melanomas. The number of positive cases and the H-score of Glut-1 increased where there was a higher Breslow thickness (p Glut-1 is a common feature of a malignant melanoma but this type of expression is very rare in benign melanocytic nevi. Our results suggest that the membranous expression of Glut-1 can be used as a surrogate marker in the assessing of the biological nature of benign and malignant melanocytic lesions. However, despite its high specificity, the sensitivity of this marker is relatively low. Moreover, due to the fact that the increased expression of Glut-1 correlates with a shorter survival period (10-year disease free survival, recurrence free survival and metastasis free survival and MFS), it can be used as a prognostically adverse factor.

  12. DMEM enhances tyrosinase activity in B16 mouse melanoma cells and human melanocytes

    Directory of Open Access Journals (Sweden)

    Panpen Diawpanich

    2008-07-01

    Full Text Available Media components may affect the activities of cultured cells. In this study, tyrosinase activity was evaluated by using B16-F10 mouse melanoma cell lines (B16-F10 and primary human melanocytes cultured in different media. An optical density measurement and a L-dopa reaction assay were used as the determination of the tyrosinase activity. The study of B16-F10 found the optical density to be 2010, 2246 and 2961 in cells cultured in RPMI Medium 1640 (RPMI1640,Minimum Essential Medium (MEM and Dulbecco’s Modified Eagle Medium (DMEM, respectively. Moreover, compared to RPMI 1640 and MEM, DMEM showed the darkest color of melanin formation in culture media and in cells after the L-dopa reaction assay. Addition of kojic acid showed a significant inhibitory effect on tyrosinase activity in all media.Whereas MCDB153 showed no significant effect on human melanocytes, DMEM caused a dramatic increase in tyrosinase activity after 4 days of cultivation. Addition of kojic acid showed a significant tyrosinase inhibitory effect in DMEM only. Furthermore, an active ingredient in green tea, epigallocathechin gallate (EGCG could inhibit tyrosinase activity in both B16-F10 and human melanocytes cultured in DMEM. In summary, these results suggest that DMEM is a suitable medium that provides high detection sensitivity in a tyrosinase inhibition assay.

  13. UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Maiko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Ichihara, Masatoshi; Tajima, Orie; Sobue, Sayaka; Kambe, Mariko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Sugiura, Kazumitsu [Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Furukawa, Koichi, E-mail: koichi@med.nagoya-u.ac.jp [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Furukawa, Keiko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan)

    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.

  14. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Directory of Open Access Journals (Sweden)

    Cécile eCoste

    2015-06-01

    Full Text Available Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL12-abundant reticular (CAR cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs, which have been recently identified as neural crest-derived cells (NCSCs. Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-to-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  15. DHODH modulates transcriptional elongation in the neural crest and melanoma.

    Science.gov (United States)

    White, Richard Mark; Cech, Jennifer; Ratanasirintrawoot, Sutheera; Lin, Charles Y; Rahl, Peter B; Burke, Christopher J; Langdon, Erin; Tomlinson, Matthew L; Mosher, Jack; Kaufman, Charles; Chen, Frank; Long, Hannah K; Kramer, Martin; Datta, Sumon; Neuberg, Donna; Granter, Scott; Young, Richard A; Morrison, Sean; Wheeler, Grant N; Zon, Leonard I

    2011-03-24

    Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.

  16. MC1R and the response of melanocytes to ultraviolet radiation

    Energy Technology Data Exchange (ETDEWEB)

    Rouzaud, Francois [Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 2132, Bethesda, MD 20892 (United States); Kadekaro, Ana Luisa [Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267 (United States); Abdel-Malek, Zalfa A. [Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267 (United States); Hearing, Vincent J. [Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 2132, Bethesda, MD 20892 (United States)]. E-mail: hearingv@nih.gov

    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 ({alpha}MSH) 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 {alpha}MSH 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

  17. Evolvable synthetic neural system

    Science.gov (United States)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  18. Simvastatin Protects Human Melanocytes from H2O2-Induced Oxidative Stress by Activating Nrf2.

    Science.gov (United States)

    Chang, Yuqian; Li, Shuli; Guo, Weinan; Yang, Yuqi; Zhang, Weigang; Zhang, Qian; He, Yuanmin; Yi, Xiuli; Cui, Tingting; An, Yawen; Song, Pu; Jian, Zhe; Liu, Ling; Li, Kai; Wang, Gang; Gao, Tianwen; Wang, Lin; Li, Chunying

    2017-06-01

    The prevention of hydrogen peroxide (H2O2)-induced oxidative stress has proved to be beneficial to vitiligo patients. Simvastatin possesses antioxidative capacity and has shown protective effect in various oxidative stress-related diseases. However, whether simvastatin can protect human melanocytes against oxidative stress has not been investigated. In this study, we initially found that pretreatment with 0.1 μmol/L to 1.0 μmol/L simvastatin led to increased cell viability and decreased cell apoptosis of melanocytes in response to H2O2. In addition, simvastatin was able to potentiate the activity of antioxidant enzymes and lessen intracellular reactive oxygen species accumulation. Furthermore, we found that simvastatin promoted the activation of nuclear erythroid 2-related factor (Nrf2) and that knockdown of Nrf2 abolished the protective effect of simvastatin against H2O2-induced oxidative damage. More importantly, the mutual enhancement between mitogen-activated protein kinase pathways and p62 contributed to simvastatin-induced Nrf2 activation in melanocytes. Finally, simvastatin showed more antioxidative capacity and better protective effect than aspirin in H2O2-treated melanocytes. Taken together, our results show that simvastatin protects human melanocytes from H2O2-induced oxidative stress by activating Nrf2, thus supporting simvastatin as a potential therapeutic agent for vitiligo. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Is it a primary or metastatic melanocytic neoplasm of the central nervous system?: A molecular based approach.

    Science.gov (United States)

    Cornejo, Kristine M; Hutchinson, Lloyd; Cosar, Ediz F; Smith, Thomas; Tomaszewicz, Keith; Dresser, Karen; Deng, April

    2013-11-01

    Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon and must be distinguished from metastatic lesions as patients with metastatic disease carry a worse prognosis. Therefore, tools to aid in the diagnosis of a primary CNS melanocytic neoplasm would be of clinical utility. Primary CNS melanocytic neoplasms, including uveal melanomas have frequent mutations in GNAQ and GNA11, but are rare in cutaneous and mucosal melanomas. Additionally, primary uveal melanomas often exhibit monosomy 3 conferring an elevated risk of metastasis. We present a 63 year-old male with a melanocytic neoplasm in the thoracic spinal cord. Molecular studies revealed the tumor contained a GNAQ mutation and four-color fluorescent in situ hybridization (FISH) composed of chromosome enumeration probes for 3, 7, 17 and a locus specific probe for 9p21/CDKN2A yielded a normal result (i.e. two copies per cell), favoring a primary versus metastatic melanocytic neoplasm of the CNS. We report a case in which the combination of mutational analysis and FISH aided in identifying the origin of the neoplasm. © 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  20. Role of microRNA508-3p in melanogenesis by targeting microphthalmia transcription factor in melanocytes of alpaca.

    Science.gov (United States)

    Zhang, J; Liu, Y; Zhu, Z; Yang, S; Ji, K; Hu, S; Liu, X; Yao, J; Fan, R; Dong, C

    2017-02-01

    It has been demonstrated that microRNAs (miRNAs) play important roles in the control of melanogenesis and hair color in mammals. By comparing miRNA expression profiles between brown and white alpaca skin, we previously identified miR508-3p as a differentially expressed miRNA suggesting its potential role in melanogenesis and hair color formation. The present study was conducted to determine the role of miR508-3p in melanogenesis in alpaca melanocytes. In situ hybridization showed that miR508-3p is abundantly present in the cytoplasma of alpaca melanocytes. miR508-3p was predicted to target the gene encoding microphthalmia transcription factor (MITF) and a luciferase reporter assay indicated that miR508-3p regulates MITF expression by directly targeting its 3'UTR. Overexpression of miR508-3p in alpaca melanocytes down-regulated MITF expression both at the messenger RNA and protein level and resulted in decreased expression of key melanogenic genes including tyrosinase and tyrosinase-related protein 2. Overexpression of miR508-3p in melanocytes also resulted in decreased melanin production including total alkali-soluble melanogenesis, eumelanogenesis and pheomelanogenesis. Results support a functional role of miR508-3p in regulating melanogenesis in alpaca melanocytes by directly targeting MITF.

  1. Influence of melanocytes in the ex-vivo reconstructed epidermal melanin unit following an acute UV irradiation; Role des melanocytes dans l'unite epidermique de melanisation reconstruite ex-vivo apres une irradiation UV aigue

    Energy Technology Data Exchange (ETDEWEB)

    Cario-Andre, M

    2000-11-15

    Influence of melanocytes in skin pigmentation is well documented, however its photo-protective role has given rise to controversy. The role of melanocytes have been investigated on reconstructed epidermis with 100 % of keratinocytes or 95 % of keratinocytes and 5 % of melanocytes. In a first time, the effect of an acute UVB dose has been studied on both reconstructed epidermis, next we have investigated UVA and UVA+B effects on these epidermis. Following irradiation, the presence of melanocytes in reconstructed epidermis protects against apoptosis without protecting significantly against DNA damage formation (CPD, 6-4PP) and protects against UV-induced unbalance of the SOD/catalase ratio (antioxidants enzymes). On the contrary, the presence of melanocytes in reconstructed epidermis amplifies lipids and proteins oxidations but seems to protect against DNA oxidations. Melanocytes differ from keratinocytes by their melanin content and their more important concentration in polyunsaturated fatty acids. To evaluate what is the part of melanin and the part of polyunsaturated fatty acids in epidermal UV responses, reconstructed epidermis with keratinocytes have been supplemented with polyunsaturated fatty acid. This study indicates that polyunsaturated fatty acids are responsible for lipids and proteins oxidations and that melanin protect against DNA oxidation induced by lipid peroxidation. All these studies demonstrate that, model of reconstructed epidermis and epidermis in-vivo have the same behaviour following UV irradiation. In the last part, sunscreens and antioxidants have been tested on reconstructed epidermis and have demonstrated that model of reconstructed epidermis is suitable for photo-protective molecules screening. (author)

  2. Melanocytes expressing MC1R polymorphisms associated with red hair color have altered MSH-ligand activated pigmentary responses in coculture with keratinocytes.

    Science.gov (United States)

    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. (c) 2007 Wiley-Liss, Inc.

  3. MicroRNA expression in melanocytic nevi: the usefulness of formalin-fixed, paraffin-embedded material for miRNA microarray profiling

    DEFF Research Database (Denmark)

    Glud, M.; Klausen, M.; Gniadecki, R.

    2009-01-01

    surgical specimens are formalin fixed and paraffin embedded (FFPE). To explore whether FFPE material would be suitable for miRNA profiling in melanocytic lesions, we compared miRNA expression patterns in FFPE versus fresh frozen samples, obtained from 15 human melanocytic nevi. Out of microarray data, we...

  4. Premalignant quiescent melanocytic nevi do not express the MHC class I chain-related protein A

    Directory of Open Access Journals (Sweden)

    Mercedes B. Fuertes

    2011-08-01

    Full Text Available The MHC class I chain-related protein A (MICA is an inducible molecule almost not expressed by normal cells but strongly up-regulated in tumor cells. MICA-expressing cells are recognized by natural killer (NK cells, CD8+ aßTCR and ?dTCR T lymphocytes through the NKG2D receptor. Engagement of NKG2D by MICA triggers IFN-? secretion and cytotoxicity against malignant cells. Although most solid tumors express MICA and this molecule is a target during immune surveillance against tumors, it has been observed that high grade tumors from different histotypes express low amounts of cell surface MICA due to a metalloprotease- induced shedding. Also, melanomas develop after a complex process of neotransformation of normal melanocytes. However, the expression of MICA in premalignant stages (primary human quiescent melanocytic nevi remains unknown. Here, we assessed expression of MICA by flow cytometry using cell suspensions from 15 primary nevi isolated from 11 patients. When collected material was abundant, cell lysates were prepared and MICA expression was also analyzed by Western blot. We observed that MICA was undetectable in the 15 primary nevi (intradermic, junction, mixed, lentigo and congenital samples as well as in normal skin, benign lesions (seborrheic keratosis, premalignant lesions (actinic keratosis and benign basocellular cancer. Conversely, a primary recently diagnosed melanoma showed intense cell surface MICA. We conclude that the onset of MICA expression is a tightly regulated process that occurs after melanocytes trespass the stage of malignant transformation. Thus, analysis of MICA expression in tissue sections of skin samples may constitute a useful marker to differentiate between benign and malignant nevi.

  5. Short-term digital surface microscopic monitoring of atypical or changing melanocytic lesions.

    Science.gov (United States)

    Menzies, S W; Gutenev, A; Avramidis, M; Batrac, A; McCarthy, W H

    2001-12-01

    To examine the outcome of short-term digital surface microscopic monitoring of suspicious or changing atypical melanocytic lesions. Digital surface microscopic (oil epiluminescence microscopy, and dermoscopy) images of clinically melanocytic lesions were taken with a color calibrated 3 CCD video instrument. In general, lesions were moderately atypical, flat or only slightly raised, without a history of change or surface microscopic evidence of melanoma, or were mildly atypical lesions with a history of change. Lesions were monitored during a 2.5- to 4.5-month period (median, 3.0 months). With the exception of overall change in pigmentation consistent with that seen in surrounding skin (solar exposure changes), any morphologic change after monitoring was considered an indication to excise. Sydney Melanoma Unit, Sydney, Australia (a referral center). A consecutive sample of 318 lesions from 245 patients (aged 4-81 years). Specificity for the diagnosis of melanoma. Of the 318 lesions, 81% remained unchanged. Of the 61 lesions that showed morphologic changes, 7 (11% of changed and 2% of total lesions) were found to be early melanoma (5 in situ and 2 invasive with a Breslow thickness of 0.25 mm and 0.28 mm, respectively). None of these melanomas developed any classic surface microscopic features of melanoma and therefore could be identified only by morphologic change. The specificity for the diagnosis of melanoma by means of short-term digital monitoring was 83%. On the assumption that all melanoma will change during the monitored period, surface microscopy digital monitoring is a useful adjunct for the management of melanocytic lesions.

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

    Science.gov (United States)

    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

  7. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    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. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2016-05-01

    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 p16(Ink4a) 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.

  9. Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy.

    Science.gov (United States)

    Balu, Mihaela; Kelly, Kristen M; Zachary, Christopher B; Harris, Ronald M; Krasieva, Tatiana B; König, Karsten; Durkin, Anthony J; Tromberg, Bruce J

    2014-05-15

    Monitoring of atypical nevi is an important step in early detection of melanoma, a clinical imperative in preventing the disease progression. Current standard diagnosis is based on biopsy and histopathologic examination, a method that is invasive and highly dependent upon physician experience. In this work, we used a clinical multiphoton microscope to image in vivo and noninvasively melanocytic nevi at three different stages: common nevi without dysplastic changes, dysplastic nevi with structural and architectural atypia, and melanoma. We analyzed multiphoton microscopy (MPM) images corresponding to 15 lesions (five in each group) both qualitatively and quantitatively. For the qualitative analysis, we identified the morphologic features characteristic of each group. MPM images corresponding to dysplastic nevi and melanoma were compared with standard histopathology to determine correlations between tissue constituents and morphology and to evaluate whether standard histopathology criteria can be identified in the MPM images. Prominent qualitative correlations included the morphology of epidermal keratinocytes, the appearance of nests of nevus cells surrounded by collagen fibers, and the structure of the epidermal-dermal junction. For the quantitative analysis, we defined a numerical multiphoton melanoma index (MMI) based on three-dimensional in vivo image analysis that scores signals derived from two-photon excited fluorescence, second harmonic generation, and melanocyte morphology features on a continuous 9-point scale. Indices corresponding to common nevi (0-1), dysplastic nevi (1-4), and melanoma (5-8) were significantly different (P < 0.05), suggesting the potential of the method to distinguish between melanocytic nevi in vivo. ©2014 American Association for Cancer Research.

  10. Complete regression of a melanocytic nevus under intense pulsed light therapy for axillary hair removal in a cosmetic center.

    Science.gov (United States)

    Martín, José M; Monteagudo, Carlos; Bella, Rebeca; Reig, Irela; Jordá, Esperanza

    2012-01-01

    Intense pulsed light (IPL) therapy using noncoherent broad-spectrum light has been reported to be effective for hair removal, and also for treating superficial pigmented lesions like ephelides and solar lentigines. We report complete regression of a pigmented melanocytic nevus, histologically confirmed, after hair removal treatment with IPL. The use of lasers and IPL is a common procedure used by dermatologists and even other professions for the treatment of cosmetically troubling skin conditions. The main advantage of such treatment is a reduction of surgical scars, thus producing a favorable cosmetic outcome, but a major limitation is that histopathologic diagnosis is not usually obtained prior to treatment. Such devices should be carefully used in patients with potentially dangerous melanocytic lesions. We also review the recent literature regarding inadequate treatment of melanocytic lesions with lasers. Copyright © 2012 S. Karger AG, Basel.

  11. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.

    Science.gov (United States)

    Jiang, Lin; Campagne, Cécile; Sundström, Elisabeth; Sousa, Pedro; Imran, Saima; Seltenhammer, Monika; Pielberg, Gerli; Olsson, Mats J; Egidy, Giorgia; Andersson, Leif; Golovko, Anna

    2014-11-21

    Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this

  12. Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.

    Science.gov (United States)

    Küsters-Vandevelde, Heidi V N; Klaasen, Annelies; Küsters, Benno; Groenen, Patricia J T A; van Engen-van Grunsven, Ilse A C H; van Dijk, Marcory R C F; Reifenberger, Guido; Wesseling, Pieter; Blokx, Willeke A M

    2010-03-01

    Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies.

  13. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    Science.gov (United States)

    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

  14. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    Directory of Open Access Journals (Sweden)

    Zalfa A. Abdel-Malek

    2016-08-01

    Full Text Available 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 (bFGF 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.

  15. MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhao

    2015-05-01

    Full Text Available 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.

  16. Cranial muscles in amphibians: development, novelties and the role of cranial neural crest cells

    Science.gov (United States)

    Schmidt, Jennifer; Piekarski, Nadine; Olsson, Lennart

    2013-01-01

    Our research on the evolution of the vertebrate head focuses on understanding the developmental origins of morphological novelties. Using a broad comparative approach in amphibians, and comparisons with the well-studied quail-chicken system, we investigate how evolutionarily conserved or variable different aspects of head development are. Here we review research on the often overlooked development of cranial muscles, and on its dependence on cranial cartilage development. In general, cranial muscle cell migration and the spatiotemporal pattern of cranial muscle formation appears to be very conserved among the few species of vertebrates that have been studied. However, fate-mapping of somites in the Mexican axolotl revealed differences in the specific formation of hypobranchial muscles (tongue muscles) in comparison to the chicken. The proper development of cranial muscles has been shown to be strongly dependent on the mostly neural crest-derived cartilage elements in the larval head of amphibians. For example, a morpholino-based knock-down of the transcription factor FoxN3 in Xenopus laevis has drastic indirect effects on cranial muscle patterning, although the direct function of the gene is mostly connected to neural crest development. Furthermore, extirpation of single migratory streams of cranial neural crest cells in combination with fate-mapping in a frog shows that individual cranial muscles and their neural crest-derived connective tissue attachments originate from the same visceral arch, even when the muscles attach to skeletal components that are derived from a different arch. The same pattern has also been found in the chicken embryo, the only other species that has been thoroughly investigated, and thus might be a conserved pattern in vertebrates that reflects the fundamental nature of a mechanism that keeps the segmental order of the head in place despite drastic changes in adult anatomy. There is a need for detailed comparative fate-mapping of pre

  17. Cranial muscles in amphibians: development, novelties and the role of cranial neural crest cells.

    Science.gov (United States)

    Schmidt, Jennifer; Piekarski, Nadine; Olsson, Lennart

    2013-01-01

    Our research on the evolution of the vertebrate head focuses on understanding the developmental origins of morphological novelties. Using a broad comparative approach in amphibians, and comparisons with the well-studied quail-chicken system, we investigate how evolutionarily conserved or variable different aspects of head development are. Here we review research on the often overlooked development of cranial muscles, and on its dependence on cranial cartilage development. In general, cranial muscle cell migration and the spatiotemporal pattern of cranial muscle formation appears to be very conserved among the few species of vertebrates that have been studied. However, fate-mapping of somites in the Mexican axolotl revealed differences in the specific formation of hypobranchial muscles (tongue muscles) in comparison to the chicken. The proper development of cranial muscles has been shown to be strongly dependent on the mostly neural crest-derived cartilage elements in the larval head of amphibians. For example, a morpholino-based knock-down of the transcription factor FoxN3 in Xenopus laevis has drastic indirect effects on cranial muscle patterning, although the direct function of the gene is mostly connected to neural crest development. Furthermore, extirpation of single migratory streams of cranial neural crest cells in combination with fate-mapping in a frog shows that individual cranial muscles and their neural crest-derived connective tissue attachments originate from the same visceral arch, even when the muscles attach to skeletal components that are derived from a different arch. The same pattern has also been found in the chicken embryo, the only other species that has been thoroughly investigated, and thus might be a conserved pattern in vertebrates that reflects the fundamental nature of a mechanism that keeps the segmental order of the head in place despite drastic changes in adult anatomy. There is a need for detailed comparative fate-mapping of pre

  18. Adult bone marrow neural crest stem cells and mesenchymal stem cells are not able to replace lost neurons in acute MPTP-lesioned mice.

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    Virginie Neirinckx

    Full Text Available Adult bone marrow stroma contains multipotent stem cells (BMSC that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC or mesenchymal stem cells (MSC survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management.

  19. Atypical melanocytic nevi of genital type: a distinctive pigmented lesion of the genital tract often confused with malignant melanoma.

    Science.gov (United States)

    Quddus, M Ruhul; Rashid, Lanita B; Sung, C James; Robinson-Bostom, Leslie; Lawrence, W Dwayne

    2010-02-15

    A 30-year-old female presented with a 0.3 cm slightly raised tan-brown papule with somewhat irregular borders on her right labia minora. The papule was detected by her gynecologist during an annual gynecologic visit. Excision of the lesion revealed an atypical melanocytic nevus of genital type (AMNGT). This nevus is often confused with other pigmented lesions especially dysplastic nevus or even malignant melanoma. This distinctive melanocytic nevus often causes significant concern to pathologists and dermatologists. The diagnostic criteria and differentiating features from dysplastic nevi and malignant melanoma are discussed.

  20. Patterns of neural differentiation in melanomas

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    Singh Avantika V

    2010-11-01

    Full Text Available Abstract Background Melanomas, highly malignant tumors arise from the melanocytes which originate as multipotent neural crest cells during neural tube genesis. The purpose of this study is to assess the pattern of neural differentiation in relation to angiogenesis in VGP melanomas using the tumor as a three dimensional system. Methods Tumor-vascular complexes [TVC] are formed at the tumor-stroma interphase, by tumor cells ensheathing angiogenic vessels to proliferate into a mantle of 5 to 6 layers [L1 to L5] forming a perivascular mantle zone [PMZ]. The pattern of neural differentiation is assessed by immunopositivity for HMB45, GFAP, NFP and synaptophysin has been compared in: [a] the general tumor [b] tumor-vascular complexes and [c] perimantle zone [PC] on serial frozen and paraffin sections. Statistical Analysis: ANOVA: Kruskal-Wallis One Way Analysis of Variance; All Pairwise Multiple Comparison Procedures [Tukey Test]. Results The cells abutting on the basement membrane acquire GFAP positivity and extend processes. New layers of tumor cells show a transition between L2 to L3 followed by NFP and Syn positivity in L4&L5. The level of GFAP+vity in L1&L2 directly proportionate to the percentage of NFP/Syn+vity in L4&L5, on comparing pigmented PMZ with poorly pigmented PMZ. Tumor cells in the perimantle zone show high NFP [65%] and Syn [35.4%] positivity with very low GFAP [6.9%] correlating with the positivity in the outer layers. Discussion From this study it is seen that melanoma cells revert to the embryonic pattern of differentiation, with radial glial like cells [GFAP+ve] which further differentiate into neuronal positive cells [NFP&Syn+ve] during angiogenic tumor-vascular interaction, as seen during neurogenesis, to populate the tumor substance.

  1. Adaptable pattern recognition system for discriminating Melanocytic Nevi from Malignant Melanomas using plain photography images from different image databases.

    Science.gov (United States)

    Kostopoulos, Spiros A; Asvestas, Pantelis A; Kalatzis, Ioannis K; Sakellaropoulos, George C; Sakkis, Theofilos H; Cavouras, Dionisis A; Glotsos, Dimitris T

    2017-09-01

    The aim of this study was to propose features that evaluate pictorial differences between melanocytic nevus (mole) and melanoma lesions by computer-based analysis of plain photography images and to design a cross-platform, tunable, decision support system to discriminate with high accuracy moles from melanomas in different publicly available image databases. Digital plain photography images of verified mole and melanoma lesions were downloaded from (i) Edinburgh University Hospital, UK, (Dermofit, 330moles/70 melanomas, under signed agreement), from 5 different centers (Multicenter, 63moles/25 melanomas, publicly available), and from the Groningen University, Netherlands (Groningen, 100moles/70 melanomas, publicly available). Images were processed for outlining the lesion-border and isolating the lesion from the surrounding background. Fourteen features were generated from each lesion evaluating texture (4), structure (5), shape (4) and color (1). Features were subjected to statistical analysis for determining differences in pictorial properties between moles and melanomas. The Probabilistic Neural Network (PNN) classifier, the exhaustive search features selection, the leave-one-out (LOO), and the external cross-validation (ECV) methods were used to design the PR-system for discriminating between moles and melanomas. Statistical analysis revealed that melanomas as compared to moles were of lower intensity, of less homogenous surface, had more dark pixels with intensities spanning larger spectra of gray-values, contained more objects of different sizes and gray-levels, had more asymmetrical shapes and irregular outlines, had abrupt intensity transitions from lesion to background tissue, and had more distinct colors. The PR-system designed by the Dermofit images scored on the Dermofit images, using the ECV, 94.1%, 82.9%, 96.5% for overall accuracy, sensitivity, specificity, on the Multicenter Images 92.0%, 88%, 93.7% and on the Groningen Images 76.2%, 73.9%, 77

  2. Neural Crest Cells Isolated from the Bone Marrow of Transgenic Mice Express JCV T-Antigen.

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    Jennifer Gordon

    Full Text Available JC virus (JCV, a common human polyomavirus, is the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML. In addition to its role in PML, studies have demonstrated the transforming ability of the JCV early protein, T-antigen, and its association with some human cancers. JCV infection occurs in childhood and latent virus is thought to be maintained within the bone marrow, which harbors cells of hematopoietic and non-hematopoietic lineages. Here we show that non-hematopoietic mesenchymal stem cells (MSCs isolated from the bone marrow of JCV T-antigen transgenic mice give rise to JCV T-antigen positive cells when cultured under neural conditions. JCV T-antigen positive cells exhibited neural crest characteristics and demonstrated p75, SOX-10 and nestin positivity. When cultured in conditions typical for mesenchymal cells, a population of T-antigen negative cells, which did not express neural crest markers arose from the MSCs. JCV T-antigen positive cells could be cultured long-term while maintaining their neural crest characteristics. When these cells were induced to differentiate into neural crest derivatives, JCV T-antigen was downregulated in cells differentiating into bone and maintained in glial cells expressing GFAP and S100. We conclude that JCV T-antigen can be stably expressed within a fraction of bone marrow cells differentiating along the neural crest/glial lineage when cultured in vitro. These findings identify a cell population within the bone marrow permissible for JCV early gene expression suggesting the possibility that these cells could support persistent viral infection and thus provide clues toward understanding the role of the bone marrow in JCV latency and reactivation. Further, our data provides an excellent experimental model system for studying the cell-type specificity of JCV T-antigen expression, the role of bone marrow-derived stem cells in the pathogenesis of JCV-related diseases

  3. Review: the role of neural crest cells in the endocrine system.

    Science.gov (United States)

    Adams, Meghan Sara; Bronner-Fraser, Marianne

    2009-01-01

    The neural crest is a pluripotent population of cells that arises at the junction of the neural tube and the dorsal ectoderm. These highly migratory cells form diverse derivatives including neurons and glia of the sensory, sympathetic, and enteric nervous systems, melanocytes, and the bones, cartilage, and connective tissues of the face. The neural crest has long been associated with the endocrine system, although not always correctly. According to current understanding, neural crest cells give rise to the chromaffin cells of the adrenal medulla, chief cells of the extra-adrenal paraganglia, and thyroid C cells. The endocrine tumors that correspond to these cell types are pheochromocytomas, extra-adrenal paragangliomas, and medullary thyroid carcinomas. Although controversies concerning embryological origin appear to have mostly been resolved, questions persist concerning the pathobiology of each tumor type and its basis in neural crest embryology. Here we present a brief history of the work on neural crest development, both in general and in application to the endocrine system. In particular, we present findings related to the plasticity and pluripotency of neural crest cells as well as a discussion of several different neural crest tumors in the endocrine system.

  4. Melanocytes respond to mechanical stretch by activation of mitogen-activated protein kinases (MAPK).

    Science.gov (United States)

    Kippenberger, S; Loitsch, S; Müller, J; Guschel, M; Ramirez-Bosca, A; Kaufmann, R; Bernd, A

    2000-08-01

    Cells of human epidermis are permanently targeted by mechanical stimuli. Besides mechanical forces from external sources the body itself generates mechanical forces via muscle contractions and growth processes. Recently, it was demonstrated that mechanical stretch is connected to enhanced proliferation in epidermal cells. The underlying biochemical events are still a matter of debate. Here we show that mechanical stretch leads to activation of both ERK1/2 and SAPK/JNK in human melanocytes and keratinocytes. In response to a 5 min single stretch ERK1/2 becomes moderately induced in melanocytes and peaked 30 min after the stimulus. In keratinocytes strong activation of ERK1/2 is present directly after the stimulus. SAPK/JNK shows the same activation pattern in both cell species--a slow but steady activation. The different kinetics of both MAPK suggest that different signalling cascades were activated. Future studies should evaluate the relevance of stretch-dependent MAPK activation in triggering the cell proliferation.

  5. Refractometry of melanocyte cell nuclei using optical scatter images recorded by digital Fourier microscopy.

    Science.gov (United States)

    Seet, Katrina Y T; Nieminen, Timo A; Zvyagin, Andrei V

    2009-01-01

    The cell nucleus is the dominant optical scatterer in the cell. Neoplastic cells are characterized by cell nucleus polymorphism and polychromism-i.e., the nuclei exhibits an increase in the distribution of both size and refractive index. The relative size parameter, and its distribution, is proportional to the product of the nucleus size and its relative refractive index and is a useful discriminant between normal and abnormal (cancerous) cells. We demonstrate a recently introduced holographic technique, digital Fourier microscopy (DFM), to provide a sensitive measure of this relative size parameter. Fourier holograms were recorded and optical scatter of individual scatterers were extracted and modeled with Mie theory to determine the relative size parameter. The relative size parameter of individual melanocyte cell nuclei were found to be 16.5+/-0.2, which gives a cell nucleus refractive index of 1.38+/-0.01 and is in good agreement with previously reported data. The relative size parameters of individual malignant melanocyte cell nuclei are expected to be greater than 16.5.

  6. Oxidative Stress Modulates DNA Methylation during Melanocyte Anchorage Blockade Associated with Malignant Transformation

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    Ana C.E. Campos

    2007-12-01

    Full Text Available Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenic melanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hey, an element in the methionine (universal methyl donor cycle. This alteration was accompanied by increase in glutathione (GSH levels and methylated DNA content. Furthermore, a significant increase in dnmti and 3b expression was identified along melan-a anchorage blockade. LG-Nitro-L-arginine methyl esther (L-NAME, known as a nitric oxide synthase (NOS inhibitor, and N-acetyl-L-cysteine (NAC prevented the increase in global DNA methylation, as well as the increase in dnmti and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.

  7. New combined laser therapy for small mass of melanocytic nevi on the face.

    Science.gov (United States)

    Ohmaru, Youkou; Ohmaru, Koichi; Koga, Noriyuki; Migita, Hisashi; Kiyokawa, Kensuke

    2011-01-01

    A small mass of melanocytic nevi on the face is commonly treated by surgical resection. This method is associated with cosmetic complications, such as scarring and scar contracture. The use of CO2 Laser treatment to avoid these complications is increasing. However, scarring or recurrence may still occur after CO2 Laser treatment. To resolve these problems, we developed a new Combined Laser Therapy (CLT) protocol using three laser instruments. We used CO2 Laser, Nd:YAG Laser and Q-Switched Ruby Laser. The first treatment was a minimal mass reduction using CO2 Laser. The surface is covered with carbonized tissue. The second treatment with Nd:YAG Laser which removes the carbonized tissue, because the laser specifically absorbs black chromatophores. Finally, any surviving nevus cells containing melanin are destroyed with Q-Switched Ruby Laser. This method was used for 12 cases presenting with small masses of melanocytic nevi on the face. The maximum size of the mass was 20 mm. All cases resulted in a cosmetic improvement and there was no scarring or recurrence. Either satisfactory or greatly improved cosmetic results were obtained in all cases. We think that the wound healing without scarring observed in all of our cases is related to the administration of both CLT and auto-simultaneous Low reactive Level Laser Therapy (LLLT) in these cases. Therefore, this method may provide the better treatment than surgical resection in the future.

  8. Development of a three-dimensional surface imaging system for melanocytic skin lesion evaluation

    Science.gov (United States)

    Tosca, Androniki; Kokolakis, Athanasios; Lasithiotakis, Konstantinos; Zacharopoulos, Athanasios; Zabulis, Xenophon; Marnelakis, Ioannis; Ripoll, Jorge; Stephanidis, Constantine

    2013-01-01

    Even though surface morphology is always taken into account when assessing clinically pigmented skin lesions, it is not captured by most modern imaging systems using digital imaging. Our aim is to develop a novel three-dimensional (3D) imaging technique to record detailed information of the surface anatomy of melanocytic lesions that will enable improved classification through digital imaging. The apparatus consists of three high-resolution cameras, a light source, and accompanying software. Volume measurements of specific phantoms using volumetric tubes render slightly lower values than those obtained by our 3D imaging system (mean%±SD, 3.8%±0.98, Plesions is carried out. The mean%±SD differences of area, major axis length, volume, and maximum height are 2.1%±1.1, 0.9%±0.8, 3.8%±2.9, and 2.5%±3.5, respectively. Thirty melanocytic lesions are assessed, including common and dysplastic nevi and melanomas. There is a significant difference between nevi and melanomas in terms of variance in height and boundary asymmetry (Ppigment density values than common nevi (Plesions. However, these findings should be confirmed in larger-scale studies.

  9. FISH as an effective diagnostic tool for the management of challenging melanocytic lesions

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    Gasparini Robert

    2011-08-01

    Full Text Available Abstract Background The accuracy of melanoma diagnosis continues to challenge the pathology community, even today with sophisticated histopathologic techniques. Melanocytic lesions exhibit significant morphological heterogeneity. While the majority of biopsies can be classified as benign (nevus or malignant (melanoma using well-established histopathologic criteria, there exists a cohort for which the prediction of clinical behaviour and invasive or metastatic potential is difficult if not impossible to ascertain on the basis of morphological features alone. Multiple studies have shown that there is significant disagreement between pathologists and even expert dermatopathologists in the diagnosis of this subgroup of difficult melanocytic lesions. Methods A four probe FISH assay was utilized to analyse a cohort of 500 samples including 157 nevus, 176 dysplastic nevus and 167 melanoma specimens. Results Review of the lesions determined the assay identified genetic abnormalities in a total of 83.8% of melanomas, and 1.9% of nevus without atypia, while genetic abnormalities were identified in 6.3%, 6.7%, and 10.3% of nevus identified with mild, moderate and severe atypia, respectively. Conclusions Based on this study, inheritable genetic damage/instability identified by FISH testing is a hallmark of a progressive malignant process, and a valuable diagnostic tool for the identification of high risk lesions.

  10. Genital melanocytic nevi in children: Experience in a pediatric dermatology practice.

    Science.gov (United States)

    Hunt, Raegan D; Orlow, Seth J; Schaffer, Julie V

    2014-03-01

    Little is known about the prevalence and clinical characteristics of genital melanocytic nevi in children. We sought to describe the epidemiology, clinical and dermoscopic features, and natural history of genital nevi in pediatric patients. We reviewed charts of 1159 children given the diagnosis of melanocytic nevi over 11 years. Those with genital nevus as a chief symptom were contacted for follow-up. Among children/adolescents evaluated for nevi, the prevalence of genital nevus was 3.5% (40/1159), with a male:female ratio of 1.3:1. There were no statistically significant differences in age, sex, total nevus number, presence of acral and scalp nevi, or family history of dysplastic nevi and melanoma between patients with and without genital nevi. Genital nevus onset was before age 2 years in 63.6% of patients. A globular dermoscopic pattern was observed in 93.3%. Most genital nevi underwent a gradual change in diameter, elevation (becoming soft papules), color, texture, or a combination of these. After median follow-up of 1.5 years, no melanoma or other adverse outcome was observed. This was a retrospective chart analysis and questionnaire-based study of a limited number of patients. Increased awareness of the clinical characteristics, dermoscopic features, and evolution of genital nevi in children may help to avoid unnecessary surgery. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  11. Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review.

    Science.gov (United States)

    Habbema, Louis; Halk, Anne Berthe; Neumann, Martino; Bergman, Wilma

    2017-10-01

    Recently, the unregulated use of untested synthetic alpha-melanocyte-stimulating hormone (α-MSH) analogues, commonly known as melanotan I and II, appears to have increased. These analogues are primarily used for their tan-stimulating effects. Dermatologists see many patients in their clinic who tan. This review provides an overview of the risks of the unregulated use of these substances. Other topics discussed here include the history and safety of afamelanotide, which is the only α-MSH analogue that is approved for use in a limited number of medical indications. Although afamelanotide has been thoroughly tested and deemed safe, illegal melanotans are likely risky for several reasons. There are questions regarding the preparation, administration, and dosage of these substances. In addition to these general risks, increasing numbers of case reports indicate that the unregulated use of both melanotan I and II is associated with cutaneous complications, particularly melanocytic changes in existing moles and newly emerging (dysplastic) nevi. Four case reports have described melanomas emerging from existing moles either during or shortly after the use of melanotan. Although conclusive evidence linking these phenomena is lacking, publications have stressed the importance of awareness that melanotan is a part of a 'tanning culture' in certain subpopulations. Multiple national health organizations have issued safety warnings regarding the use of melanotan I and II. © 2017 The International Society of Dermatology.

  12. Multidirectional Vector Excision Leads to Better Outcomes than Traditional Elliptical Excision of Facial Congenital Melanocytic Nevus

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    Seung Il Oh

    2013-09-01

    Full Text Available Background The elliptical excision is the standard method of removing benign skin lesions,such as congenital melanocytic nevi. This technique allows for primary closure, with little to nodog-ear deformity, but may sacrifice normal tissue adjacent to the lesion, resulting in scarswhich are unnecessarily long. This study was designed to compare the predicted results ofelliptical excision with those resulting from our excision technique.Methods Eighty-two patients with congenital melanocytic nevus on the face were prospectivelystudied. Each lesion was examined and an optimal ellipse was designed and marked onthe skin. After an incision on one side of the nevus margin, subcutaneous undermining wasperformed in the appropriate direction. The skin flap was pulled up and approximated alongseveral vectors to minimize the occurrence of dog-ear deformity.Results Overall, the final wound length was 21.1% shorter than that achieved by ellipticalexcision. Only 8.5% of the patients required dog-ear repair. There was no significant distortionof critical facial structures. All of the scars were deemed aesthetically acceptable based ontheir Patient and Observer Scar Assessment Scale scores.Conclusions When compared to elliptical excision, our technique appears to minimize dogeardeformity and decrease the final wound length. This technique should be considered analternative method for excision of facial nevi.

  13. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor.

    Science.gov (United States)

    Lu, D; Willard, D; Patel, I R; Kadwell, S; Overton, L; Kost, T; Luther, M; Chen, W; Woychik, R P; Wilkison, W O

    1994-10-27

    The genetic loci agouti and extension control the relative amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments in mammals: extension encodes the receptor for melanocyte-stimulating hormone (MSH) and agouti encodes a novel 131-amino-acid protein containing a signal sequence. Agouti, which is produced in the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified agouti protein to demonstrate that agouti is a high-affinity antagonist of the MSH receptor and blocks alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.

  14. MC1R is a potent regulator of PTEN after UV exposure in melanocytes.

    Science.gov (United States)

    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. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Extended follow-up of small melanocytic choroidal tumors treated with transpupillary thermotherapy.

    Science.gov (United States)

    Win, Peter H; Robertson, Dennis M; Buettner, Helmut; McCannel, Colin A; Bennett, Steven R

    2006-04-01

    To report our longer-term follow-up observations in patients with small choroidal melanomas primarily treated with transpupillary thermotherapy (TTT). In this noncomparative interventional case series, 40 patients with small melanocytic tumors of the choroid (thickness cryotherapy (1 case). The mean interval between initial TTT and recurrence in this subgroup was 15 months (range, 7-22 months). Of 36 eyes that were successfully treated with TTT or cryotherapy, 26 eyes (72%) had posttreatment visual acuity better than or equal to pretreatment visual acuity. Four (10%) of 40 tumors were not controlled with TTT and eventually required brachytherapy (n = 1), proton radiation (n = 1), or enucleation (n = 2). The initial basal diameters of these tumors ranged from 7.5 x 7.5 mm to 9 x 7.5 mm, with a mean initial thickness of 2.6 mm. The mean interval between treatment and determination of treatment failure was 22 months (range, 7-30 months). Transpupillary thermotherapy resulted in tumor regression of most small melanocytic choroidal tumors. Tumor edge recurrences were successfully treated with additional TTT in most cases. Four tumors required irradiation or enucleation because of treatment failures with TTT. Transpupillary thermotherapy as a stand-alone therapy is insufficient for some small choroidal melanomas.

  16. High-definition optical coherence tomography imaging of melanocytic lesions: a pilot study.

    Science.gov (United States)

    Boone, Marc A L M; Norrenberg, Sarah; Jemec, Gregor B E; Del Marmol, V

    2014-01-01

    High-definition optical coherence tomography (HD-OCT) is a non-invasive in vivo imaging technique with cellular resolution based on the principle of conventional optical coherence tomography. The objective of this study was to evaluate HD-OCT for its ability to identify architectural patterns and cytologic features of melanocytic lesions. All lesions were examined by one observer clinically and using dermoscopy. Cross-sectional HD-OCT images were compared with histopathology. En face HD-OCT images were compared with reflectance confocal microscopy (RCM). Twenty-six melanocytic lesions of 26 patients were imaged. Identification of architectural patterns in cross-sectional mode and cytologic features of pigmented cells in the epidermis, dermo-epidermal junction, papillary dermis, and superficial reticular dermis in the en face mode was possible by HD-OCT. HD-OCT provides morphological imaging with sufficient resolution and penetration depth to discriminate architectural patterns and cytologic features of pigmented cells in epidermis and dermis. The method appears to offer the possibility of additional three-dimensional structural information complementary to that of RCM, albeit at a slightly lower lateral resolution. The diagnostic potential of HD-OCT regarding malignant melanoma is not high enough for ruling out a diagnosis of malignant melanoma.

  17. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet

    2013-01-01

    , 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 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...

  18. The amphibian melanization inhibiting factor (MIF) blocks the alpha-MSH effect on mouse malignant melanocytes.

    Science.gov (United States)

    López-Contreras, A M; Martínez-Liarte, J H; Solano, F; Samaraweera, P; Newton, J M; Bagnara, J T

    1996-12-01

    We have found that a melanization inhibitory factor (MIF) extracted from the ventral skin of Rana forreri has a slight inhibitory effect on the activity levels of tyrosinase and dopachrome tautomerase in B16/F10 and Cloudman S-91 murine melanoma cell lines. Furthermore, this factor appears to block the effects of alpha-MSH on these enzymatic activities. However, MIF treatment does not affect the melanogenic action of theophylline on the same cells, suggesting that MIF acts proximal to MSH-mediated cAMP formation, possibly by interaction with the MSH receptor. In this way, we show that this amphibian factor has biological activity on mammalian melanocytes. This suggests the existence of mammalian counterparts of amphibian MIF in the mouse integument that might regulate epidermal melanocytes. These peptides might be related to the agouti protein, as they share similar mechanisms of action. The interaction of different peptides with the MSH receptor would be a complex but general mechanism responsible for many mammalian coat color variants.

  19. Abundance of the benign melanocytic universe: Dermoscopic-histopathological correlation in nevi.

    Science.gov (United States)

    Woltsche, Nora; Schmid-Zalaudek, Karin; Deinlein, Teresa; Rammel, Katrin; Hofmann-Wellenhof, Rainer; Zalaudek, Iris

    2017-05-01

    The broad universe of "melanocytic nevi" includes a variety of different subtypes, which can be classified either due to their morphology, epidemiology, genetic alterations or risk for developing melanoma. Regarding morphology, on the one hand macroscopic/clinical and on the other hand histopathological appearance were used to subdivide in the past, often resulting in confusion and poor interobserver agreement, while nowadays dermoscopy presents the clinician's precious bridge between naked-eye examination and histopathological diagnostics, allowing prediction of the lesions' histopathology, follow up and monitoring over time without need of excision. The non-invasive dermoscopic examination relies on the assessment of colors, patterns and the distribution of both within a cutaneous lesion. Until today, the correspondence of certain dermoscopic colors and patterns to certain histopathological correlates has been reported for a huge amount of different cutaneous lesions. Moreover, the correspondence of certain dermoscopic features to certain body sites, age groups and pigmentary traits, but also to specific genetic alterations in lesions, has been broadly investigated. Dermoscopy has led us to a new understanding of melanocytic nevi's biology and evolution and, last but not least, to a new classification system, which we want to present herein. © 2017 Japanese Dermatological Association.

  20. Non-Melanocytic Benign Tumors of the Face: A Retrospective Study

    Directory of Open Access Journals (Sweden)

    Kyoung Min Lee

    2015-03-01

    Full Text Available BackgroundAlthough plastic surgeons daily encounter various facial tumors in the field, reports limited on face are scarce. In our study, we want to provide basic epidemiologic data to help clinicians to decide the proper management for their patients.MethodsWe retrospectively reviewed the medical records of patients including age and gender, location and size of the tumor, histopathologic result, recurrence, type of anesthesia and any associated disorders who had undergone a surgical removal of their facial tumors and received the histopathologic report in the same institution between January 2009 and October 2012.ResultsOne hundred eighty-nine patients with 203 non-melanocytic benign tumors were included. The most frequent site of tumors was the central subunit of the forehead, followed by the lateral subunit of the cheek and the auricular unit. Of 36 different histopathologic results, the epidermal cyst was most frequent, followed by lipoma, pilomatricoma and osteoma. Statistical analysis showed that males were dominant in the epidermal cyst and lipoma groups. While, females were dominant in the osteoma and pilomatricoma groups. No associations were found between lesions and other diseases.ConclusionsOur study is the at most specific and concentrated study on non-melanocytic benign tumors of the face. We expect the epidemiologic data of our study may help plastic surgeons who are confronted with so many facial lesions in the field to decide on the most proper management for their patients.

  1. Short- and long-term effects of acetylsalicylic acid treatment on the proliferation and lipid peroxidation of skin cultured melanocytes of active vitiligo.

    Science.gov (United States)

    Zailaie, Mohammad Z

    2004-11-01

    Recent in vitro and in vivo studies have shown that the nonsteroidal anti-inflammatory agent, acetylsalicylic acid (ASA) or aspirin has antioxidant properties on various cell lines and tissues. Hence, the aim of the present study is to investigate the effects of ASA at 2 different concentrations (75 and 300 microg/ml) on the proliferative capacities and lipid peroxidation of in vitro skin cultured melanocytes obtained from patients with active vitiligo. The present work was carried out from February 2001 through to November 2001, at the Vitiligo Unit, King Abdul-Aziz University Medical Center, Jeddah, Kingdom of Saudi Arabia. Employing methods described in this section, cryopreserved primary cultured melanocytes that were originally cultured from skin biopsies of normal healthy individuals and patients with active vitiligo (n=7), were subcultured to confluence. The malondialdehyde (MDA) concentrations in the cell culture medium were determined at 6 hours and 21 days following cultured melanocytes treatment with ASA (75 and 300 microg/ml). Also, the number of viable melanocytes was determined 21 days following the treatment of melanocytes with ASA (75 and 300 microg/ml). Following ASA treatment at 75 microg/ml, the cultured melanocytes from the normal and active vitiligo donors showed significant increase in the proliferative capacities as judged by the increase in the number of viable melanocytes after 21 days of cell culture (28.2% and 26.9%, p<0.001). Concomitantly, the same ASA concentration resulted in significant decrease in the concentrations of MDA in the cell culture medium of the normal and active vitiligo melanocytes 6 hour and 21-day period following the ASA treatment [6 hour: 16.2% (p<0.05) and 18.4% (p<0.001); 21 day: 32% and 38.6% (p<0.001)]. However, the long-term (21 days) treatment of cultured melanocytes from the normal and active vitiligo donors with ASA at 300 microg/ml resulted in a significant reduction in the number of viable melanocytes (33

  2. Altered protein localization in melanocytes from Hermansky-Pudlak syndrome: support for the role of the HPS gene product in intracellular trafficking.

    Science.gov (United States)

    Boissy, R E; Zhao, Y; Gahl, W A

    1998-09-01

    Patients with Hermansky-Pudlak syndrome (HPS) exhibit moderate to mild hypopigmentation of the skin, hair, and eyes. To understand the inherent basis for this reduced pigmentation, pure cultures of melanocytes were derived using skin biopsies obtained from four patients with HPS. A nucleotide lesion in the HPS gene was identified in these individuals. Expression of HPS mRNA, parameters of melanin synthesis, characteristics in ultrastructural morphology, and expression of melanocyte-specific proteins were assessed in HPS melanocytes. The patients' cells appeared microscopically hypopigmented, and melanin content ranged from 0% to 50% of that for normal melanocytes. In cell lysates of HPS melanocytes, tyrosine hydroxylase activity was within the normal range, but in intact HPS melanocytes, it was almost half that of normal melanocytes. HPS melanocytes also appeared refractory to stimulators of melanization, eg, a combination of isobutyl methylxanthine and cholera toxin (IBMX/CT). HPS melanocytes contained many morphologically normal melanosomes, mostly Stage II with a few Stage I or III. After dihydroxyphenylalanine (DOPA) incubation, there appeared to be an equal number of Stage II and III melanosomes with the addition of a moderate number of Stage IV melanosomes. A characteristic ultrastructural feature of most HPS melanocytes was a variety of unusual cellular structures. These aberrancies include the following: (a) large membrane-bound complexes containing membranous chambers, unpigmented, and pigmented melanosomes, irregular deposits of DOPA reaction products, and granular/amorphous material sometimes resembling the cytoplasm; and (b) DOPA-positive rings delineated on either side by limiting membranes. The expression of tyrosinase-related protein-1 and granulophysin, a 40-kd membrane protein originally identified as a component of platelet-dense bodies that are undetectable in HPS, was assessed by light microscopy immunofluorescence. For both proteins, HPS

  3. Migration of limbal melanocytes onto the central cornea after ocular surface reconstruction: an in vivo confocal microscopic case report.

    Science.gov (United States)

    Huang, Hsin-Wei; Hu, Fung-Rong; Wang, I-Jong; Hou, Yu-Chih; Chen, Wei-Li

    2010-02-01

    To report the in vivo confocal microscopic findings of migrated melanocytes onto the central cornea in a patient with Stevens-Johnson syndrome who received ocular surface reconstruction by amniotic membrane transplantation (AMT). Single interventional case report. A 37-year-old man presented with bilateral symblepharon because of Stevens-Johnson syndrome. Release of the bilateral symblepharon with AMT on the bare sclera was performed. Three weeks after the surgery, slit-lamp biomicroscopy of the right eye revealed patchy brown pigmentation on the surface of the cornea and the amniotic membrane transplanted to the bare sclera. In vivo confocal microscopy of the affected cornea revealed abnormal basal epithelial cells with hyperreflective nuclei and loss of cellular borders. Multiple dendritiform cells, which appeared to be melanocytes, were distributed mainly on the corneal basal epithelial layer and superficial stroma. The number of the migrated melanocytes gradually decreased over 6 months of observation. Melanocytes can migrate into the central cornea after reconstruction of the ocular surface with AMT. In vivo confocal microscopy can be a useful tool to observe these changes.

  4. Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma

    NARCIS (Netherlands)

    Speeckaert, Reinhart; van Geel, Nanja; Luiten, Rosalie M.; van Gele, Mireille; Speeckaert, Marijn; Lambert, Jo; Vermaelen, Karim; Tjin, Esther P. M.; Brochez, Lieve

    2011-01-01

    Regressing nevi are considered an example of an efficient early antitumoral response preventing the development of neoplasia. The underlying mechanism has not been elucidated, although an immune-based destruction of melanocytes is supposed. The aim of this study was to provide evidence of an

  5. Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes

    NARCIS (Netherlands)

    Smit, N.P.M.; Vink, A.A.; Kolb, R.M.; Steenwinkel, M.J.S.T.; Berg, P.T.M. van den; Nieuwpoort, F. van; Roza, L.; Pavel, S.

    2001-01-01

    The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals

  6. Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes

    Science.gov (United States)

    Cheng, Tsing; Orlow, Seth J.; Manga, Prashiela

    2013-01-01

    Summary Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of proapoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. PMID:23962237

  7. Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes

    Directory of Open Access Journals (Sweden)

    Ayaka Yatsu

    2015-02-01

    Full Text Available Varp (VPS9-ankyrin repeat protein was originally identified as an activator of small GTPase Rab21 through its VPS9 domain, but it has subsequently been shown to function as a Rab32/38 effector through its first ANKR1 domain. Although these functions of Varp are important for melanogenesis, Varp contains a second ANKR2 domain, whose function remained completely unknown. Here we identified Rab40C, an atypical Rab containing a SOCS box that recruits a ubiquitin ligase complex, as a novel ANKR2-binding protein and investigated its involvement in melanogenic enzyme trafficking in melanocytes. The results showed that overexpression of Rab40C in melanocytes caused a dramatic reduction in melanogenic enzyme Tyrp1 signals by promoting proteasomal degradation of Varp in a SOCS-box-dependent manner and that knockdown of Rab40C in melanocytes caused an increase in the amount of Varp. Intriguingly, Rab40C knockdown also caused a dramatic reduction in Tyrp1 signals, the same as Varp overexpression did. These findings indicated that Rab40C is a previously unexpected regulator of Tyrp1 trafficking in melanocytes through controlling the proteasomal degradation of Varp.

  8. Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models.

    Directory of Open Access Journals (Sweden)

    Masato Asanuma

    Full Text Available Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease.

  9. Neural Networks

    Directory of Open Access Journals (Sweden)

    Schwindling Jerome

    2010-04-01

    Full Text Available This course presents an overview of the concepts of the neural networks and their aplication in the framework of High energy physics analyses. After a brief introduction on the concept of neural networks, the concept is explained in the frame of neuro-biology, introducing the concept of multi-layer perceptron, learning and their use as data classifer. The concept is then presented in a second part using in more details the mathematical approach focussing on typical use cases faced in particle physics. Finally, the last part presents the best way to use such statistical tools in view of event classifers, putting the emphasis on the setup of the multi-layer perceptron. The full article (15 p. corresponding to this lecture is written in french and is provided in the proceedings of the book SOS 2008.

  10. Retinoid-X-receptors (α/β in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.

    Directory of Open Access Journals (Sweden)

    Daniel J Coleman

    2014-05-01

    Full Text Available 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.

  11. Selective cytotoxicity of 4-S-cysteaminylphenol on follicular melanocytes of the black mouse: rational basis for its application to melanoma chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    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.

  12. IMP-3 EXPRESSION IN BENIGN MELANOCYTIC NEVI, DYSPLASTIC NEVI AND MALIGNANT MELANOMA: PRELIMINARY FINDINGS IN BULGARIAN PATIENTS.

    Science.gov (United States)

    Chokoeva, A A; Ananiev, J; Wollina, U; Tana, C; Lotti, T; Cardoso, J C; Tchernev, G

    2015-01-01

    IMP-3 is generally considered as an oncofetal protein, which plays a critical role in regulation of cell proliferation via an IGF-II-dependent pathway in K562 leukemia cells. IMP-3 expression has been detected in malignancies with various origins, while its appearance in adult tissue is generally considered abnormal, with some exceptions. IMP3 is also considered a prognostic biomarker in patients with renal cell carcinoma and clear-cell type ovarian carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma and in patients with poorly differentiated thyroid carcinoma and uterine cervical carcinomas, testicular cancer and malignant melanoma. To our knowledge, no more than 4 PubMed-indexed studies have investigated the expression of IMP-3 in melanocytic lesions, namely its role in the differentiation between benign and malignant neoplasms. We investigated the expression of IMP-3 in a small series of benign melanocytic lesions, dysplastic nevi and melanomas, aiming to establish its significance as a marker for their distinction, comparing the results with those from the literature. IMP- 3 immunostaining was performed in 30 melanocytic lesions: 10 malignant melanomas, 10 dysplastic nevi and 10 benign melanocytic nevi. Our results revealed expression in 20% of dysplastic lesions and 40% of melanoma cases, while none of the benign nevi showed positive expression. These data contradict some of the results from other studies and raise some questions regarding the correlation between IMP- 3 and the degree of dysplasia of melanocytic nevi, as well as its potential relationship with prognostic parameters in melanoma, including tumor thickness and mitotic rate. Our results suggest that IMP-3 expression could be only an auxiliary marker for differentiation between dysplastic nevi and benign nevi, since although it is not expressed in all dysplastic lesions, staining correlates with the degree of dysplasia/atypia. It seems that IMP-3 expression is not a useful

  13. Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis.

    Science.gov (United States)

    Krenacs, T; Kiszner, G; Stelkovics, E; Balla, P; Teleki, I; Nemeth, I; Varga, E; Korom, I; Barbai, T; Plotar, V; Timar, J; Raso, E

    2012-10-01

    The 180 kDa transmembrane collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-antibodies targeting collagen XVII cause blistering skin disease. Collagen XVII is down-regulated in mature keratinocytes but re-expressed in skin cancer. By recently detecting collagen XVII in melanocyte hyperplasia, here we tested its expression in benign and malignant melanocytic tumors using endodomain and ectodomain selective antibodies. We found the full-length collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic melanomas, 8/9 melanoma cell lines, HT199 metastatic melanoma xenografts and atypical nests in 8/63 dysplastic nevi. The rest of 19 nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations. Collagen XVII immunoreaction-stained spindle cell melanomas, showed partly overlapping profiles with those of S100B, Melan A and HMB45. It was concentrated at vertical melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507-529 terminus of collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of collagen XVII endodomain in melanocytic tumors is associated with malignant transformation to be a potential marker of malignancy and a target for antibody-induced melanoma apoptosis.

  14. Anterior Hox Genes Interact with Components of the Neural Crest Specification Network to Induce Neural Crest Fates

    Science.gov (United States)

    Gouti, Mina; Briscoe, James; Gavalas, Anthony

    2011-01-01

    Hox genes play a central role in neural crest (NC) patterning particularly in the cranial region of the body. Despite evidence that simultaneous loss of Hoxa1 and Hoxb1 function resulted in NC specification defects, the role of Hox genes in NC specification has remained unclear due to extended genetic redundancy among Hox genes. To circumvent this problem, we expressed anterior Hox genes in the trunk neural tube of the developing chick embryo. This demonstrated that anterior Hox genes play a central role in NC cell specification by rapidly inducing the key transcription factors Snail2 and Msx1/2 and a neural progenitor to NC cell fate switch characterized by cell adhesion changes and an epithelial-to-mesenchymal transition (EMT). Cells delaminated from dorsal and medial neural tube levels and generated ectopic neurons, glia progenitors, and melanocytes. The mobilization of the NC genetic cascade was dependent upon bone morphogenetic protein signaling and optimal levels of Notch signaling. Therefore, anterior Hox patterning genes participate in NC specification and EMT by interacting with NC-inducing signaling pathways and regulating the expression of key genes involved in these processes. Stem Cells 2011;29:858–870 PMID:21433221

  15. CASH algorithm versus 3-point checklist and its modified version in evaluation of melanocytic pigmented skin lesions: The 4-point checklist.

    Science.gov (United States)

    di Meo, Nicola; Stinco, Giuseppe; Bonin, Serena; Gatti, Alessandro; Trevisini, Sara; Damiani, Giovanni; Vichi, Silvia; Trevisan, Giusto

    2016-06-01

    Dermoscopy, in expert hands, increases accuracy, sensitivity and specificity in diagnosis of pigmented skin lesions of a single operator, compared with clinical examination. Simplified algorithmic methods have been developed to help less expert dermoscopists in diagnosis of melanocytic lesions. This study included 125 melanocytic skin lesions divided into melanocytic nevi, dysplastic nevi and thin melanomas (<1 mm). We compared the 3-point checklist and CASH algorithm to analyze different pigmented skin lesions. Based on preliminary results, we proposed a new modified algorithm, called the 4-point checklist, whose accuracy is similar to the CASH algorithm and whose simplicity is similar to the 3-point checklist. © 2015 Japanese Dermatological Association.

  16. Melanocytic nevi with features of Spitz nevi and Clark's/dysplastic nevi ("Spark's" nevi).

    Science.gov (United States)

    Ko, Christine J; McNiff, Jennifer M; Glusac, Earl J

    2009-10-01

    Nevi with cytologic characteristics of Spitz nevus and architectural features of Clark's/dysplastic nevus are not well recognized in the literature. Twenty-seven nevi with characteristics of Spitz nevus and Clark's/dysplastic nevus are reviewed. The patients' mean age was 33 years, and 17/27(63%) patients were female. Lesions were most frequent on the trunk and lower extremities. Histopathologically, these nevi were composed of large, monomorphous spindled and/or epithelioid melanocytes. Spindle cells were often oriented parallel to the epidermis, with fused rete and lamellar fibroplasias. Lateral extension of the junctional component was a feature of compound lesions. An average of 10 years of clinical follow up in 12 patients revealed no recurrence or metastasis. Recognition of this type of nevus is important to avoid confusion with malignant melanoma. 2009 John Wiley & Sons A/S.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. Differential effects of selenite and selenate on human melanocytes, keratinocytes, and melanoma cells.

    Science.gov (United States)

    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.

  19. Discoidin domain receptor-1 as a player in impairment of melanocytes adhesion process in vitiligo.

    Science.gov (United States)

    Elgarhy, Lamia H; Abdullatif, Amani; Abdelazim, Rehab; El-Desouky, Karima I

    2016-10-01

    The aim of this paper was to study immunohistochemical expression of discoidin domain receptor 1 (DDR1) in lesional and non-lesional skin of vitiligo patients in comparison to controls, to explore its possible implication vitiligo pathogenesis. Twenty patients with non-segmental vitiligo (NSV) were subjected to punch biopsy from lesional and non-lesional vitiligo skin, in addition to punch biopsy from ten healthy subjects. All specimens were examined by H&E staining and by immunohistochemistry for DDR1 expression. Significantly decreased expression of DDR1 in lesional vitiligo skin in comparison to non-lesional skin was observed. In addition, decreased lesional and non-lesional DDR1 expression in vitiligo skin in comparison to controls was found. Reduced DDR1 expression may be implicated in impaired melanocyte adhesion process involved in vitiligo pathogenesis.

  20. Melanin pigments in the melanocytic nevus regress spontaneously after inactivation by high hydrostatic pressure.

    Science.gov (United States)

    Sakamoto, Michiharu; Morimoto, Naoki; Jinno, Chizuru; Mahara, Atsushi; Ogino, Shuichi; Suzuki, Shigehiko; Kusumoto, Kenji; Yamaoka, Tetsuji

    2017-01-01

    We report a novel treatment for giant congenital melanocytic nevi (GCMN) that involves the reuse of resected nevus tissue after high hydrostatic pressurization (HHP). However, the remaining melanin pigments in the inactivated nevus tissue pose a problem; therefore, we performed a long-term observation of the color change of inactivated nevus tissue after HHP. Pressurized nevus specimens (200 MPa group, n = 9) and non-pressurized nevus tissues (control group, n = 9) were subcutaneously implanted into nude mice (BALB/c-nu) and then harvested 3, 6, and 12 months later. Color changes of the nevus specimens were evaluated. In the 200 MPa group, the specimen color gradually regressed and turned white, and brightness values were significantly higher in the 200 MPa group than in the control group after 6 months. This indicated that melanin pigments in the pressurized nevus tissue had spontaneously degraded and regressed. Therefore, it is not necessary to remove melanin pigments in HHP-treated nevus tissue.

  1. Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

    DEFF Research Database (Denmark)

    Jehs, Tina; Faber, Carsten; Udsen, Maja S.

    2016-01-01

    Purpose: To determine to which extent inflammatory cytokines affect chemokine secretion by primary human choroidal melanocytes (HCMs), their capacity to attract monocytes, and whether HCMs are able to influence the proliferation of activated T cells. Methods: Primary cultures of HCMs were...... and secretion of CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5 and intercellular adhesion molecule 1. Vascular endothelial growth factor and monocyte migration inhibitory factor were constitutively expressed without changes in response to proinflammatory cytokines. Supernatants derived from unstimulated cultures...... of 10 HCM donors induced a high initial level of monocyte migration, which decreased upon stimulation with either TCM or IFN-γ and TNF-α. The supernatants from three HCM donors initially showed a low level of monocyte attraction, which increased after exposure to proinflammatory cytokines. Direct...

  2. Giant congenital melanocytic nevus of the face. A clinical case report

    Directory of Open Access Journals (Sweden)

    Маргарита Сергеевна Цыплакова

    2015-06-01

    Full Text Available This article describes a rare case of congenital anomalies: giant melanocytic nevus of the face. Errors in the choice of treatment strategy of children with this disease and their complications can lead to poor aesthetic and functional results. When choosing a method of plastic eliminate defects formed after removal of nevi, it is necessary to take into account anatomical features of the maxillofacial region. The department developed the scheme of complex treatment of these patients. Surgical treatment in combination with massage and myogymnastics, regular medical observation, provides a good aesthetic results. Integrated approach in the treatment of children with giant nevi of the face allows for an early medico-social rehabilitation of children with this pathology.

  3. Neural Tube Defects

    Science.gov (United States)

    ... vitamin, before and during pregnancy prevents most neural tube defects. Neural tube defects are usually diagnosed before the infant is ... or imaging tests. There is no cure for neural tube defects. The nerve damage and loss of function ...

  4. The effect of MC1R variants and sunscreen on the response of human melanocytes in vivo to ultraviolet radiation and implications for melanoma.

    Science.gov (United States)

    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. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Low-energy helium-neon laser induces melanocyte proliferation via interaction with type IV collagen: visible light as a therapeutic option for vitiligo.

    Science.gov (United States)

    Lan, C-C E; Wu, C-S; Chiou, M-H; Chiang, T-Y; Yu, H-S

    2009-08-01

    The treatment of vitiligo remains a challenge for clinical dermatologists. We have previously shown that the helium-neon laser (He-Ne laser, 632.8 nm) is a therapeutic option for treatment of this depigmentary disorder. Addressing the intricate interactions between melanocytes, the most important cellular component in the repigmentation scheme of vitiligo, and their innate extracellular matrix collagen type IV, the current study aimed to elucidate the effects of the He-Ne laser on melanocytes. Cultured melanocytes were irradiated with the He-Ne laser. Relevant biological parameters including cell attachment, locomotion and growth were evaluated. In addition, the potentially involved molecular pathways were also determined. Our results show that in addition to suppressing mobility but increasing attachment to type IV collagen, the He-Ne laser stimulates melanocyte proliferation through enhanced alpha2beta1 integrin expression. The expression of phosphorylated cyclic-AMP response element binding protein (CREB), an important regulator of melanocyte growth, was also upregulated by He-Ne laser treatment. Using a specific mitochondrial uncoupling agent [carbonyl cyanide m-chlorophenyl-hydrazone (CCCP)], the proliferative effect of the He-Ne laser on melanocytes was abolished and suppression of melanocyte growth was noted. In summary, we have demonstrated that the He-Ne laser imparts a growth stimulatory effect on functional melanocytes via mitochondria-related pathways and proposed that other minor pathways including DNA damage may also be inflicted by laser treatment on irradiated cells. More importantly, we have completed the repigmentation scheme of vitiligo brought about by He-Ne laser light in vitro and provided a solid theoretical basis regarding how the He-Ne laser induces recovery of vitiligo in vivo.

  6. New procedure for epidermal cell isolation using kiwi fruit actinidin, and improved culture of melanocytes in the presence of leukaemia inhibitory factor and forskolin

    DEFF Research Database (Denmark)

    Yarani, Reza; Mansouri, Kamran; Mohammadi-Motlagh, Hamid Reza

    2013-01-01

    factor (LIF) and forskolin. MATERIALS AND METHODS: Dermo-epidermal separation and epidermal sheet cell dispersion were performed using actinidin compared to conventional proteases including collagenase, thermolysin or trypsin. Thereafter, melanocyte culture was performed in two common media and one......, and of more viable native cells. Also, melanocytes proliferated better in phorbol ester- and cholera toxin-free proliferation medium supplemented with LIF and forskolin. CONCLUSION: Less contamination and higher numbers of viable cells were actinidin preferential for separation of epidermis and isolation...

  7. The Ap3b1 gene regulates the ocular melanosome biogenesis and tyrosinase distribution differently from the Hps1 gene.

    Science.gov (United States)

    Jing, Renwei; Dong, Xuan; Li, Kailin; Yan, Jie; Chen, Xiangyuan; Feng, Lijun

    2014-11-01

    Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder in humans and mice. The pearl (pe) mouse, a mouse model for the human HPS-2, bears a mutation in Ap3b1 gene. Here we investigated the pigmentation in eyes of pearl (pe) mice, and compared it with our previously published data in pale ear (ep) mice. We revealed that the hypopigmentation in eyes of pearl mice was more severe than pale ear mice, especially in the neural crest-derived tissues. However, the total tyrosinase activity in eyes of pearl mice was stronger than pale ear mice, suggesting that the degradation of aberrantly transported tyrosinase in eyes of pearl mice was weaker than that of pale ear mice. Furthermore, the pigmentation in eyes of mice doubly heterozygous for Hps1 and Ap3b1 genes was similar to the wild-type, while the hypopigmentation in iris of double mutant mice was more severe than either single mutant. Besides, we found several previously reported characters in pale ear mice, including macromelanosomes in the neural crest-derived melanocytes and increased accumulation of lipofuscin in the RPE, were absent in pearl mice. Our study indicates that Ap3b1 gene play distinct roles in melanin production and tyrosinase distribution compared with Hps1 gene. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Melanocytes from the outer root sheath of human hair and epidermal melanocytes display improved melanotic features in the niche provided by cGEL, oligomer-cross-linked gelatin-based hydrogel.

    Science.gov (United States)

    Sülflow, Katharina; Schneider, Marie; Loth, Tina; Kascholke, Christian; Schulz-Siegmund, Michaela; Hacker, Michael C; Simon, Jan-Christoph; Savkovic, Vuk

    2016-12-01

    Non-invasively based cell treatments of depigmented skin disorders are largely limited by means of cell sampling as much as by their routes of application. Human melanocytes cultivated from the outer root sheath of hair follicle (HUMORS) are among the cell types that fit the non-invasive concept by being cultivated out of a minimal sample: hair root. Eventual implementation of HUMORS as a graft essentially depends on a choice of suitable biocompatible, biodegradable carrier that would mechanically and biologically support the cells as transient niche and facilitate their engraftment. Hence, the melanotic features of follicle-derived HUMORS and normal human epidermal melanocytes (NHEM) in engineered scaffolds based on collagen, the usual leading candidate for graft material for a variety of skin transplantation procedures were tested. Hydrogel named cGEL, an enzymatically degraded bovine gelatin chemically cross-linked with an oligomeric copolymer synthesized from pentaerythritol diacrylate monostearate (PEDAS), maleic anhydride (MA), and N-isopropylacrylamide (NiPAAm) or diacetone acrylamide (DAAm), was used. The cGEL provided a friendly three-dimensional (3D) cultivation environment for human melanocytes with increased melanin content of the 3D cultures in comparison to Collagen Cell Carrier® (CCC), a commercially available bovine decellularized collagen membrane, and electrospun polycaprolactone (PCL) matrices. One of the cGEL variants fostered not only a dramatic increase in melanin production but also a significant enhancement of melanotic gene PAX3, PMEL, TYR, and MITF expression in comparison to that of both CCC full-length collagen and PCL scaffolds, providing a clearly superior melanocyte niche that may be a suitable candidate for grafting carriers. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3115-3126, 2016. © 2016 Wiley Periodicals, Inc.

  9. 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.

    Science.gov (United States)

    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.

  10. [Neural repair].

    Science.gov (United States)

    Kitada, Masaaki; Dezawa, Mari

    2008-05-01

    Recent progress of stem cell biology gives us the hope for neural repair. We have established methods to specifically induce functional Schwann cells and neurons from bone marrow stromal cells (MSCs). The effectiveness of these induced cells was evaluated by grafting them either into peripheral nerve injury, spinal cord injury, or Parkinson' s disease animal models. MSCs-derived Schwann cells supported axonal regeneration and re-constructed myelin to facilitate the functional recovery in peripheral and spinal cord injury. MSCs-derived dopaminergic neurons integrated into host striatum and contributed to behavioral repair. In this review, we introduce the differentiation potential of MSCs and finally discuss about their benefits and drawbacks of these induction systems for cell-based therapy in neuro-traumatic and neuro-degenerative diseases.

  11. Punch biopsy of melanoma causing tumour cell implantation: another peril of utilising partial biopsies for melanocytic tumours.

    Science.gov (United States)

    Luk, Peter P; Vilain, Ricardo; Crainic, Oana; McCarthy, Stanley W; Thompson, John F; Scolyer, Richard A

    2015-08-01

    The recommended initial management for suspected melanoma is excisional biopsy. The use of partial biopsies of melanocytic tumours poses potential problems including misdiagnosis due to either unrepresentative sampling or the difficulty in evaluating important diagnostic features; an inaccurate assessment of Breslow thickness and other important prognostic features; and the induction of changes capable of mimicking melanoma (i.e., pseudomelanoma). Misdiagnosis, in turn, may lead to inappropriate management of the patient and an adverse outcome. In this report we document a previously unrecognised pitfall of partial biopsies of melanocytic tumours: implantation of tumour cells at the biopsy site potentially leading to the overestimation of tumour thickness or a misdiagnosis of the presence of microsatellites in the subsequent wide excision specimen. © 2015 The Australasian College of Dermatologists.

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier España, S.L.U. y AEDV. All rights reserved.

  13. Melanocytic nevus count and dermoscopic features do not differ in psoriatic patients undergoing biological agent versus conventional drug therapy.

    Science.gov (United States)

    Pirmit, Serpil; Onsun, Nahide; Su, Ozlem; Ozkaya, Dilek B

    2017-04-01

    Psoriasis is a chronic immune-mediated disease and treatment of psoriasis includes conventional immunosuppressive agents and biological agents. There are a few data on the relationship between psoriasis and melanocytic lesions. Either benign or malignant proliferations may be seen with immunosuppressive treatment. Eruptive nevi and malignant melanoma (MM) have been reported also associated with biological agents There is raising link biological treatment and malignancies. The objective of this paper is to examine the effects of biological agents versus conventional drugs on melanocytic nevi count and dermoscopical features. Sixty-seven patients receiving TNF-α antagonists (etanercept, infliximab and adalimumab) and 62 patients receiving methotrexate and cyclosporin included to the trial. Duration of treatment with biological agents ranged from 6 months to 4 years, and between 6 months to 3 years for conventional drugs. Total and regional nevi count and structurel changes of biological treatment was evaluated. All melanocytic lesions checked for dermoscopic features by using Dermogenius Ultra (Linos Photonics GmbH & Co, Munich, Germany). Diagnosis of atypical nevi and doubtful lesions for melanoma was made by using ABCD clinically and, by three point check list (asymmetry, atypical pigment network and blue whitish structures) dermoscopically. There were no significant changes in number of total and regional nevi count and in the dermoscopic features of nevi between biological and conventional treatment groups. We observed dermoscopical changes in only one nevus of a patient receiving etanercept. Histopathological examination of this nevi confirmed the diagnosis of dysplastic nevi. There were no MM and non-melanoma skin cancers in both groups. We did not observe significant changes in biological and conventional treatment groups there is a need for further studies to determine long-term effects of biological agents on the melanocytic lesions in patients with

  14. UVB-Stimulated TNFα Release from Human Melanocyte and Melanoma Cells Is Mediated by p38 MAPK

    Directory of Open Access Journals (Sweden)

    Visalini Muthusamy

    2013-08-01

    Full Text Available Ultraviolet (UV radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase, JNK and NFκB pathways to determine which plays a major role in stimulating TNFα secretion in human HEM (melanocytes and MM96L (melanoma cells. MM96L cells exhibited 3.5-fold higher p38 activity than HEM cells at 5 min following UVA + B radiation and 1.6-fold higher JNK activity at 15–30 min following UVB+A radiation, while NFκB was minimally activated in both cells. Irradiated HEM cells had the greatest fold of TNFα secretion (UVB: 109-fold, UVA + B: 103-fold & UVB+A: 130-fold when co-exposed to IL1α. The p38 inhibitor, SB202190, inhibited TNFα release by 93% from UVB-irradiated HEM cells. In the UVB-irradiated MM96L cells, both SB202190 and sulfasalazine (NFκB inhibitor inhibited TNFα release by 52%. Although, anisomycin was a p38 MAPK activator, it inhibited TNFα release in UV-irradiated cells. This suggests that UV-mediated TNFα release may occur via different p38 pathway intermediates compared to those stimulated by anisomycin. As such, further studies into the functional role p38 MAPK plays in regulating TNFα release in UV-irradiated melanocyte-derived cells are warranted.

  15. Estradiol differently affects melanin synthesis of malignant and normal melanocytes: a relationship with clock and clock-controlled genes.

    Science.gov (United States)

    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.

  16. Immunohistochemical investigation of alpha1 (IV) and alpha5 (IV) collagen chains in a broad spectrum of melanocytic tumours.

    Science.gov (United States)

    Quatresooz, Pascale; Piérard, Gérald E

    2005-06-01

    Cells of melanocytic naevi and cutaneous malignant melanomas (MM) are surrounded by a basement membrane (BM). To scrutinize any difference between the deposits of alpha1 (IV) and alpha5 (IV) collagen chains in melanocytic naevi and MM. A total of 27 common melanocytic naevi, 11 dysplastic naevi, 21 atypical naevi (melanocytomas) including Spitz and non-Spitz types, as well as 24 MM were studied. Their phenotypic and functional characteristics defined by immunohistochemistry using a panel of antibodies, including those directed to the alpha1 (IV), alpha3 (IV) and alpha5 (IV) collagen chains. Almost all naevi and half the melanocytomas exhibited a strong positivity for the alpha1 (IV) collagen chain. By contrast, the remaining melanocytomas and MM presented a heterogeneous staining pattern for the alpha1 (IV) collagen chain. One third of the naevi, 23% of the MM without cutaneous micrometastasis and 83% of MM with cutaneous micrometastasis showed discrete cytoplasmic positivity for the alpha5 (IV) collagen chain. All other melanocytic tumours were negative for this antibody. Rare MM cells in transepidermal migration were stained with the anti-alpha1 (IV) or alpha5 (IV) collagen chain antibodies. No immunoreactivity for the alpha3 (IV) collagen chain was disclosed in any of the samples. We report the expression of alpha1 (IV) and alpha5 (IV) collagen chains in naevi and MM. The inconsistent staining pattern for alpha1 (IV) collagen chain in phenotypically atypical melanocytomas and in MM highlight the heterogeneity in both cell differentiation and stroma-tumour interactions. This biological aspect may be related to neoplastic progression and influence metastatic potential.

  17. Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45.

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Prevalence and implications of TERT promoter mutation in uveal and conjunctival melanoma and in benign and premalignant conjunctival melanocytic lesions.

    Science.gov (United States)

    Koopmans, Anna E; Ober, Kimberley; Dubbink, Hendrikus J; Paridaens, Dion; Naus, Nicole C; Belunek, Stephan; Krist, Bart; Post, Edward; Zwarthoff, Ellen C; de Klein, Annelies; Verdijk, Robert M

    2014-08-26

    Hot-spot mutations in the promoter region of telomerase reverse transcriptase (TERT promoter mutations) occur frequently in cutaneous and conjunctival melanoma and are exceedingly rare in uveal melanoma. No information is available on the presence of these mutations in the conjunctival melanocytic precursor lesion primary acquired melanosis (PAM). We tested a cohort of uveal and conjunctival melanomas as well as conjunctival benign and premalignant melanocytic lesions for TERT promoter mutations in order to elucidate the role of these mutations in tumor progression. TERT promoter mutation analysis on fresh tumor DNA and DNA from formalin-fixed, paraffin-embedded specimens was performed by SNaPshot analysis in 102 uveal melanomas, 39 conjunctival melanomas, 26 PAM with atypia, 14 PAM without atypia, and 56 conjunctival nevi. Mutations of the TERT promoter were not identified in conjunctival nevi or PAM without atypia, but were detected in 2/25 (8%) of PAM with atypia and 16/39 (41%) of conjunctival melanomas. A single TERT promoter mutation was detected in 102 uveal melanomas (1%). We present the second documented case of TERT promoter mutation in uveal melanoma. In comparison with other types of melanoma, TERT promoter mutations occur at extremely low frequency in uveal melanoma. TERT promoter mutations are frequent in conjunctival melanoma and occur at lower frequency in PAM with atypia but were not detected in benign conjunctival melanocytic lesions. These findings favor a pathogenetic tumor progression role for TERT promoter mutations in conjunctival melanocytic lesions. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  19. Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma.

    Science.gov (United States)

    Speeckaert, Reinhart; van Geel, Nanja; Luiten, Rosalie M; van Gele, Mireille; Speeckaert, Marijn; Lambert, Jo; Vermaelen, Karim; Tjin, Esther P M; Brochez, Lieve

    2011-11-01

    Regressing nevi are considered an example of an efficient early antitumoral response preventing the development of neoplasia. The underlying mechanism has not been elucidated, although an immune-based destruction of melanocytes is supposed. The aim of this study was to provide evidence of an effective immunosurveillance of pigment lesions in a patient at high risk of melanoma. A patient with the dysplastic nevus syndrome and a history of melanoma was included in this study. Since 2003, a marked regression of almost all nevi was observed. Immunohistochemistry was performed and the antigen specificity of T-cells was analyzed on T-cells isolated from a regressing nevus by flow cytometry using HLA-A2-peptide tetramers containing Mart-1(26-35), gp100(280-288), gp100(209-217) and tyrosinase(369-377). Immunohistochemistry of the regressing nevi showed a strong infiltrate of CD4 + and CD8 + T-cells. Flow cytometric analyses demonstrated the presence of a CD8 + T-cell response against gp100(280-288) and Mart-1(26-35) both in peripheral blood and in a regressing nevus. These findings indicate that an immune reaction against melanocyte differentiation antigens can target specifically nevi without signs of vitiligo and suggests that boosting the anti-melanocyte immune response in patients at high risk for melanoma may prevent tumor development at an early stage.

  20. Silencing of GPNMB by siRNA Inhibits the Formation of Melanosomes in Melanocytes in a MITF-Independent Fashion

    Science.gov (United States)

    Zhu, Cansheng; Yuan, Xiaoying; Li, Dongguang; Gu, Weijie; Ma, Huimin; Xie, Xin; Gao, Tianwen

    2012-01-01

    Background Melanosomes are specialized membrane-surrounded organelles, which are involved in the synthesis, storage and transport of melanin. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB), a melanosome-specific structural protein, shares significant amino acid sequence homology with Pmel-17. Proteomic analysis demonstrated that GPNMB is present in all stages (I-IV) of melanosomes. However, little is known about the role of GPNMB in melanosomes. Methodology/Principal Findings Using real-time quantitative PCR, Western blotting and immunofluorescence analysis, we demonstrated that the expression of GPNMB in PIG1 melanocytes was up-regulated by ultraviolet B (UVB) radiation. Transmission electron microscopy analysis showed that the total number of melanosomes in PIG1 melanocytes was sharply reduced by GPNMB-siRNA transfection. Simultaneously, the expression levels of tyrosinase (Tyr), tyrosinase related protein 1 (Trp1), Pmel17/gp100 and ocular albinism type 1 protein (OA1) were all significantly attenuated. But the expression of microphthalmia-associated transcription factor (MITF) was up-regulated. Intriguingly, in GPNMB silenced PIG1 melanocytes, UVB radiation sharply reduced MITF expression. Conclusion Our present work revealed that the GPNMB was critical for the formation of melanosomes. And GPNMB expression down-regulation attenuated melanosome formation in a MITF-independent fashion. PMID:22912767

  1. Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis.

    Science.gov (United States)

    Loftus, Stacie K; Baxter, Laura L; Cronin, Julia C; Fufa, Temesgen D; Pavan, William J

    2017-05-01

    Hypoxia and HIF1α signaling direct tissue-specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1α knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1α-dependent/hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP-Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for 10 of the HIF1α direct targets - GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 - are significantly correlated with reduced time of disease-free status in melanoma by logistic regression (P-value = 0.0013) and ROC curve analysis (AUC = 0.826, P-value < 0.0001). This HIF1α-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  2. Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

    Directory of Open Access Journals (Sweden)

    Amrita Dasgupta

    2015-08-01

    Full Text Available Cutaneous Melanoma (CM is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR. UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics.

  3. Piebald trait: implication of kit mutation on in vitro melanocyte survival and on the clinical application of cultured epidermal autografts.

    Science.gov (United States)

    Bondanza, Sergio; Bellini, Melissa; Roversi, Gaia; Raskovic, Desanka; Maurelli, Riccardo; Paionni, Emanuel; Paterna, Patrizia; Dellambra, Elena; Larizza, Lidia; Guerra, Liliana

    2007-03-01

    Piebald trait leukoderma results from "loss-of-function" mutations in the kit gene. Correlations between mutation type and clinical phenotype have been reported. However, mutation classification has been mainly based on the clinical features of patients. The aim of this study was to get a better understanding of the pathogenesis of human piebaldism by establishing whether the kit mutation type may affect the in vitro survival/proliferation of patient melanocytes. Overall, the research was finalized to implement the clinical application of the autologous cultured epidermis in the treatment of piebald patients. Seven patients, who were transplanted with autologous in vitro reconstituted epidermis, showed an average percentage of repigmentation of 90.7. Six novel and one previously reported mutations were found and their postulated effects discussed in relation to the clinical phenotype and in vitro behavior of epidermal cells. Although mutation type did not impair repigmentation given by autotransplantation, it was shown to influence the survival/proliferation of co-cultured melanocytes and keratinocytes. In particular, tyrosine kinase domain mutations were found with melanocyte loss and keratinocyte senescence during expansion of epidermal cultures. Results indicate that the clinical application of cultured epidermis in piebald patients may be optimized by investigating mutation functional effects before planning surgical operations.

  4. Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

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    Dasgupta, Amrita [Hampton University Skin of Color Research Institute, Hampton, VA 23668 (United States); Katdare, Meena, E-mail: mkatdare@gmail.com [Hampton University Skin of Color Research Institute, Hampton, VA 23668 (United States); Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA 23507 (United States)

    2015-08-14

    Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics.

  5. Nevo melanocítico congênito Congenital melanocytic nevi

    Directory of Open Access Journals (Sweden)

    Francisco Macedo Paschoal

    2002-12-01

    Full Text Available O nevo melanocitico congênito está presente em aproximadamente 1% dos recém nascidos. As lesões classificadas como pequenas e medias são relativamente comuns, ao passo que o nevo gigante, maior que 20 cm no maior diâmetro, é uma condição mais rara cuja a incidência esta estimada em 1 para cada 20 mil nascimentos. As lesões melanociticas congênitas pequenas e médias têm um risco de degeneração maligna baixo, raramente ocorrendo na infância. Por outro lado, estima-se um risco entre 5 a 12 % de um melanoma se desenvolver a partir ou relacionado com um nevo gigante, e de regra, metade dos casos ocorrem antes dos 3 anos de idade. Alem da possibilidade de degeneração maligna, o acometimento neurológico e as implicações psicológicas devido ao aspecto estético são dois aspectos importantes relacionados com as lesões gigantes, influindo também na decisão e na abordagem terapêutica.Congenital melanocytic nevi is present in approximately 1% of new born. The lesions classified as small and medium are relatively common, while giant pigmented nevus, measuring over 20cm in the largest diameter, is a rarer condition, the incidence of which is estimated to be one in every 20 thousand births. The small and medium congenital melanocytic lesions present a low risk of malignant degeneration and this rarely occurs in childhood. On the other hand, there is a risk estimated between 5 to 12% of a melanoma growing from or being related to a giant nevus, furthermore in half of the cases this occurs before three years of age. Besides the possibility of malignant degeneration, the neurological involvement and psychological implications arising from aesthetic aspect are two important factors related to the giant lesions and also influence the therapeutic approach.

  6. NEAR-INFRARED AUTOFLUORESCENCE IN BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION ASSOCIATED WITH ESOPHAGEAL CARCINOMA AND CHOROIDAL METASTASIS.

    Science.gov (United States)

    Golshahi, Azadeh; Bornfeld, Norbert; Weinitz, Silke; Kellner, Ulrich

    2016-01-01

    To investigate the advantage of near-infrared autofluorescence (787 nm) for the detection of melanocytic lesions in a patient with bilateral diffuse uveal melanocytic proliferation in association with esophageal carcinoma complicated by most likely unilateral choroidal metastasis. In this retrospective case report, a 55-year-old woman referred for the evaluation of sudden visual loss underwent normal ophthalmological evaluation and, in addition, was examined with near-infrared reflectance, near-infrared autofluorescence, fundus autofluorescence (Heidelberg Retina Angiograph II [HRA2; Heidelberg Engineering]), spectral domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering), and multifocal electroretinography (RetiScan; Roland Consult). The patient had been diagnosed with esophageal carcinoma 3 months before the onset of visual symptoms. The visual acuity was 20/40 in the right eye and 20/20 in the left eye. Bilateral patchy melanocytic proliferation was detected on ophthalmoscopy. The extent of lesions was best detected with near-infrared reflectance and near-infrared autofluorescence, whereas fundus autofluorescence and spectral domain optical coherence tomography did not reveal alterations of the outer retina or retinal pigment epithelium in this early stage of bilateral diffuse uveal melanocytic proliferation. The right eye showed in addition to the findings on the left eye choroidal folds in the fovea and an elevated lesion inferotemporal of the fovea suspicious of a choroidal metastasis. In the B-scan ultrasonography, a homogenous lesion was seen. Spectral domain optical coherence tomography demonstrated a mild accumulation of subretinal fluid adjacent to and over the choroidal metastasis. Transretinal biopsy of this elevated lesion revealed a low differentiated carcinoma of squamous epithelium, compatible with choroidal metastasis of the esophageal carcinoma. The choroidal metastasis increased within 3 months after the first visit. The

  7. MC1R variant allele effects on UVR-induced phosphorylation of p38, p53, and DDB2 repair protein responses in melanocytic cells in culture.

    Science.gov (United States)

    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.

  8. The impact of melanocytic cell destruction in pediatric facial burns and plastic surgery therapeutic management.

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    Ungureanu, Anca Roxana; Ioniţă, Dan; Drăghici, Liviu; Andrei, Daniel; Enescu, Dan Mircea; Drăghici, Isabela Magdalena

    2014-01-01

    The main role of the melanin production belongs to the keratinocyte-Langerhans-melanocyte complex that within a burn injury might be destroyed. A particular aspect has the pediatric patient with burns due to a deficit in pigment synthesis and particularities involving the growth process of facial structures. This article presents four eloquent cases of pediatric patients with sequelae, consequence of facial burns that varied in depth and etiology. The age of patients at time of admission was between four and 18 years, and the interval between production of the primary lesion and admission was variable (0-17 years). Conservative treatments prove to be insufficient, requiring the destroyed structures to be replaced with compatible tissue by surgical intervention. The therapeutic success of skin grafts and dermal substituents acknowledges the main role of plastic surgery. New technologies as well as new cell focused studies support the clinical proven results as well as they enlarge the spectrum of potential available therapeutic methods in order to obtain the best therapeutic results.

  9. Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation.

    Science.gov (United States)

    Campos, Ana C E; Molognoni, Fernanda; Melo, Fabiana H M; Galdieri, Luciano C; Carneiro, Célia R W; D'Almeida, Vânia; Correa, Mariangela; Jasiulionis, Miriam G

    2007-12-01

    Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. L(G)-Nitro-L-arginine methyl esther (L-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-L-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.

  10. Oxidative Stress Modulates DNA Methylation during Melanocyte Anchorage Blockade Associated with Malignant Transformation1

    Science.gov (United States)

    Campos, Ana C E; Molognoni, Fernanda; Melo, Fabiana H M; Galdieri, Luciano C; Carneiro, Célia R W; D'Almeida, Vânia; Correa, Mariangela; Jasiulionis, Miriam G

    2007-01-01

    Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. lG-Nitro-l-arginine methyl esther (l-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-l-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both l-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism. PMID:18084618

  11. Oral delivery of Bifidobacterium longum expressing α-melanocyte-stimulating hormone to combat ulcerative colitis.

    Science.gov (United States)

    Wei, Pijin; Yang, Yan; Ding, Qing; Li, Xiuying; Sun, Hanxiao; Liu, Zhaobing; Huang, Junli; Gong, Yahui

    2016-02-01

    α-Melanocyte-stimulating hormone (α-MSH) is a tridecapeptide derived from pro-opiomelanocortin that exhibits potent anti-inflammatory properties by regulating the production of inflammatory mediators. This peptide has been well established in several inflammatory models, including inflammatory bowel disease (IBD). However, its extremely short duration in vivo limits its clinical application. To address this limitation, Bifidobacterium was used here as a carrier to deliver α-MSH. We utilized α-MSH-engineered Bifidobacterium against IBD, which is closely linked to immune and intestinal microbiota dysfunction. First, we constructed a Bifidobacterium longum secreting α-MSH (B. longum-α-MSH). We then tested the recombinant α-MSH expression and determined its bioactivity in HT-29 cells. To assess its effectiveness, B. longum-α-MSH was used against an ulcerative colitis (UC) model in rats induced by dextran sulfate sodium. The data showed that α-MSH expression in B. longum-α-MSH was effective, and its biological activity was similar to the synthesized one. This UC model experiment indicated that B. longum-α-MSH successfully colonized the intestinal gut, expressed bioactive α-MSH and had a significant anti-inflammatory effect. The results demonstrate the feasibility of preventing IBD by using B. longum-α-MSH.

  12. The influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms.

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    Gerardo Ferrara

    Full Text Available BACKGROUND: We tested the relevance of clinical information in the histopathologic evaluation of melanocytic skin neoplasm (MSN. METHODS: Histopathologic specimens from 99 clinically atypical MSN were circulated among ten histopathologists; each case had clinical information available in a database with a five-step procedure (no information; age/sex/location; clinical diagnosis; clinical image; dermoscopic image; each step had a histopathologic diagnosis (D1 through D5; each diagnostic step had a level of diagnostic confidence (LDC ranging from 1 (no diagnostic certainty to 5 (absolute diagnostic certainty. The comparison of the LDC was employed with an analysis of variance (ANOVA for repeated measures. FINDINGS: In D1 (no information, 36/99 cases (36.3% had unanimous diagnosis; in D5 (full information available, 51/99 cases (51.5% had unanimous diagnosis (p for difference between proportions <0.001. The observer agreement expressed as kappa increased significantly from D1 to D5. The mean LDC linearly increased for each observer from D1 through D5 (p for linear trend <0.001. On average, each histopathologist changed his initial diagnosis in 7 cases (range: 2-23. Most diagnostic changes were in D2 (age/sex/location. INTERPRETATION: The histopathologic criteria for the diagnosis of MSN can work as such, but the final histopathologic diagnosis is a clinically-aided interpretation. Clinical data sometimes reverse the initial histopathologic evaluation.

  13. Dysplastic melanocytic nevi of the lower leg: sex- and site-specific histopathology.

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    Coras, Brigitte; Landthaler, Michael; Stolz, Wilhelm; Vogt, Thomas

    2010-08-01

    Site-specific histopathology features have been reported for acral, auricular, flexural, and genital melanocytic nevi, however, to the best of our knowledge, site- and sex-specific histology of dysplastic nevi on the lower leg (between knee and ankle) of women (DN-LW) has not been reported. In this retrospective histopathology study, we compared DN-LW (N = 42) with appropriate control groups of (1) DN of the lower leg of men (N = 20; DN-LM), (2) DN from the back of women (N = 20), (3) common nevi of the lower leg of women (N = 40), and (4) levels 1-2 superficial spreading melanoma of the lower leg of women (N = 20). Compared with dysplastic nevi on the back, DN-LW were smaller in diameter and exhibited a significantly higher score for pagetoid spread (P nevus (54% in DN-LW vs. 15% in DN-LM). As with other body sites, the dermatopathologist should be aware that dysplastic nevi occurring on the lower leg in women have site- and sex-specific features. Knowing this profile may lower the risk of misdiagnosing DN-LW and melanoma of the lower leg of women.

  14. Afamelanotide, an agonistic analog of α-melanocyte-stimulating hormone, in dermal phototoxicity of erythropoietic protoporphyria.

    Science.gov (United States)

    Minder, Elisabeth I

    2010-12-01

    Afamelanotide, an α-melanocyte stimulating hormone (MSH) agonistic analog is a first-in-class therapeutic. Its application to protoporphyria (PP), a disease associated with absolute sunlight-intolerance is discussed. The genetics and existing therapy of the inherited disease PP comprising both erythropoietic protoporphyria and X-linked dominant protoporphyria. The physiological and pharmacological actions of α-MSH and afamelanotide including receptor-mediated intracellular signaling and effects of receptor polymorphisms. Adverse effects and safety issues. The clinical severity and the necessity for an effective therapy for the rare disease PP are illustrated by a short, up-to-date portrait. A condensed description of clinically important aspects of α-MSH signaling, physiological, pharmacological and safety issues of afamelanotide applied to humans and the rational for its potential efficacy in PP are given. The different trials of afamelanotide in PP and their most recent results are discussed. Although early, results of the first trials of afamelanotide for PP are promising and the risk-safety profile appears favorable today. We expect afamelanotide and analogs thereof to be a prospective therapeutic tool in light-related skin diseases, and in future this drug class might prove effectiveness in other medical conditions.

  15. Mitigating photosensitivity of erythropoietic protoporphyria patients by an agonistic analog of alpha-melanocyte stimulating hormone.

    Science.gov (United States)

    Harms, Juergen H; Lautenschlager, Stephan; Minder, Christoph E; Minder, Elisabeth I

    2009-01-01

    Erythropoietic protoporphyria (EPP) is a rare hereditary disorder characterized by dermal accumulation of the photosensitizer protoporphyrin IX. Following sunlight exposure, the resulting photosensitivity is manifested first as pain, later as erythema, edema and dermal lesions. Afamelanotide (Nle(4)-D-Phe(7)-alpha-MSH), a synthetic analog of alpha-melanocyte stimulating hormone and agonist of the melanocortin-1-receptor, promotes melanin synthesis, increasing skin pigmentation. This study examines the efficacy of afamelanotide in preventing symptoms in patients with EPP. A sustained-release subcutaneous implant of 20 mg afamelanotide was administered twice, with a 60-day interval to five EPP patients. Therapeutic efficacy was assessed by a photoprovocation test using standardized white light irradiation, melanin density (MD) determination and daily recording of sunlight exposure and symptoms. From Day 30 to Day 120 tolerance to photoprovocation significantly increased compared with baseline (P = 0.007) and skin MD was significantly higher than that recorded at baseline (P = 0.004). Except for two low-grade pain episodes, patients recorded no phototoxic events past Day 4 of treatment. Tolerance to natural sunlight was up to 24 times longer than prior to therapy. The findings demonstrate beneficial effects of afamelanotide in patients with EPP. Due to the limited number of patients enrolled and the design being an open-label study, confirmation by a large-scale trial is required.

  16. Human giant congenital melanocytic nevus exhibits potential proteomic alterations leading to melanotumorigenesis

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    Kim Hyoung Kyu

    2012-08-01

    Full Text Available Abstract Background A giant congenital melanocytic nevus (GCMN is a malformation of the pigment cells. It is a distress to the patients for two reasons: one is disfigurement, and the other is the possibility of malignant changes. However, the underlying mechanisms of the development of GCMN and melanotumorigenesis in GCMN are unknown. Hence, the aim of this study was to identify the proteomic alterations and associated functional pathways in GCMN. Results Proteomic differences between GCMN (n = 3 and normal skin samples (n = 3 were analyzed by one-dimensional-liquid chromatography-tandem mass spectrometry Relative levels of the selected proteins were validated using western blot analysis. The biological processes associated with the abundance modified proteins were analyzed using bioinformatic tools. Among the 46 abundance modified proteins, expression of 4 proteins was significantly downregulated and expression of 42 proteins was significantly upregulated in GCMN compared to normal skin samples (p  Conclusion These findings suggest that GCMN exhibits potential proteomic alterations, which may play a role in melanotumorigenesis, and the significant alteration of 14-3-3 family proteins could be a key regulator of the biological pathway remodeling in GCMN.

  17. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma.

    Science.gov (United States)

    Matatall, Katie A; Agapova, Olga A; Onken, Michael D; Worley, Lori A; Bowcock, Anne M; Harbour, J William

    2013-08-05

    Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential. We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in the tumor suppressor BAP1. The aim of this study was to investigate the role of BAP1 in uveal melanoma progression. Uveal melanoma cells were studied following RNAi-mediated depletion of BAP1 using proliferation, BrdU incorporation, flow cytometry, migration, invasion, differentiation and clonogenic assays, as well as in vivo tumorigenicity experiments in NOD-SCID-Gamma mice. Depletion of BAP1 in uveal melanoma cells resulted in a loss of differentiation and gain of stem-like properties, including expression of stem cell markers, increased capacity for self-replication, and enhanced ability to grow in stem cell conditions. BAP1 depletion did not result in increased proliferation, migration, invasion or tumorigenicity. BAP1 appears to function in the uveal melanocyte lineage primarily as a regulator of differentiation, with cells deficient for BAP1 exhibiting stem-like qualities. It will be important to elucidate how this effect of BAP1 loss promotes metastasis and how to reverse this effect therapeutically.

  18. The Effects of Biological Agents on Melanocytic Nevi: A Preliminary Report

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    Nurşah Doğan

    2016-03-01

    Full Text Available Objective: The aim of our study was to evaluate the changes of the melanocytic nevi during the biological agent therapy. Methods: For this purpose, 40 index nevi of 25 adult patients who were treated with infliximab, adalimumab, etanercept or rituximab were included in this study. All of the patients underwent clinical and dermoscopic evaluation before the beginning of the treatment, 6 months and 1 year after the beginning of the treatment. Among dermoscopic examination methods, pattern analysis, ABCD score system and three-point checklist were performed. Results: In terms of the diameter of the index nevi, there was no statistically significant difference between the first examination and that of the sixth month, but differences was observed between the first examination and that of the twelfth month. There was also no statistically significant difference in total dermoscopy scores calculated by ABCD score system application on 31 nevi at the times of assessment. At the end of the study, we detected 24 new nevi formation in 7 patients, whom all of were over 35 years of age, however no eruptive nevi or melanoma formation were observed. Conclusion: An increase in the diameters of the present nevi and formation of new nevi may be seen with biological agent therapy in one-year-follow-up.

  19. Variation among pathologists’ treatment suggestions for melanocytic lesions: a survey of pathologists

    Science.gov (United States)

    Lee, Kachiu C.; Peacock, Sue; Weinstock, Martin A.; Zhao, Ge Alice; Knezevich, Stevan R.; Elder, David E.; Barnhill, Raymond L.; Piepkorn, Michael W.; Reisch, Lisa M.; Carney, Patricia A.; Onega, Tracy; Lott, Jason P.; Elmore, Joann G.

    2016-01-01

    Background The extent of variability in treatment suggestions for melanocytic lesions made by pathologists is unknown. Objective We investigated how often pathologists rendered suggestions, reasons for providing suggestions, and concordance with national guidelines. Methods We conducted a cross-sectional survey of pathologists. Data included physician characteristics, experience, treatment recommendation practices. Results Of 301 pathologists, 207 (69%) from 10 states (CA, CT, HI, IA, KY, LA, NJ, NM, UT, WA), enrolled. Fifteen percent and 7% reported never and always including suggestions, respectively. Reasons for offering suggestions included improved care (79%), clarification (68%), and legal liability (39%). Reasons for not offering suggestions included referring physician preference (48%), lack of clinical information (44%), and expertise (29%). Training and caseload were associated with offering suggestions (p<0.05). Physician suggestions were most consistent for mild/moderate dysplastic nevi and melanoma. For melanoma in-situ, 18 (9%) and 32 (15%) pathologists made suggestions that under- or over-treated lesions based on NCCN guidelines, respectively. For invasive melanoma, 14 (7%) of pathologists made treatment suggestions that under-treated lesions based on NCCN guidelines. Limitations Treatment suggestions were self-reported. Conclusions Pathologists made recommendations ranging in consistency. These findings may inform efforts to reduce treatment variability and optimize patterns of care delivery for patients. PMID:27692732

  20. Assessment of melanocytic skin lesions with a high-definition laser Doppler imaging system.

    Science.gov (United States)

    Hunger, Robert E; Della Torre, Rocco; Serov, Alexandre; Hunziker, Thomas

    2012-05-01

    Early detection is a major goal in the management of malignant melanoma. Besides clinical assessment many noninvasive technologies such as dermoscopy, digital dermoscopy and in vivo laser scanner microscopy are used as additional methods. Herein we tested a system to assess lesional perfusion as a tool for early melanoma detection. Laser Doppler flow (FluxExplorer) and mole analyser (MA) score (FotoFinder) were applied to histologically verified melanocytic nevi (33) and malignant melanomas (12). Mean perfusion and MA scores were significantly increased in melanoma compared to nevi. However, applying an empirically determined threshold of 16% perfusion increase only 42% of the melanomas fulfilled the criterion of malignancy, whereas with the mole analyzer score 82% of the melanomas fulfilled the criterion of malignancy. Laser Doppler imaging is a highly sensitive technology to assess skin and skin tumor perfusion in vivo. Although mean perfusion is higher in melanomas compared to nevi the high numbers of false negative results hamper the use of this technology for early melanoma detection. © 2011 John Wiley & Sons A/S.

  1. Copy number variation in archival melanoma biopsies versus benign melanocytic lesions.

    Science.gov (United States)

    Mahas, Ahmed; Potluri, Keerti; Kent, Michael N; Naik, Sameep; Markey, Michael

    2016-03-11

    Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations. This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi. Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi. We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis. Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.

  2. Melanin pigments in the melanocytic nevus regress spontaneously after inactivation by high hydrostatic pressure.

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    Michiharu Sakamoto

    Full Text Available We report a novel treatment for giant congenital melanocytic nevi (GCMN that involves the reuse of resected nevus tissue after high hydrostatic pressurization (HHP. However, the remaining melanin pigments in the inactivated nevus tissue pose a problem; therefore, we performed a long-term observation of the color change of inactivated nevus tissue after HHP. Pressurized nevus specimens (200 MPa group, n = 9 and non-pressurized nevus tissues (control group, n = 9 were subcutaneously implanted into nude mice (BALB/c-nu and then harvested 3, 6, and 12 months later. Color changes of the nevus specimens were evaluated. In the 200 MPa group, the specimen color gradually regressed and turned white, and brightness values were significantly higher in the 200 MPa group than in the control group after 6 months. This indicated that melanin pigments in the pressurized nevus tissue had spontaneously degraded and regressed. Therefore, it is not necessary to remove melanin pigments in HHP-treated nevus tissue.

  3. Resveratrol Inhibits Alpha-Melanocyte-Stimulating Hormone Signaling, Viability, and Invasiveness in Melanoma Cells

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    Yu-Jen Chen

    2013-01-01

    Full Text Available Melanoma is a malignancy with high potential to invasion and treatment resistance. The α-melanocyte-stimulating hormone (α-MSH signal transduction involving Wnt/β-catenin, c-Kit, and microphthalmia-associated transcription factor (MITF, a known pathway to produce melanin, has been demonstrated as one of cancer stem cell characteristics. This study was aimed to examine the effect of resveratrol, an abundant ingredient of grape and medicinal plants, on α-MSH signaling, viability, and invasiveness in melanoma cells. By α-MSH treatment, the melanin production in B16 melanoma cells was augmented as a validation for activation of α-MSH signaling. The upregulated expression of α-MSH signaling-related molecules β-catenin, c-Kit, and MITF was suppressed by resveratrol and/or STI571 treatment. Nuclear translocation of MITF, a hallmark of α-MSH signaling activation, was inhibited by combined treatment of resveratrol and STI571. At effective concentration, resveratrol and/or STI571 inhibited cell viability and α-MSH-activated matrix metalloproteinase- (MMP-9 expression and invasion capacity of B16 melanoma cells. In conclusion, resveratrol enhances STI571 effect on suppressing the α-MSH signaling, viability, and invasiveness in melanoma cells. It implicates that resveratrol may have potential to modulate the cancer stem cell characteristics of melanoma.

  4. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.

    Science.gov (United States)

    Sznajer, Yves; Coldéa, Cristina; Meire, Françoise; Delpierre, Isabelle; Sekhara, Tayeb; Touraine, Renaud L

    2008-04-15

    Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient. Copyright 2008 Wiley-Liss, Inc.

  5. The chick embryo as an experimental system for melanoma cell invasion.

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    Christian Busch

    Full Text Available BACKGROUND: A primary cutaneous melanoma will not kill the patient, but its metastases. Since in vitro studies on melanoma cells in 2-D cultures do often not reflect reality, 3-D models might come closer to the physiological situation in the patient during cancer initiation and progression. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe the chick embryo model for in vivo studies of melanoma cell migration and invasion. After transplantation of neural crest-derived melanoma cells into the neural tube, the melanoma cells resume neural crest cell migration along the medial and lateral pathways and finally undergo apoptosis in the target areas. Upon transplantation into ectopic areas such as the hindbrain or the optic cup malignant invasion and local tissue destruction occurs. In contrast, melanocytes are not able to spontaneously resume neural crest cell migration. However, malignant invasion can be induced in melanocytes by pre-treatment with the TGF-beta family members bone morphegenetic protein-2 or nodal. Transplantation of MCF7 breast cancer cells yields a different growth pattern in the rhombencephalon than melanoma cells. CONCLUSIONS/SIGNIFICANCE: The chick embryo model is a feasible, cost-effective in vivo system to study invasion by cancer cells in an embryonic environment. It may be useful to study invasive behavior induced by embryonic oncogenes and for targeted manipulation of melanoma or breast cancer cells aiming at ablation of invasive properties.

  6. 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.

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    Kazuhisa Takeda

    Full Text Available 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

  7. Polygonum multiflorum Radix extract protects human foreskin melanocytes from oxidative stress in vitro and potentiates hair follicle pigmentation ex vivo.

    Science.gov (United States)

    Sextius, P; Betts, R; Benkhalifa, I; Commo, S; Eilstein, J; Massironi, M; Wang, P; Michelet, J-F; Qiu, J; Tan, X; Jeulin, S

    2017-08-01

    To examine the ability of an extract from traditional Chinese medicine, Polygonum multiflorum Radix, to protect melanocyte viability from oxidative stress, a key mechanism in the initiation and progression of hair greying. To assess the antioxidant capacity of Polygonum multiflorum Radix extract, primary human foreskin melanocytes were treated with a commercially available Polygonum multiflorum Radix extract added to culture medium and exposed to hydrogen peroxide (H 2 O 2 ), using intracellular reactive oxygen species concentrations and glutathione/protein ratios as endpoints. To improve solubility for cosmetic uses, a new Polygonum multiflorum Radix extract was derived. As hair greying is the consequence of melanocyte disappearance in an oxidative stress environment, we checked whether the antioxidant capacity of the new Polygonum multiflorum Radix extract could preserve melanocyte viability in response to H 2 O 2 -induced oxidative stress, and preserve pigmentation within ex vivo human hair follicles. In vitro treatment of primary human foreskin melanocytes with traditional available Polygonum multiflorum Radix extract resulted in decreased intracellular ROS accumulation in response to H 2 O 2 exposure with a concomitant preservation of glutathione-to-protein ratio, consistent with a protective response against H 2 O 2 exposure and demonstrating the promise of this extract for protecting melanocytes against oxidative stress. Melanocytes treated with the improved Polygonum multiflorum Radix extract exhibited attenuated H 2 O 2 -induced cell death, demonstrating a clear cytoprotective effect. Treatment of ex vivo human hair follicles with the improved Polygonum multiflorum Radix extract resulted in a higher level of melanin compared to vehicle-treated controls, demonstrating an ex vivo protective effect on hair pigmentation. Polygonum multiflorum Radix extract protects in vitro primary human foreskin melanocytes from the deleterious effects of H 2 O 2

  8. New procedure for epidermal cell isolation using kiwi fruit actinidin, and improved culture of melanocytes in the presence of leukaemia inhibitory factor and forskolin.

    Science.gov (United States)

    Yarani, Reza; Mansouri, Kamran; Mohammadi-Motlagh, Hamid Reza; Bakhtiari, Mitra; Mostafaie, Ali

    2013-06-01

    Conventional isolation of epidermis from the dermis and disruption of epidermal sheets to liberate the cells, are performed using proteolytic enzymes such as thermolysin or collagenase. Selective population expansion of melanocytes is achieved by suppressing proliferation of keratinocytes and fibroblasts in epidermal cell suspensions, using phorbol esters and cholera toxin. Here, we introduce a new procedure for isolation of epidermal cells, using proteolytic activity of kiwi fruit actinidin, and also an improved growth medium for melanocytes in the presence of leukaemia inhibitory factor (LIF) and forskolin. Dermo-epidermal separation and epidermal sheet cell dispersion were performed using actinidin compared to conventional proteases including collagenase, thermolysin or trypsin. Thereafter, melanocyte culture was performed in two common media and one modified medium to discover optimization for these cells. We found that dermo-epidermal separation and epidermal sheet cell dispersion using kiwi fruit actinidin were considerably better than previously used methods, both from the aspect of less fibroblast and keratinocyte contamination, and of more viable native cells. Also, melanocytes proliferated better in phorbol ester- and cholera toxin-free proliferation medium supplemented with LIF and forskolin. Less contamination and higher numbers of viable cells were actinidin preferential for separation of epidermis and isolation of epidermal cells. Supplementation of LIF and forskolin to new medium increased proliferation potential of melanocytes in comparison to exogenous mitogens. © 2013 Blackwell Publishing Ltd.

  9. Acral melanocytic lesions in the United States: Prevalence, awareness, and dermoscopic patterns in skin-of-color and non-Hispanic white patients.

    Science.gov (United States)

    Madankumar, Reshmi; Gumaste, Priyanka V; Martires, Kathryn; Schaffer, Panta R; Choudhary, Sonal; Falto-Aizpurua, Leyre; Arora, Harleen; Kallis, Penelope J; Patel, Shailee; Damanpour, Shadi; Sanchez, Margaret I; Yin, Natalie; Chan, Aegean; Sanchez, Miguel; Polsky, David; Kanavy, Holly; Grichnik, James M; Stein, Jennifer A

    2016-04-01

    Acral lentiginous melanoma has increased mortality compared with other melanoma subtypes and disproportionately affects ethnic minorities. Acral melanocytic lesions have not been well studied in diverse populations of the United States. We sought to assess the prevalence, awareness, and dermoscopic patterns of acral melanocytic lesions in skin-of-color and non-Hispanic white patients. We prospectively examined the palms and soles of 1052 patients presenting to dermatology clinics in New York, NY, and Miami, FL, from October 2013 to April 2015. Acral melanocytic lesions were observed in 36% of our cohort. Skin-of-color patients were more likely to have acral melanocytic lesions than non-Hispanic white patients (P white patients. The majority of lesions demonstrated benign dermoscopic patterns. We observed 2 lesions with the parallel ridge pattern in our cohort, both found to be atypical nevi on biopsy specimen. Patients often lacked awareness of the presence of their lesions. Interobserver variability in assessing dermoscopic patterns is a limitation. Melanocytic lesions of the palms and soles are common, particularly in a cohort of multiple ethnicities from the United States. Dermoscopy of acral lesions is an important clinical tool for diagnosis and management of these lesions. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  10. Introduction to neural networks

    CERN Document Server

    James, Frederick E

    1994-02-02

    1. Introduction and overview of Artificial Neural Networks. 2,3. The Feed-forward Network as an inverse Problem, and results on the computational complexity of network training. 4.Physics applications of neural networks.

  11. Morphological neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Ritter, G.X.; Sussner, P. [Univ. of Florida, Gainesville, FL (United States)

    1996-12-31

    The theory of artificial neural networks has been successfully applied to a wide variety of pattern recognition problems. In this theory, the first step in computing the next state of a neuron or in performing the next layer neural network computation involves the linear operation of multiplying neural values by their synaptic strengths and adding the results. Thresholding usually follows the linear operation in order to provide for nonlinearity of the network. In this paper we introduce a novel class of neural networks, called morphological neural networks, in which the operations of multiplication and addition are replaced by addition and maximum (or minimum), respectively. By taking the maximum (or minimum) of sums instead of the sum of products, morphological network computation is nonlinear before thresholding. As a consequence, the properties of morphological neural networks are drastically different than those of traditional neural network models. In this paper we consider some of these differences and provide some particular examples of morphological neural network.

  12. Attenuated hypothalamic responses to α-melanocyte stimulating hormone during pregnancy in the rat.

    Science.gov (United States)

    Ladyman, S R; Augustine, R A; Scherf, E; Phillipps, H R; Brown, C H; Grattan, D R

    2016-02-15

    Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) are suppressed. This study investigated hypothalamic responses to α-MSH during pregnancy, using c-fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative α-MSH-responsive neuronal population that shows a well-characterised α-MSH-induced inhibition of firing. While icv injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic α-MSH-induced inhibition of firing that was observed in non-pregnant animals. Given the known functions of α-MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy. During pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic α-MSH target neurons, non-pregnant and pregnant rats were treated with α-MSH or vehicle and c-fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known α-MSH responsive neuronal population, was examined in non-pregnant and pregnant rats following α-MSH treatment. Intracerebroventricular injection of α-MSH significantly

  13. Laser Erbium: YAG no tratamento de nevos melanocíticos Erbium: YAG laser in treatment of acquired melanocytic nevi

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    Mauricio Martins

    2008-12-01

    Full Text Available FUNDAMENTOS - Os nevos melanocíticos adquiridos são observados em grande parte da população e o resultado da sua excisão, dependendo da localização, extensão e fatores inerentes ao paciente, pode ser insatisfatório. OBJETIVO - Avaliar o uso do laser Erbium: YAG no tratamento de nevos melanocíticos adquiridos MÉTODOS - Foram selecionados nove pacientes, seis homens e três mulheres, brancos, com idade entre 20 e 60 anos e desejo de remover um nevo melanocítico composto no tronco. Metade do nevo foi tratada com laser, e a outra metade foi utilizada como controle. Após um mês da aplicação, foram avaliados a cicatrização, o resultado estético e a persistência de células névicas e melanina. RESULTADOS - Houve rápida cicatrização e ótimo resultado estético, no entanto, o exame histopatológico demonstrou a permanência de células névicas e melanina em sete e em nove das amostras examinadas, respectivamente. CONCLUSÃO - A utilização do laser Erbium:YAG, com os parâmetros utilizados neste estudo, não foi capaz de destruir completamente as células névicas melanocíticas e a melanina, não sendo, portanto, recomendada para o tratamento dessas lesões, dada a possibilidade de transformação maligna futura.BACKGROUND- Acquired melanocytic nevi are commonly found and the result of their excision may not be satisfactory depending on their location, extension and factors associated to the patient. OBJECTIVE - To evaluate the use of Erbium:YAG laser in treatment of acquired melanocytic nevi. METHOD - Nine white-skinned patients were selected, six men and three women with aged 20-60 years. All desired to remove one compound acquired melanocytic nevus on the trunk. Half of the nevi was treated with Erbium YAG laser while the remaining were used as control. One month after application, healing, aesthetic results and persistence of melanocytic cells and melanin were evaluated. RESULTS - All patients presented fast healing and

  14. Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents.

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    Roaten, J Brent; Partrick, David A; Pearlman, Nate; Gonzalez, Ricardo J; Gonzalez, Rene; McCarter, Martin D

    2005-01-01

    Melanoma is rare, accounting for only 1% of all pediatric malignancies. The management of pediatric melanoma is controversial but largely parallels that of an adult occurrence. Sentinel lymph node biopsy (SLNBX) has become a standard of care for adults with melanoma, but the role of this procedure in the staging of pediatric patients remains to be established. The goal of this study was to determine outcomes and complications of children and adolescent patients undergoing SLNBX at the authors' institution. A retrospective review of patients younger than 21 years (N = 20) undergoing SLNBX for melanoma or other melanocytic skin lesions at the University of Colorado Health Science Center between 1996 and 2003 was conducted. Sentinel lymph node biopsy was successful in all 20 patients, and 8 patients (40%) were found to have metastases within the sentinel node. As in adults, the sentinel node status correlates with primary tumor depth. No complications occurred in patients undergoing SLNBX, but 4 clinically significant complications (57%) occurred in the 7 patients undergoing a completion lymph node dissection. At 33 months median follow-up, all patients were disease free. Sentinel lymph node biopsy can be successfully and safely performed in pediatric patients for melanoma and atypical nevi. However, the prognostic information and therapeutic implications of SLNBX results for children and adolescents remain unclear. Completion lymph node dissection for microscopic disease is a morbid procedure with uncertain benefit to pediatric or adult patients with a positive SLNBX result. Long-term follow-up data are needed before SLNBX can become a standard of care in pediatric melanoma or as a diagnostic tool to distinguish the atypical Spitz nevus from melanoma.

  15. Variables predicting change in benign melanocytic nevi undergoing short-term dermoscopic imaging.

    Science.gov (United States)

    Menzies, Scott W; Stevenson, Mary L; Altamura, Davide; Byth, Karen

    2011-06-01

    To determine whether certain patient demographics are associated with poorer specificity for the diagnosis of melanoma in nevi undergoing short-term sequential digital dermoscopic imaging. Retrospective cohort study performed from April 1, 1998, through May 31, 2007. Sydney Melanoma Diagnostic Centre, a tertiary referral institution. A total of 2497 benign melanocytic lesions in 1765 patients undergoing short-term sequential digital dermoscopic imaging during 2.5 to 4.5 months (42.3% male; mean [SD] age, 40 [14] years; age range, 1-86 years). Proportion of changed nevi as a function of age, sex, lesion diameter, and anatomical site. The only variable significantly associated with nevus change was age group (P = .002). When compared with the middle-aged (aged 36-50 years) group, the odds of change were significantly increased in the child and adolescent (aged 0-18 years: odds ratio, 2.60; 95% confidence interval, 1.30-5.22), young adult (aged 19-35 years: 1.50; 1.04-2.17), and elderly (> 65 years old: 2.04; 1.04-3.99) age groups. Within the changed benign lesions, a significant association was observed between histologic subtype and age group (P = .01). The proportion of changed lesions of the banal nevi type decreased and the proportion of the dysplastic nevi type increased with age. In the elderly group, 75.9% of changed lesions were of the dysplastic nevi type compared with 35.7% in the youngest group. A poorer specificity is observed for the diagnosis of melanoma for nevi undergoing short-term sequential digital dermoscopic imaging in children and adolescents (75.7%) and elderly patients (77.9%) compared with other patients (84.6%).

  16. Melanocytic Nevi Prevalence and the Relationship with Sun Exposure Among School Children

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    Neslihan Şendur

    2009-12-01

    Full Text Available Background and Design: Melanocytic nevi (MN count is known as the strongest risk factor for melanoma development. So it is important to know the MN count in public. We aimed to determine the MN prevalence in schoolchildren and also clarify the possible relation between MN counts, constitutional variables and sun exposure. Material and Method: In this randomized, cross-sectional study, a questionnaire asking skin phenotypes and sun exposure in previous summer was prepared for primary-school children. Nine hundred and sixty questionnaires distributed to the parents. Children who were given permission by parents for examination were examined for whole body MN. Results: Questionnaires were answered by parents of 939 children and 622 children (316 boys and 306 girls were examined. Mean age of children was 8.8±1.5 (6-12. Mean MN count was 19.6±16.6 and this count was increasing with age (p<0.001. MN count was significantly related with sex, skin phototype and skin colour. More MN were found in boys (p<0.001, children with sun sensitive phototypes (p=0.03 and light skin colour (p<0.001. Time spent outside on midday in previous summer was not related with the MN count (p=0.35. Sunburns experienced in previous summer were not related with MN count (p=0.11. MN were most densely located on the face, and then on upper extremity, trunk and lower extremity in decreasing order. There were more MN on the more sun exposed sites of the arms, hands and feet. Conclusion: It was found that previous summer sun exposure had no effect on MN count in schoolchildren. However, relation between MN count and skin phenotype and distribution of the MN on the body suggest that sun exposure could affect MN count and this effect could be seen in a long period of time.

  17. Clinical and histological characteristics of melanocytic nevus in external auditory canals and auricles.

    Science.gov (United States)

    Lim, Hye Jin; Kim, Yun Tae; Choo, Oak-Sung; Park, Keehyun; Park, Hun Yi; Choung, Yun-Hoon

    2013-11-01

    Nevi, which consist of nevus cells arising from external auditory canals (EACs) and auricles, are rare and their characteristics are not thoroughly understood. The purpose of this study was to analyze the clinicopathological characteristics of melanocytic nevus (MN) in EACs and auricles. Medical records were reviewed in 35 cases with junctional, compound and intradermal nevi treated in Ajou University Hospital, Korea between 2001 and 2011. Patient demographic, location, shape, and diameter of nevi, and pathologic results were analyzed according to the location, EACs (23 cases) and auricles (12 cases). Female predominance was noted in both EAC (60.9 %, 14 cases) and auricular (75 %, 9 cases) nevi. The mean age of EAC nevi (37.1 years) was younger than that of auricular nevi (42.2 years). The chief complaint was a symptomless mass in both groups, mostly in dome-like gross appearances. The mean diameter of EAC and auricular nevi was 9.6 (3-16) mm and 12.2 (3-25) mm, respectively. Histological findings chiefly presented intradermal nevi in EACs (78.3 %) and auricles (83.3 %) which showed preference to older patients, in contrast to the compound type. All nevi including five cases with skin grafts were completely excised without any recurrence within the follow-up period (average 5.3 months). A possible dysplastic nevus was detected in only one case. All MNs in EACs or auricles reveal similar characteristics. Early and complete excision is recommended to avoid skin graft, functional problems, and the risk of malignant melanoma.

  18. Non-Melanocytic Skin Cancers of the Head and Neck: A Clinical Study in Jeju Province

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    Jae Kyoung Kang

    2017-07-01

    Full Text Available Background Jeju Island is geographically and socioeconomically distinct from the mainland of South Korea. Thus, the presentation and management of non-melanocytic skin cancers (NMSC of the head and neck may differ from those in other regions of the country. We compared the clinical characteristics and treatment modalities of NMSC on Jeju Island with the findings of similar regional studies. Methods Patient data, including age, sex, diagnosis, tumor site, treatment, and recurrence, were obtained from the medical and pathology records of patients diagnosed with NMSC between January 2010 and June 2015. Results In total, 190 patients (57 men with a mean age of 75 years (range, 42–97 were assessed. Overall, 203 NMSCs were diagnosed, including 123 basal cell carcinomas and 80 squamous cell carcinomas. The tumor sites included the nose, cheeks, periorbital area, and lips (n=55, 54, 25, and 20, respectively. We identified 92 T1-stage and 60 T2-stage tumors, and 120 cases were treated with wide surgical resection and 17 cases were treated with radiation therapy at the medical center. Of the 120 cases treated surgically, 69 required reconstructive surgery using a local skin flap, 22 required full-thickness skin grafting, and 12 underwent primary closure. Basal and squamous cell carcinomas recurred in 2 and 1 cases, respectively. Conclusions Compared to the reports from other regions, the average patient age was 10 years higher, with a marked female preponderance. While the proportion of squamous cell carcinoma was higher than in other regions, the tumor distribution and surgical management profiles were similar.

  19. JARID1B expression in human melanoma and benign melanocytic skin lesions.

    Science.gov (United States)

    Kuźbicki, Lukasz; Lange, Dariusz; Strączyńska-Niemiec, Anita; Chwirot, Barbara W

    2013-02-01

    It has been suggested that dynamically regulated expression of the JARID1B protein is required for the continuous growth of tumors and at the same time downregulated in melanoma. The majority of the data on a role of JARID1B in maintaining tumor growth has come from in-vitro and xenografting experiments, with only one immunohistochemical study involving human tissues. We compared JARID1B expression levels in human melanomas and benign nevi and analyzed patterns of spatial distributions of positive cells among different skin layers of the lesions. The expression of JARID1B was evaluated by immunohistochemistry in formalin-fixed paraffin-embedded samples of 30 nevi, 27 primary melanomas, four lymph node metastases, and one local recurrence of melanoma. Staining for JARID1B protein was stronger in melanomas compared with nevi. We also found a significant difference in the spatial distribution of positive cells in individual skin layers of nevi and melanomas. Staining of melanocytes located in granular and spinous layers of nevi was observed very rarely, whereas for melanomas, the mean percentage fractions of positive cells present in these layers exceeded the maximum values found for nevi. The spatial patterns and expression levels of JARID1B did not change significantly with melanoma progression and were similar for primary, metastatic, and recurrent melanomas. Contrary to earlier reports, this study shows enhanced expression of JARID1B by melanoma cells and indicates that such an enhancement may be an early event in the disease progression, is not correlated with melanoma invasiveness, and therefore may not be a suitable candidate as a prognostic marker.

  20. Blood supply--susceptible formation of melanin pigment in hair bulb melanocytes of mice.

    Science.gov (United States)

    Maeda, Shogo; Ueda, Koichi; Yamana, Hidenori; Tashiro-Yamaji, Junko; Ibata, Minenori; Mikura, Ayako; Okada, Masashi; Yasuda, Emi; Shibayama, Yuro; Yoshino, Miya; Kubota, Takahiro; Yoshida, Ryotaro

    2015-03-01

    Allogeneic skin grafts onto C57BL/6 mice are rejected, and the rejected skin is replaced by surrounding skin with black hair. In contrast, syngeneic skin grafts are tolerated, and gray hair grows on the grafts. To explore the mechanism of gray hair growing on the tolerated skin grafts, we prepared full-thickness skin (2-cm square) autografts, 2 (2 cm + 2 cm) horizontal or vertical parallel incisions, and U-shaped (2 cm × 2 cm × 2 cm) flaps with or without pedicle vessels. The grafts, incisions, and flaps were fixed by suturing with string and protected by a transparent bandage. On day 14 after the operation, the bandages were removed to observe the color of the hair growing on the skin. Skin autografts from wild-type or hepatocyte growth factor-transgenic (Tg) C57BL/6 mice survived with gray hair, whereas those from steel factor (Kitl)-Tg C57BL/6 mice survived with black hair. In addition, U-shaped flaps lacking both of the 2 main feeding vessels of wild-type mice had gray hair at the tip of the flaps. Light microscopy after staining with hematoxylin and eosin or dihydroxyphenylalanine showed that the formation of melanin pigment in the follicles, but not in the interadnexal skin, was susceptible to the blood supply. Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

  1. HGF/SF increases number of skin melanocytes but does not alter quality or quantity of follicular melanogenesis.

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    Agnieszka Wolnicka-Glubisz

    Full Text Available Melanins are an important factor determining the vulnerability of mammalian skin to UV radiation and thus to UV-induced skin cancers. Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF have extra-follicular dermal melanocytes, notably in the papillary upper dermis, and are susceptible to UV-induced melanoma. Pigmented HGF/SF neonatal mice are more susceptible than albino HGF/SF animals to UVA -induced melanoma, indicating an involvement of melanin in melanoma formation. This raises the question of the effect of transgenic HGF/SF on melanization. We developed a methodology to accurately quantitate both the production of melanin and the efficiency of melanogenesis in normal, and HGF/SF transgenic mice in vivo. Skin and hair shafts of 5 day old and adult (3 week old C57BL/6-HGF/SF and corresponding C57BL/6 wild type mice were investigated by electron paramagnetic resonance spectroscopy (EPR to quantitate melanin, by transmission electron microscopy (TEM for the presence of melanosomes, and by standard histology and by Western blotting and zymography to determine the expression and activity of melanogenesis-related proteins. Eumelanin but no phaeomelanin was detected in transgenic C57BL/6-HGF and C57BL/6 wild type mice. Transgenic HGF/SF overexpression did not change the type of melanin produced in the skin or hair, did not affect the terminal content of melanin production in standard samples of hair and did not influence hair cycle/morphogenesis-related changes in skin thickness. No melanocytes were found in the epidermis and no melanosomes were found in epidermal keratinocytes. HGF/SF transgenic mice thus lack the epidermal melanin UV-protection found in constitutively dark human skin. We conclude that melanocytes in the HGF/SF transgenic mouse, particularly in the papillary dermis, are vulnerable to UVA which interacts with eumelanin but not phaeomelanin to induce melanoma.

  2. HGF/SF increases number of skin melanocytes but does not alter quality or quantity of follicular melanogenesis.

    Science.gov (United States)

    Wolnicka-Glubisz, Agnieszka; Pecio, Anna; Podkowa, Dagmara; Plonka, Przemyslaw Mieszko; Grabacka, Maja

    2013-01-01

    Melanins are an important factor determining the vulnerability of mammalian skin to UV radiation and thus to UV-induced skin cancers. Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF) have extra-follicular dermal melanocytes, notably in the papillary upper dermis, and are susceptible to UV-induced melanoma. Pigmented HGF/SF neonatal mice are more susceptible than albino HGF/SF animals to UVA -induced melanoma, indicating an involvement of melanin in melanoma formation. This raises the question of the effect of transgenic HGF/SF on melanization. We developed a methodology to accurately quantitate both the production of melanin and the efficiency of melanogenesis in normal, and HGF/SF transgenic mice in vivo. Skin and hair shafts of 5 day old and adult (3 week old) C57BL/6-HGF/SF and corresponding C57BL/6 wild type mice were investigated by electron paramagnetic resonance spectroscopy (EPR) to quantitate melanin, by transmission electron microscopy (TEM) for the presence of melanosomes, and by standard histology and by Western blotting and zymography to determine the expression and activity of melanogenesis-related proteins. Eumelanin but no phaeomelanin was detected in transgenic C57BL/6-HGF and C57BL/6 wild type mice. Transgenic HGF/SF overexpression did not change the type of melanin produced in the skin or hair, did not affect the terminal content of melanin production in standard samples of hair and did not influence hair cycle/morphogenesis-related changes in skin thickness. No melanocytes were found in the epidermis and no melanosomes were found in epidermal keratinocytes. HGF/SF transgenic mice thus lack the epidermal melanin UV-protection found in constitutively dark human skin. We conclude that melanocytes in the HGF/SF transgenic mouse, particularly in the papillary dermis, are vulnerable to UVA which interacts with eumelanin but not phaeomelanin to induce melanoma.

  3. Differentiated squamous intraepithelial lesion (dSIL)-like changes in the epidermis overlying anogenital melanocytic nevi: A diagnostic pitfall.

    Science.gov (United States)

    Michalova, Kvetoslava; Kazakov, Dmitry V; Michal, Michael; Hadravsky, Ladislav; Kacerovska, Denisa; Rychly, Boris; Miesbauerova, Marketa; Michal, Michal

    2017-02-01

    Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemically analogous in the whole anogenital region. dSIL is a premalignant lesion frequently misinterpreted histopathologically as a benign dermatosis. The authors describe a peculiar change in the basal cell layer of the epidermis/epithelium overlying anogenital melanocytic nevi that may histopathologically imitate dSIL. The aim of this study is to familiarize the pathologists with this pitfall to avoid its possible overdiagnosis as dysplasia. Further, we tried to explore the biological characteristics of the dSIL-like changes and to focus on the differential diagnostic aspects. Seventy cases of anogenital nevi were retrieved from our registry. All cases were stained with hematoxylin and eosin (H&E) and reviewed. Cases in which the epidermis overlying nevi featured atypical appearing basal keratinocytes in otherwise fully differentiated epithelium, variable degrees of acanthosis and parakeratosis were selected for additional investigation. Thirty cases meeting the above described criteria were identified. The patients were 8 males and 22 females, with age at the time of diagnosis ranging from 4 to 68years. Follow-up data were available for 28 patients (range 0.5-19years, mean 5.1), and to date, no signs of epithelial malignancy have been recorded. Immunohistochemically (IHC), the epidermis overlying nevi showed insignificant positivity for p53 in all tested cases. Melanocytic markers (S-100 protein, SOX10, Melan A) and cytokeratin AE1/3 labeled melanocytes and keratinocytes, respectively, enabling their distinction, especially in nevi featuring a junctional component. Differentiated squamous intraepithelial lesion-like changes seem to occur relatively often in the epidermis overlying anogenital melanocytic nevi. Since morphologically they are virtually identical to the "true" dSIL, their distinction largely depends on p53 expression in basal keratinocytes with normal p53

  4. Transcription analysis in the MeLiM swine model identifies RACK1 as a potential marker of malignancy for human melanocytic proliferation

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    Vincent-Naulleau Silvia

    2008-04-01

    Full Text Available Abstract Background Metastatic melanoma is a severe disease. Few experimental animal models of metastatic melanoma exist. MeLiM minipigs exhibit spontaneous melanoma. Cutaneous and metastatic lesions are histologically similar to human's. However, most of them eventually spontaneously regress. Our purpose was to investigate whether the MeLiM model could reveal markers of malignancy in human melanocytic proliferations. Results We compared the serial analysis of gene expression (SAGE between normal pig skin melanocytes and melanoma cells from an early pulmonary metastasis of MeLiM minipigs. Tag identification revealed 55 regulated genes, including GNB2L1 which was found upregulated in the melanoma library. In situ hybridisation confirmed GNB2L1 overexpression in MeLiM melanocytic lesions. GNB2L1 encodes the adaptor protein RACK1, recently shown to influence melanoma cell lines tumorigenicity. We studied the expression of RACK1 by immunofluorescence and confocal microscopy in tissues specimens of normal skin, in cutaneous and metastatic melanoma developped in MeLiM minipigs and in human patients. In pig and human samples, the results were similar. RACK1 protein was not detected in normal epidermal melanocytes. By contrast, RACK1 signal was highly increased in the cytoplasm of all melanocytic cells of superficial spreading melanoma, recurrent dermal lesions and metastatic melanoma. RACK1 partially colocalised with activated PKCαβ. In pig metastases, additional nuclear RACK1 did not associate to BDNF expression. In human nevi, the RACK1 signal was low. Conclusion RACK1 overexpression detected in situ in human melanoma specimens characterized cutaneous and metastatic melanoma raising the possibility that RACK1 can be a potential marker of malignancy in human melanoma. The MeLiM strain provides a relevant model for exploring mechanisms of melanocytic malignant transformation in humans. This study may contribute to a better understanding of melanoma

  5. Melanoblast development coincides with the late emerging cells from the dorsal neural tube in turtle Trachemys scripta.

    Science.gov (United States)

    Rice, Ritva; Cebra-Thomas, Judith; Haugas, Maarja; Partanen, Juha; Rice, David P C; Gilbert, Scott F

    2017-09-21

    Ectothermal reptiles have internal pigmentation, which is not seen in endothermal birds and mammals. Here we show that the development of the dorsal neural tube-derived melanoblasts in turtle Trachemys scripta is regulated by similar mechanisms as in other amniotes, but significantly later in development, during the second phase of turtle trunk neural crest emigration. The development of melanoblasts coincided with a morphological change in the dorsal neural tube between stages mature G15 and G16. The melanoblasts delaminated and gathered in the carapacial staging area above the neural tube at G16, and differentiated into pigment-forming melanocytes during in vitro culture. The Mitf-positive melanoblasts were not restricted to the dorsolateral pathway as in birds and mammals but were also present medially through the somites similarly to ectothermal anamniotes. This matched a lack of environmental barrier dorsal and lateral to neural tube and the somites that is normally formed by PNA-binding proteins that block entry to medial pathways. PNA-binding proteins may also participate in the patterning of the carapacial pigmentation as both the migratory neural crest cells and pigment localized only to PNA-free areas.

  6. A comparative immunohistochemical study of MART-1 expression in Spitz nevi, ordinary melanocytic nevi, and malignant melanomas.

    Science.gov (United States)

    Bergman, R; Azzam, H; Sprecher, E; Manov, L; Munichor, M; Friedman-Birnbaum, R; Ben-Itzhak, O

    2000-03-01

    The histopathologic differential diagnosis of Spitz nevus (SN) from malignant melanoma (MM) may be difficult. We attempted to elucidate the pattern of expression of a newly recognized melanocyte-specific melanosomal protein MART-1 in routinely processed specimens of SNs, MMs, and ordinary melanocytic nevi (MNs) and to see whether it can help to differentiate between them. Twenty SN, 22 MM, and 27 ordinary MN were immunostained with anti-MART-1 monoclonal antibody (clone A103). All SNs, MNs, and MMs demonstrated cytoplasmic staining for MART-1 in some of their tumor cells, of which 17 of 20 (85%) and 24 of 27 (89%) of SN and MN, respectively, demonstrated positive stainings in more than half of their tumor cells, as compared with only 10 of 22 (45%) of the MM (P <.05). The majority of lesions in all 3 types of tumors showed a homogeneous mode of staining, although MM tended to show a more heterogeneous pattern. A consistent pattern of stratification of staining with progressive descent into the dermis was not demonstrated in these tumors. MART-1 does not differentiate between SN, MM, and ordinary MN in a consistent pattern, but it may be used as a marker for these tumors.

  7. New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes

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    Rong-Dih Lin

    2015-12-01

    Full Text Available Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9 and 3,4-dihydroxy-5-methoxybiphenyl-2ʹ-O-β-d-glucopyranoside (13, as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver–Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics.

  8. Can early malignant melanoma be differentiated from atypical melanocytic nevus by in vivo techniques?: Part II. Automatic machine vision classification.

    Science.gov (United States)

    Gutkowicz-Krusin, D; Elbaum, M; Szwaykowski, P; Kopf, A W

    1997-02-01

    Differentiation between early (Breslow thickness less than 1 mm) malignant melanoma (MM) and atypical melanocytic nevus (AMN) remains a challenge even to trained clinicians. The purpose of this study is to determine the feasibility of reliable discrimination between early MM and AMN with noninvasive, objective, automatic machine vision techniques. A data base of 104 digitized dermoscopic color transparencies of melanocytic lesions was used to develop and test our computer-based algorithms for classification of such lesions as malignant (MM) or benign (AMN). Histopathologic diagnoses (30 MM and 74 AMN) were used as the "gold standard" for training and testing the algorithms. A fully automatic, objective technique for differentiating between early MM and AMN from their dermoscopic digital images was developed. The multiparameter linear classifier was trained to provide 100% sensitivity for MM. In the blind test, this technique did not miss a single MM and its specificity was comparable to that of skilled dermatologists. Reliable differentiation between early MM and AMN with high sensitivity is possible using machine vision techniques to analyze digitized dermoscopic lesion images.

  9. A Micro-RNA Connection in BRafV600E-Mediated Premature Senescence of Human Melanocytes

    Directory of Open Access Journals (Sweden)

    Gang Ren

    2012-01-01

    Full Text Available Recent high-throughput-sequencing of the cancer genome has identified oncogenic mutations in BRaf genetic locus as one of the critical events in melanomagenesis. In normal cells, the activity of BRaf is tightly regulated. Gain-of-function mutations like those identified in melanoma frequently lead to enhanced cell-survival and unrestrained growth. The activating mutation of BRaf will also induce the cells to senesce. However, the mechanism by which the oncogenic BRaf induces the senescent barrier remains poorly defined. microRNAs have regulatory functions toward the expression of genes that are important in carcinogenesis. Here we show that expression of several microRNAs is altered when the oncogenic version of BRaf is introduced in cultured primary melanocytes and these cells undergo premature cellular senescence. These include eight microRNAs whose expression rates are significantly stimulated and three that are repressed. While most of the induced microRNAs have documented negative effects on cell cycle progression, one of the repressed microRNAs has proven oncogenic functions. Ectopic expression of some of these induced microRNAs increased the expression of senescence markers and induced growth arrest and senescence in primary melanocytes. Taken together, our results suggest that the change in microRNA expression rates may play a vital role in senescence induced by the oncogenic BRaf.

  10. Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: A pilot study.

    Science.gov (United States)

    Cabaret, Odile; Perron, Emilie; Bressac-de Paillerets, Brigitte; Soufir, Nadem; de la Fouchardière, Arnaud

    2017-09-01

    Melanocytic BAP1-associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer-predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1-related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild-type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood-tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing. © 2017 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    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.

  12. [Body distribution and density of acquired melanocytic nevi in adolescents of low socioeconomic status of Santiago, Chile].

    Science.gov (United States)

    Zemelman D, Viviana; Molina C, Paula; Valenzuela, Carlos Y; Honeyman M, Juan

    2008-06-01

    There is an increase in the incidence of malignant melanoma in Chile. Previous studies have shown that the density and size of acquired melanocytic nevi (AMN) are a risk factor for developing malignant melanoma. To assess the number and anatomical distribution of acquired melanocytic nevi in Chilean adolescents. The number of AMN was counted in 30 anatomical sites in 201 Chilean school children (111 females), aged from 11 to 15 years. The number of small AMN (2-4.9 mm) and large AMN (>5 mm of diameter) was determined. Mean AMN number per person was 32.7 (95% confidence interval (CI) 30.7-42.3) in males and 29 (95% CI 271-38.6) in females (p =NS). Males had a higher number of AMN in the face, neck and trunk. Females had a higher number of AMN in the upper and lower limbs. Older children, adolescents with history of sunburns and with lighter skin had a higher number of total, small and large nevi. The average number of AMN found in this study is similar to that reported in the literature. The differences in site distribution between males and females may be explained by a different sun exposure pattern.

  13. ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment.

    Science.gov (United States)

    Pérez-Alea, M; McGrail, K; Sánchez-Redondo, S; Ferrer, B; Fournet, G; Cortés, J; Muñoz, E; Hernandez-Losa, J; Tenbaum, S; Martin, G; Costello, R; Ceylan, I; Garcia-Patos, V; Recio, J A

    2017-10-12

    Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

  14. How concerns and experiences with medical malpractice affect dermatopathologists' perceptions of their diagnostic practices when interpreting cutaneous melanocytic lesions.

    Science.gov (United States)

    Carney, Patricia A; Frederick, Paul D; Reisch, Lisa M; Knezevich, Stevan; Piepkorn, Michael W; Barnhill, Raymond L; Elder, David E; Geller, Berta M; Titus, Linda; Weinstock, Martin A; Nelson, Heidi D; Elmore, Joann G

    2016-02-01

    We sought to identify characteristics associated with past malpractice lawsuits and how malpractice concerns may affect interpretive practices. We surveyed 207 of 301 (68.8%) eligible dermatopathologists who interpret melanocytic skin lesions in 10 states. The survey assessed dermatopathologists' demographic and clinical practice characteristics, perceptions of how medical malpractice concerns could influence their interpretive practices, and past malpractice lawsuits. Of dermatopathologists, 33% reported past malpractice experiences. Factors associated with being sued included older age (57 vs 48 years, P 20 years: 52.9% vs 20.1%, P practices were associated with past malpractice. Most dermatopathologists reported concerns about potential harms to patients that may result from their assessments of melanocytic lesions. Limitations of this study include lack of validation of and details about the malpractice suits experienced by participating dermatopathologists. In addition, the study assessed perceptions of practice rather than actual practices that might be associated with malpractice incidents. Most dermatopathologists reported apprehension about how malpractice affects their clinical practice and are concerned about patient safety irrespective of whether they had actually experienced a medical malpractice suit. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  15. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    Energy Technology Data Exchange (ETDEWEB)

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  16. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients

    Directory of Open Access Journals (Sweden)

    Shishioh-Ikejima Nobue

    2010-08-01

    Full Text Available Abstract Background Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (α-MSH have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased α-MSH plasma levels may also occur in CFS patients. We therefore examined α-MSH levels in CFS patients. Methods Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of α-MSH, adrenocorticotropic hormone (ACTH, serum cortisol and dehydroepiandrosterone sulfate (DHEA-S. Mean levels of α-MSH were compared between the CFS and control groups using Welch's t test. Results The mean plasma α-MSH concentration in the CFS group (17.9 ± 1.0 pg/mL was significantly higher than that in healthy controls (14.5 ± 1.0 pg/mL, p = 0.02. However, there was a wide range of values in the CFS group. The factors correlated with the plasma α-MSH values were analyzed using Spearman's rank correlation. A negative correlation was found between the duration of the CFS and the plasma α-MSH values (p = 0.04, rs = -0.28, but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively. The CFS patients were divided into two groups: patients diagnosed for ≤ 5 years' duration, and those diagnosed for 5-10 years' duration. They were compared with the healthy controls using one-way ANOVA and Tukey-Kramer multiple comparison tests. The mean α-MSH concentration in the ≤ 5 years group was 20.8 ± 1.2 pg/mL, which was significantly higher than that in the healthy controls (p Conclusions CFS patients with

  17. Light-emitting diode 585nm photomodulation inhibiting melanin synthesis and inducing autophagy in human melanocytes.

    Science.gov (United States)

    Chen, Li; Xu, Zhongyi; Jiang, Min; Zhang, Chengfeng; Wang, Xuan; Xiang, Leihong

    2018-01-01

    Melasma is a common hyperpigmentation skin disease on face. Light-emitting diode (LED) photomodulation (585nm) is reported to be effective for the treatment of melasma. However, whether and how LED photomodulation would influence melanogenesis of human epidermal melanocytes (HEMs) is unknown. To evaluate the effects of LED photomodulation (585nm) on melanogenesis in HEMs. HEMs were irradiated with fluences of 0, 5, 10 and 20J/cm 2 585nm LED light. After 5-day treatment, cell viability was analyzed by CCK-8 assay, and apoptosis was assessed by Annexin V APC assay. Melanin content and tyrosinase activity were measured by spectrophotometer. Melanosome stage and autophagosomes were determined under transmission electron microscope (TEM). The formation of autophagic punctate structures was observed under confocal microscope. RT-PCR and western blotting were used to assess the expression of relative mRNA and protein levels. Yellow light LED 585nm had no effects on HEMs cell viability and apoptosis. Treatment with LED 585nm from 5J/cm 2 to 20J/cm 2 inhibited melanosome maturation, decreased melanin content and tyrosinase activity. Inhibition was accompanied by the decreased expression of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and microphthalmia-associated transcription factor (MITF) on both mRNA and protein levels. Autophagosomes were observed under TEM. Autophagic punctate structures of microtubule-associated protein light chain 3 (LC3) proteins were induced by LED 585nm light. The configuration change of LC3 from LC3-I to LC3-II, and the degradation of p62 protein were observed after LED 585nm. Furthermore, we also revealed that the anti-melanogenic effect of LED 585nm photomodulation was reversed by 3-Methyladenine (3-MA), which inhibits autophagy by blocking autophagosome formation via the inhibition of type III Phosphatidylinositol 3-kinases (PI-3K). Our finding demonstrated that LED photomodulation with 585nm wavelength suppressed melanin content in

  18. Melanoma Classification on Dermoscopy Images Using a Neural Network Ensemble Model.

    Science.gov (United States)

    Xie, Fengying; Fan, Haidi; Li, Yang; Jiang, Zhiguo; Meng, Rusong; Bovik, Alan

    2017-03-01

    We develop a novel method for classifying melanocytic tumors as benign or malignant by the analysis of digital dermoscopy images. The algorithm follows three steps: first, lesions are extracted using a self-generating neural network (SGNN); second, features descriptive of tumor color, texture and border are extracted; and third, lesion objects are classified using a classifier based on a neural network ensemble model. In clinical situations, lesions occur that are too large to be entirely contained within the dermoscopy image. To deal with this difficult presentation, new border features are proposed, which are able to effectively characterize border irregularities on both complete lesions and incomplete lesions. In our model, a network ensemble classifier is designed that combines back propagation (BP) neural networks with fuzzy neural networks to achieve improved performance. Experiments are carried out on two diverse dermoscopy databases that include images of both the xanthous and caucasian races. The results show that classification accuracy is greatly enhanced by the use of the new border features and the proposed classifier model.

  19. Evolvable Neural Software System

    Science.gov (United States)

    Curtis, Steven A.

    2009-01-01

    The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

  20. Consciousness and neural plasticity

    DEFF Research Database (Denmark)

    In contemporary consciousness studies the phenomenon of neural plasticity has received little attention despite the fact that neural plasticity is of still increased interest in neuroscience. We will, however, argue that neural plasticity could be of great importance to consciousness studies....... If consciousness is related to neural processes it seems, at least prima facie, that the ability of the neural structures to change should be reflected in a theory of this relationship "Neural plasticity" refers to the fact that the brain can change due to its own activity. The brain is not static but rather...... a dynamic entity, which physical structure changes according to its use and environment. This change may take the form of growth of new neurons, the creation of new networks and structures, and change within network structures, that is, changes in synaptic strengths. Plasticity raises questions about...

  1. Fuzzy and neural control

    Science.gov (United States)

    Berenji, Hamid R.

    1992-01-01

    Fuzzy logic and neural networks provide new methods for designing control systems. Fuzzy logic controllers do not require a complete analytical model of a dynamic system and can provide knowledge-based heuristic controllers for ill-defined and complex systems. Neural networks can be used for learning control. In this chapter, we discuss hybrid methods using fuzzy logic and neural networks which can start with an approximate control knowledge base and refine it through reinforcement learning.

  2. Germline Melanocortin-1-Receptor Genotype Is Associated with Severity of Cutaneous Phenotype in Congenital Melanocytic Nevi: A Role for MC1R in Human Fetal Development

    NARCIS (Netherlands)

    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

    2012-01-01

    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

  3. Nevo melanocítico congénito gigante: presentación de tres casos Giants congenital melanocytic nevus: Report of three cases

    Directory of Open Access Journals (Sweden)

    V Estrella

    Full Text Available Los Nevos Melanocíticos Congénitos (NMC son lesiones pigmentarias, que pueden aparecer en el nacimiento, aunque hay casos comunicados hasta el primer año de vida (Nevo Melanocítico Congénito Tardío. Presentan ciertas características clínicas y evolutivas de gran importancia: el compromiso estético de las formas gigantes, la asociación con melanocitosis meníngea y su transformación maligna de la lesión cutánea o meníngea. Presentamos tres casos de nevos melanocíticos congénitos gigantes. Cabe destacar, que el objetivo de este artículo es realizar una revisión del tema, orientar al seguimiento y control de los mismos y destacar la dificultad para su tratamiento debido a su gran tamaño.The Congenital Melanocytic Nevus are lesions melanocytic pigmented. Already apparent at birth but there are cases reported to the first year of life (Late Congenital Melanocytic Nevus. Certain features and evolution clinics that are important: the great compromise of aesthetic forms giant, meningeal melanocitosis association and its malignant transformation. We present three cases of Giants Congenital Melanocytic Nevus. It should be noted, that the purpose of this article is a review of the issue and guide the monitoring and control of them and point out the difficult treatment.

  4. Stereological estimation of nuclear volume in benign and malignant melanocytic lesions of the skin. Inter- and intraobserver variability of malignancy grading

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Ottosen, P D

    1991-01-01

    tumors, the observer variability of estimates of nuclear vv is studied. Routinely processed, paraffin embedded tissue specimens from 22 malignant melanomas and nine benign melanocytic cutaneous lesions are retrospectively investigated. The sampling scheme for estimation of nuclear vv is easy to use...

  5. CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients.

    Science.gov (United States)

    Bassoli, Sara; Maurichi, Andrea; Rodolfo, Monica; Casari, Alice; Frigerio, Simona; Pupelli, Gaia; Farnetani, Francesca; Pelosi, Giuseppe; Santinami, Mario; Pellacani, Giovanni

    2013-06-01

    Non-invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild-type genes were also compared. In patients with melanoma, a lighter phototype (P = 0.051), a higher number of nevi (P melanoma genetically tested, CDKN2A G101W mutation carriers were more frequently younger (P = 0.023), with clinically atypical nevi (P = 0.050), with cytological atypia (P = 0.033) at confocal. G101W mutation and MC1R variants carriers showed hypopigmented nevi (P = 0.002) and, at confocal, roundish cells infiltrating the junction (P = 0.019). These data suggest an influence of CDKN2A mutation and MC1R variants in the development of dysplastic melanocytic lesions. Non-invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient-tailored management. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Effects of Extremely Low Frequency Electromagnetic Fields on Melanogenesis through p-ERK and p-SAPK/JNK Pathways in Human Melanocytes

    Directory of Open Access Journals (Sweden)

    Yu-Mi Kim

    2017-10-01

    Full Text Available This study evaluated frequency-dependent effects of extremely low frequency electromagnetic fields (ELF-EMFs on melanogenesis by melanocytes in vitro. Melanocytes were exposed to 2 mT EMFs at 30–75 Hz for 3 days before melanogenesis was examined. Exposure to ELF-EMFs at 50 and 60 Hz induced melanogenic maturation without cell damage, without changing cell proliferation and mitochondrial activity. Melanin content and tyrosinase activity of cells exposed to 50 Hz were higher than in controls, and mRNA expression of tyrosinase-related protein-2 was elevated relative to controls at 50 Hz. Phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB levels were higher than controls in cells exposed to ELF-EMFs at 50–75 Hz. Immunohistochemical staining showed that melanocyte-specific markers (HMB45, Melan-A were strongly expressed in cells exposed to EMFs at 50 and 60 Hz compared to controls. Thus, exposure to ELF-EMFs at 50 Hz could stimulate melanogenesis in melanocytes, through activation of p-CREB and p-p38 and inhibition of phosphorylated extracellular signal-regulated protein kinase and phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase. The results may form the basis of an appropriate anti-gray hair treatment or be applied in a therapeutic device for inducing repigmentation in the skin of vitiligo patients.

  7. What Is Neural Plasticity?

    Science.gov (United States)

    von Bernhardi, Rommy; Bernhardi, Laura Eugenín-von; Eugenín, Jaime

    2017-01-01

    "Neural plasticity" refers to the capacity of the nervous system to modify itself, functionally and structurally, in response to experience and injury. As the various chapters in this volume show, plasticity is a key component of neural development and normal functioning of the nervous system, as well as a response to the changing environment, aging, or pathological insult. This chapter discusses how plasticity is necessary not only for neural networks to acquire new functional properties, but also for them to remain robust and stable. The article also reviews the seminal proposals developed over the years that have driven experiments and strongly influenced concepts of neural plasticity.

  8. Neural Systems Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — As part of the Electrical and Computer Engineering Department and The Institute for System Research, the Neural Systems Laboratory studies the functionality of the...

  9. A neural flow estimator

    DEFF Research Database (Denmark)

    Jørgensen, Ivan Harald Holger; Bogason, Gudmundur; Bruun, Erik

    1995-01-01

    is implemented using switched-current technique and is capable of estimating flow in the μl/s range. The neural estimator is built around a multiplierless neural network, containing 96 synaptic weights which are updated using the LMS1-algorithm. An experimental chip has been designed that operates at 5 V......This paper proposes a new way to estimate the flow in a micromechanical flow channel. A neural network is used to estimate the delay of random temperature fluctuations induced in a fluid. The design and implementation of a hardware efficient neural flow estimator is described. The system...

  10. A comparative study of the effects of different low-level lasers on the proliferation, viability, and migration of human melanocytes in vitro.

    Science.gov (United States)

    AlGhamdi, Khalid M; Kumar, Ashok; Ashour, Abdelkader E; AlGhamdi, Attieh A

    2015-07-01

    The aim of this study was to investigate the effects of different low-level laser therapies (LLLTs) of various wavelengths and energies on normal cultured human melanocytes. Various studies have shown the effects of LLLs on various types of cultured cells. Presently, little is known about the biological effects of LLLTs on melanocytes. Melanocytes were exposed to LLLT at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 J/cm(2) using a blue (457 nm), red (635 nm), or ultraviolet (UV) (355 nm) laser. Melanocyte viability, proliferation, and migration were monitored at 72 h after irradiation. The blue (P < 0.001) and red (P < 0.001 and P < 0.01) lasers significantly enhanced viability at 0.5 to 2.0 J/cm(2), whereas the UV laser (P < 0.001) could significantly enhance viability only at 0.5 and 1.0 J/cm(2) compared with controls. The blue and red lasers also significantly enhanced the proliferation of the melanocytes at 0.5 to 2.0 J/cm(2) (P < 0.001), and the UV laser significantly enhanced proliferation at 0.5 to 1.5 J/cm(2) (P < 0.001 and P < 0.01) compared with controls. The blue laser significantly enhanced melanocyte migration at 0.5 to 4.0 J/cm(2) (P < 0.001 to P < 0.05), but the red (P < 0.001 and P < 0.01) and UV (P < 0.001 to P < 0.05) lasers could significantly enhance such migration at 0.5 to 1.0 J/cm(2) and 0.5 to 2.0 J/cm(2), respectively, compared with controls. LLLT at low energy densities is able to significantly increase melanocyte viability, proliferation, and migration in vitro, and at higher energy densities, it gives non-stimulatory results. Additionally, the blue laser was the best among the three lasers. These findings might have potential application in vitiligo treatment in future.

  11. Ultra-structural effects of different low-level lasers on normal cultured human melanocytes: an in vitro comparative study.

    Science.gov (United States)

    AlGhamdi, Khalid M; Kumar, Ashok; A Al-Ghamdi, Attieh; Al-Rikabi, Ammar C; Mubarek, Mohammed; Ashour, Abdelkader E

    2016-12-01

    The aim of this study was to investigate the effects of the different types of low-level laser therapy (LLLT) on the ultra-structure and number of melanosomes in normal cultured human melanocytes. Specific effects of various types of LLLT on the ultra-structure of melanosomes have not yet been reported. Melanocytes were exposed to LLLT at an energy level of 2.0 J/cm(2), using a blue (457 nm), red (635 nm), or ultraviolet (UV) (355 nm) laser. After 72 h of irradiation, the melanocytes were fixed in 2.5 % glutaraldehyde (pH 7.2) phosphate buffer for 8 h and analyzed by transmission electron microscopy. Four developmental stages (I to IV) of melanosomes were observed, and their numbers were counted manually. The percentage of stages I, II, III, and IV melanosomes was 12.8, 14.2, 22.6, and 50.3 %, respectively, in the control (sham light). However, the melanosome percentages were 41.2, 5.4, 8.2, and 24.2 % in stages I, II, III, and IV, respectively, in the blue laser-treated group; 58.4, 6.1, 9.3, and 26.2 % for stages I, II, III, and IV, respectively, in the red laser-treated group; and 31.3, 11.1, 16.5, and 41.1 % for stages I, II, III, and IV, respectively, in the UV laser-treated group. The present data show that the amount of stage I is significantly higher (P < 0.0001) in the LLLT-treated cells compared to the control, which indicates significant stimulation of melanogenesis. The red laser was more effective than the other lasers. Moreover, the effects of LLLT on the ultra-structure of melanosomes need to be studied in a larger number of subject groups.

  12. In vivo multiplex quantitative analysis of 3 forms of alpha melanocyte stimulating hormone in pituitary of prolyl endopeptidase deficient mice

    Directory of Open Access Journals (Sweden)

    Perroud Bertrand

    2009-06-01

    Full Text Available Abstract Background In vitro reactions are useful to identify putative enzyme substrates, but in vivo validation is required to identify actual enzyme substrates that have biological meaning. To investigate in vivo effects of prolyl endopeptidase (PREP, a serine protease, on alpha melanocyte stimulating hormone (α-MSH, we developed a new mass spectrometry based technique to quantitate, in multiplex, the various forms of α-MSH. Methods Using Multiple Reaction Monitoring (MRM, we analyzed peptide transitions to quantify three different forms of α-MSH. Transitions were first confirmed using standard peptides. Samples were then analyzed by mass spectrometry using a triple quadrupole mass spectrometer, after elution from a reverse phase C18 column by a gradient of acetonitrile. Results We first demonstrate in vitro that PREP digests biological active alpha melanocyte stimulating hormone (α-MSH1–13, by cleaving the terminal amidated valine and releasing a truncated alpha melanocyte stimulating hormone (α-MSH1–12 product – the 12 residues α-MSH form. We then use the technique in vivo to analyze the MRM transitions of the three different forms of α-MSH: the deacetylated α-MSH1–13, the acetylated α-MSH1–13 and the truncated form α-MSH1–12. For this experiment, we used a mouse model (PREP-GT in which the serine protease, prolyl endopeptidase, is deficient due to a genetrap insertion. Here we report that the ratio between acetylated α-MSH1–13 and α-MSH1–12 is significantly increased (P-value = 0.015, N = 6 in the pituitaries of PREP-GT mice when compared to wild type littermates. In addition no significant changes were revealed in the relative level of α-MSH1–13 versus the deacetylated α-MSH1–13. These results combined with the demonstration that PREP digests α-MSH1–13 in vitro, strongly suggest that α-MSH1–13 is an in vivo substrate of PREP. Conclusion The multiplex targeted quantitative peptidomics technique we

  13. An unusual case of congenital melanocytic nevus presenting as neurocutaneous melanoma coexisting with Tuberous Sclerosis complex: A case report.

    Science.gov (United States)

    Rai, Santosh; Kalakoti, Piyush; Syed, Mm Aarif; Thacker, Purujit J; Jain, Rishi; Kalra, Gaurav

    2011-07-01

    Congenital melanocytic nevi are among the several known risk factors for the development of melanoma. Neurocutaneous melanosis is a rare, congenital, non-hereditary disorder characterized by the presence of multiple and/or giant congenital melanocytic nevi. It is a rare condition, with fewer than 200 cases reported in the literature. Its association with tuberous sclerosis complex, a form of the neurocutaneous syndrome, is an unusual finding which, to the best of our knowledge, has not been documented in the English literature so far. Herein we present the first case documenting such an association in a 16-year-old post-pubertal Indian girl. In this report, we describe the case of a 16-year-old Indian girl who presented to our hospital with swelling on the scalp which had progressed from the hairline to just above the left brow, causing mechanical ptosis. She was born with a black-pigmented triangular patch covered with hair over the scalp which had increased in size over a period of eight years after birth. An X-ray of her skull and ultrasonography revealed soft tissue swelling in the left temporofrontoparietal region. Magnetic resonance imaging of her brain showed the presence of 8.99 cm × 2.26 cm abnormal signal intensity involving the scalp, a few small tubers with cortical dysplasia in the left frontoparietal region with asymmetric dilatation, and the presence of calcified subependymal nodules within the left lateral ventricle. These findings were suggestive of tuberous sclerosis. A histopathological examination of the swelling was suggestive of congenital melanocytic nevi. The patient underwent surgery. Excision of the tumor with primary skin grafting was done, with the graft being taken from the medial aspect of the right thigh. This case warrants further research to provide concrete evidence of an association of neurocutaneous melanoma with tuberous sclerosis complex. Research should be conducted to prove whether this is an unusual association or a new

  14. An unusual case of congenital melanocytic nevus presenting as neurocutaneous melanoma coexisting with Tuberous Sclerosis complex: A case report

    Directory of Open Access Journals (Sweden)

    Thacker Purujit J

    2011-07-01

    Full Text Available Abstract Introduction Congenital melanocytic nevi are among the several known risk factors for the development of melanoma. Neurocutaneous melanosis is a rare, congenital, non-hereditary disorder characterized by the presence of multiple and/or giant congenital melanocytic nevi. It is a rare condition, with fewer than 200 cases reported in the literature. Its association with tuberous sclerosis complex, a form of the neurocutaneous syndrome, is an unusual finding which, to the best of our knowledge, has not been documented in the English literature so far. Herein we present the first case documenting such an association in a 16-year-old post-pubertal Indian girl. Case presentation In this report, we describe the case of a 16-year-old Indian girl who presented to our hospital with swelling on the scalp which had progressed from the hairline to just above the left brow, causing mechanical ptosis. She was born with a black-pigmented triangular patch covered with hair over the scalp which had increased in size over a period of eight years after birth. An X-ray of her skull and ultrasonography revealed soft tissue swelling in the left temporofrontoparietal region. Magnetic resonance imaging of her brain showed the presence of 8.99 cm × 2.26 cm abnormal signal intensity involving the scalp, a few small tubers with cortical dysplasia in the left frontoparietal region with asymmetric dilatation, and the presence of calcified subependymal nodules within the left lateral ventricle. These findings were suggestive of tuberous sclerosis. A histopathological examination of the swelling was suggestive of congenital melanocytic nevi. The patient underwent surgery. Excision of the tumor with primary skin grafting was done, with the graft being taken from the medial aspect of the right thigh. Conclusion This case warrants further research to provide concrete evidence of an association of neurocutaneous melanoma with tuberous sclerosis complex. Research should be

  15. Neural Networks: Implementations and Applications

    NARCIS (Netherlands)

    Vonk, E.; Veelenturf, L.P.J.; Jain, L.C.

    1996-01-01

    Artificial neural networks, also called neural networks, have been used successfully in many fields including engineering, science and business. This paper presents the implementation of several neural network simulators and their applications in character recognition and other engineering areas

  16. Preclinical Melanoma Imaging with 68Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET.

    Science.gov (United States)

    Zhang, Chengcheng; Zhang, Zhengxing; Lin, Kuo-Shyan; Pan, Jinhe; Dude, Iulia; Hundal-Jabal, Navjit; Colpo, Nadine; Bénard, François

    2017-01-01

    It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized α-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex (CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex (CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex (CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Ki values, rapid internalization into B16F10 melanoma cells and high in vivo stability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three 68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of 68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study

  17. Critical Branching Neural Networks

    Science.gov (United States)

    Kello, Christopher T.

    2013-01-01

    It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical…

  18. Kunstige neurale net

    DEFF Research Database (Denmark)

    Hørning, Annette

    1994-01-01

    Artiklen beskæftiger sig med muligheden for at anvende kunstige neurale net i forbindelse med datamatisk procession af naturligt sprog, specielt automatisk talegenkendelse.......Artiklen beskæftiger sig med muligheden for at anvende kunstige neurale net i forbindelse med datamatisk procession af naturligt sprog, specielt automatisk talegenkendelse....

  19. Analysis of an electrical impedance spectroscopy system in short-term digital dermoscopy imaging of melanocytic lesions.

    Science.gov (United States)

    Rocha, L; Menzies, S W; Lo, S; Avramidis, M; Khoury, R; Jackett, L; Guitera, P

    2017-11-01

    Electrical impedance spectroscopy (EIS) is a noninvasive diagnostic technique that measures tissue impedance. To evaluate the effect of adding an EIS measurement at baseline to suspicious melanocytic lesions undergoing routine short-term sequential digital dermoscopy imaging (SDDI). Patients presented with suspicious melanocytic lesions that were eligible for short-term SDDI (with no clear feature of melanoma on dermoscopy). EIS measurement was performed at the first visit following dermoscopic photography. Normally, an EIS score of ≥ 4 is considered positive; however, this protocol investigated a higher cut-off in combination with SDDI. When the EIS score was ≥ 7 the lesion was excised immediately owing to the high risk of melanoma. Lesions with a score melanoma of 83·1% [95% confidence interval (CI) 76·3-88·7]. Five of the six melanomas found in this study had an EIS score ≥ 7, with a sensitivity for melanoma diagnosis of 83·3% (95% CI 35·9-99·6). When EIS 0-6 lesions were subsequently followed up with SDDI, one additional melanoma was detected (EIS = 6) giving a sensitivity for the diagnosis of melanoma overall of 100% (95% CI 54·1-100; six of six malignant melanomas excised) and a specificity of 69·5% (95% CI 61·5-76·6; 107 of 154 benign lesions not excised). If utilizing a protocol where an EIS score ≤ 3 requires no SDDI and ≥ 7 requires immediate excision, it reduced the need for SDDI by 46·9% (n = 75/160; 95% CI 39·0-54·9). © 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics.

    Science.gov (United States)

    Magro, Cynthia M; Abraham, Ronnie M; Guo, Ruifeng; Li, Shibo; Wang, Xuan; Proper, Steven; Crowson, A Neil; Mihm, Martin

    2014-01-01

    Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevus-like borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed plexiform melanomas. 40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained, along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH). The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the progressed melanoma. DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.

  2. A 3.7 kb fragment of the mouse Scn10a gene promoter directs neural crest but not placodal lineage EGFP expression in a transgenic animal.

    Science.gov (United States)

    Lu, Van B; Ikeda, Stephen R; Puhl, Henry L

    2015-05-20

    Under physiological conditions, the voltage-gated sodium channel Nav1.8 is expressed almost exclusively in primary sensory neurons. The mechanism restricting Nav1.8 expression is not entirely clear, but we have previously described a 3.7 kb fragment of the Scn10a promoter capable of recapitulating the tissue-specific expression of Nav1.8 in transfected neurons and cell lines (Puhl and Ikeda, 2008). To validate these studies in vivo, a transgenic mouse encoding EGFP under the control of this putative sensory neuron specific promoter was generated and characterized in this study. Approximately 45% of dorsal root ganglion neurons of transgenic mice were EGFP-positive (mean diameter = 26.5 μm). The majority of EGFP-positive neurons bound isolectin B4, although a small percentage (∼10%) colabeled with markers of A-fiber neurons. EGFP expression correlated well with the presence of Nav1.8 transcript (95%), Nav1.8-immunoreactivity (70%), and TTX-R INa (100%), although not all Nav1.8-expressing neurons expressed EGFP. Several cranial sensory ganglia originating from neurogenic placodes, such as the nodose ganglion, failed to express EGFP, suggesting that additional regulatory elements dictate Scn10a expression in placodal-derived sensory neurons. EGFP was also detected in discrete brain regions of transgenic mice. Quantitative PCR and Nav1.8-immunoreactivity confirmed Nav1.8 expression in the amygdala, brainstem, globus pallidus, lateral and paraventricular hypothalamus, and olfactory tubercle. TTX-R INa recorded from EGFP-positive hypothalamic neurons demonstrate the usefulness of this transgenic line to study novel roles of Nav1.8 beyond sensory neurons. Overall, Scn10a-EGFP transgenic mice recapitulate the majority of the Nav1.8 expression pattern in neural crest-derived sensory neurons. Copyright © 2015 the authors 0270-6474/15/358021-14$15.00/0.

  3. Dynamics of neural cryptography.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-05-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

  4. Cell fate regulated by nuclear factor-κB- and activator protein-1-dependent signalling in human melanocytes exposed to ultraviolet A and ultraviolet B

    Science.gov (United States)

    Wäster, P; Rosdahl, I; Öllinger, K

    2014-01-01

    Summary Background Ultraviolet (UV) radiation constitutes an important risk factor for malignant melanoma, but the wavelength responsible for the initiation of this disease is not fully elucidated. Solar UV induces multiple signalling pathways that are critical for initiation of apoptotic cell death as a cellular defence against malignant transformation. Objectives To evaluate the involvement of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1 in the signalling pathways induced by UVA or UVB irradiation in human melanocytes. Methods Primary cultures of normal human melanocytes were irradiated with UVA or UVB, and the concomitant DNA damage and redox alterations were monitored. The resulting activation of the NF-κB and AP-1 signalling pathways and subsequent apoptosis were studied. Results UVB irradiation causes DNA damage detected as formation of cyclobutane pyrimidine dimers, while UVA induces increased levels of 8-hydroxydeoxyguanosine and lipid peroxidation. UVA and UVB initiate phosphorylation of c-Jun N-terminal protein kinase and extracellular signal-regulated kinase, and the apoptosis signalling pathways converge into a common mechanism. Downregulation of c-Jun suppresses AP-1-mediated signalling and prevents apoptosis upstream of lysosomal and mitochondrial membrane permeabilization, whereas inhibition of NF-κB by SN50 increases apoptosis. Conclusions We conclude that AP-1 induces proapoptotic signalling, whereas NF-κB is a key antiapoptotic/prosurvival factor in both UVA- and UVB-induced cellular damage in human melanocytes, which might in turn impact melanoma development and progression. What's already known about this topic? Melanocytes are the target cells of ultraviolet (UV) irradiation, and the cells from which melanoma originates. The mitogen-activated protein kinase signalling pathway is important for regulation of UV-induced cellular responses. Previous studies have strongly implicated the transcription factors

  5. ANT Advanced Neural Tool

    Energy Technology Data Exchange (ETDEWEB)

    Labrador, I.; Carrasco, R.; Martinez, L.

    1996-07-01

    This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs.

  6. Hidden neural networks

    DEFF Research Database (Denmark)

    Krogh, Anders Stærmose; Riis, Søren Kamaric

    1999-01-01

    A general framework for hybrids of hidden Markov models (HMMs) and neural networks (NNs) called hidden neural networks (HNNs) is described. The article begins by reviewing standard HMMs and estimation by conditional maximum likelihood, which is used by the HNN. In the HNN, the usual HMM probability...... parameters are replaced by the outputs of state-specific neural networks. As opposed to many other hybrids, the HNN is normalized globally and therefore has a valid probabilistic interpretation. All parameters in the HNN are estimated simultaneously according to the discriminative conditional maximum...... likelihood criterion. The HNN can be viewed as an undirected probabilistic independence network (a graphical model), where the neural networks provide a compact representation of the clique functions. An evaluation of the HNN on the task of recognizing broad phoneme classes in the TIMIT database shows clear...

  7. [Neural codes for perception].

    Science.gov (United States)

    Romo, R; Salinas, E; Hernández, A; Zainos, A; Lemus, L; de Lafuente, V; Luna, R

    This article describes experiments designed to show the neural codes associated with the perception and processing of tactile information. The results of these experiments have shown the neural activity correlated with tactile perception. The neurones of the primary somatosensory cortex (S1) represent the physical attributes of tactile perception. We found that these representations correlated with tactile perception. By means of intracortical microstimulation we demonstrated the causal relationship between S1 activity and tactile perception. In the motor areas of the frontal lobe is to be found the connection between sensorial and motor representation whilst decisions are being taken. S1 generates neural representations of the somatosensory stimuli which seen to be sufficient for tactile perception. These neural representations are subsequently processed by central areas to S1 and seem useful in perception, memory and decision making.

  8. Neural Oscillators Programming Simplified

    Directory of Open Access Journals (Sweden)

    Patrick McDowell

    2012-01-01

    Full Text Available The neurological mechanism used for generating rhythmic patterns for functions such as swallowing, walking, and chewing has been modeled computationally by the neural oscillator. It has been widely studied by biologists to model various aspects of organisms and by computer scientists and robotics engineers as a method for controlling and coordinating the gaits of walking robots. Although there has been significant study in this area, it is difficult to find basic guidelines for programming neural oscillators. In this paper, the authors approach neural oscillators from a programmer’s point of view, providing background and examples for developing neural oscillators to generate rhythmic patterns that can be used in biological modeling and robotics applications.

  9. Neural cryptography with feedback.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Shacham, Lanir; Kanter, Ido

    2004-04-01

    Neural cryptography is based on a competition between attractive and repulsive stochastic forces. A feedback mechanism is added to neural cryptography which increases the repulsive forces. Using numerical simulations and an analytic approach, the probability of a successful attack is calculated for different model parameters. Scaling laws are derived which show that feedback improves the security of the system. In addition, a network with feedback generates a pseudorandom bit sequence which can be used to encrypt and decrypt a secret message.

  10. Neural cryptography with feedback

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Shacham, Lanir; Kanter, Ido

    2004-04-01

    Neural cryptography is based on a competition between attractive and repulsive stochastic forces. A feedback mechanism is added to neural cryptography which increases the repulsive forces. Using numerical simulations and an analytic approach, the probability of a successful attack is calculated for different model parameters. Scaling laws are derived which show that feedback improves the security of the system. In addition, a network with feedback generates a pseudorandom bit sequence which can be used to encrypt and decrypt a secret message.

  11. Neural network applications

    Science.gov (United States)

    Padgett, Mary L.; Desai, Utpal; Roppel, T.A.; White, Charles R.

    1993-01-01

    A design procedure is suggested for neural networks which accommodates the inclusion of such knowledge-based systems techniques as fuzzy logic and pairwise comparisons. The use of these procedures in the design of applications combines qualitative and quantitative factors with empirical data to yield a model with justifiable design and parameter selection procedures. The procedure is especially relevant to areas of back-propagation neural network design which are highly responsive to the use of precisely recorded expert knowledge.

  12. Building Neural Net Software

    OpenAIRE

    Neto, João Pedro; Costa, José Félix

    1999-01-01

    In a recent paper [Neto et al. 97] we showed that programming languages can be translated on recurrent (analog, rational weighted) neural nets. The goal was not efficiency but simplicity. Indeed we used a number-theoretic approach to machine programming, where (integer) numbers were coded in a unary fashion, introducing a exponential slow down in the computations, with respect to a two-symbol tape Turing machine. Implementation of programming languages in neural nets turns to be not only theo...

  13. NEMEFO: NEural MEteorological FOrecast

    Energy Technology Data Exchange (ETDEWEB)

    Pasero, E.; Moniaci, W.; Meindl, T.; Montuori, A. [Polytechnic of Turin (Italy). Dept. of Electronics

    2004-07-01

    Artificial Neural Systems are a well-known technique used to classify and recognize objects. Introducing the time dimension they can be used to forecast numerical series. NEMEFO is a ''nowcasting'' tool, which uses both statistical and neural systems to forecast meteorological data in a restricted area close to a meteorological weather station in a short time range (3 hours). Ice, fog, rain are typical events which can be anticipated by NEMEFO. (orig.)

  14. Giant Congenital Melanocytic Naevus with Proliferative Nodules Mimicking Congenital Malignant Melanoma: A Case Report and Review of the Literature of Congenital Melanoma

    Directory of Open Access Journals (Sweden)

    Massimiliano Scalvenzi

    2013-01-01

    Full Text Available Congenital malignant melanoma (CMM is a rare condition that is defined as malignant melanoma recognized at birth. CMM may develop in utero in one of three ways: (1 transmission by metastasis through the placenta from a mother with melanoma; (2 primary melanoma arising within a giant congenital melanocytic naevus (GCMN; (3 primary de novo cutaneous CMM arising in utero. CMM can be confused clinically and histologically with benign proliferative melanocytic lesions such as giant congenital nevi. We describe the case of a patient presenting a GCMN with proliferative nodules, clinically and dermoscopically resembling a CMM, demonstrating the importance of caution in making a diagnosis of MM and highlighting the possibility that benign lesions as GCMN can mimic a malignant melanoma in this age group.

  15. Xp11 neoplasm with melanocytic differentiation of the prostate harbouring the novel NONO-TFE3 gene fusion: report of a unique case expanding the gene fusion spectrum.

    Science.gov (United States)

    Wang, Xiao-Tong; Xia, Qiu-Yuan; Ni, Hao; Wang, Zi-Yu; Ye, Sheng-Bing; Li, Rui; Wang, Xuan; Lv, Jing-Huan; Shi, Shan-Shan; Ma, Heng-Hui; Lu, Zhen-Feng; Shen, Qin; Zhou, Xiao-Jun; Rao, Qiu

    2016-09-01

    Recently, an increasing number of TFE3 rearrangement-associated tumours have been reported, such as TFE3 rearrangement-associated perivascular epithelioid cell tumours (PEComas), melanotic Xp11 translocation renal cancers and melanotic Xp11 neoplasms. We have suggested that these tumours belong to a single clinicopathological spectrum. 'Xp11 neoplasm with melanocytic differentiation' or 'melanotic Xp11 neoplasm' have been proposed to designate this unique neoplasm. Herein, we describe the first case of an Xp11 neoplasm with melanocytic differentiation to be described in the prostate, bearing the novel NONO-TFE3 gene fusion. This study both adds to the spectrum regarding melanotic Xp11 neoplasms and expands its gene fusion spectrum. Moreover, we discuss the relationship of these rare tumours to neoplasms such as conventional PEComas, alveolar soft part sarcomas, malignant melanomas, clear cell sarcomas and Xp11 translocation renal cancers. © 2016 John Wiley & Sons Ltd.

  16. Prostaglandin D2 production in FM55 melanoma cells is regulated by α-melanocyte-stimulating hormone and is not related to melanin production

    Science.gov (United States)

    Masoodi, Mojgan; Nicolaou, Anna; Gledhill, Karl; Rhodes, Lesley E; Tobin, Desmond J; Thody, Anthony J

    2010-01-01

    This study shows that prostaglandins in human FM55 melanoma cells and epidermal melanocytes are produced by COX-1. Prostaglandin production in FM55 melanoma cells was unrelated to that of melanin suggesting that the two processes can occur independently. α-Melanocyte-stimulating hormone, which had no effect on melanin production in FM55 cells, stimulated PGD2 production in these cells without affecting PGE2. While cAMP pathways may be involved in regulating PGD2 production, our results suggest that α-MSH acts independently of cAMP, possibly by regulating the activity of lipocalin-type PGD synthase. This α-MSH-mediated effect may be associated with its role as an immune modulator. PMID:20482620

  17. Association of Multiple Melanocytic Naevi with Education, Sex and Skin Type. A Northern Finland Birth Cohort 1966 Study with 46 Years Follow-up.

    Science.gov (United States)

    Sinikumpu, Suvi-Päivikki; Huilaja, Laura; Jokelainen, Jari; Auvinen, Juha; Timonen, Markku; Tasanen, Kaisa

    2017-02-08

    Having multiple melanocytic naevi (sex, socioeconomic status (education) in childhood and adulthood, skin type and sunbathing habits. The prevalence of multiple melanocytic naevi was 11.6% (223/1,930). Higher education (odds ratio (OR) 2.11, 95% confidence interval (95% CI) 1.51-2.96), male sex (OR 1.48, 95% CI 1.07-2.06), sun-sensitive skin type (OR 2.09, 95% CI 1.34-3.27) and regular use of sunscreen (OR 2.03, 95% CI 1.23-3.37) were associated with increased risk of multiple naevi. Inflammatory skin diseases decreased (OR 0.49, 95 CI% 0.33-0.72) the risk of multiple naevi. In conclusion, several risk factors were found for multiple naevi among adults living in high latitudes, in Northern Finland.

  18. Fluorescence-Activated Cell Sorting of EGFP-Labeled Neural Crest Cells From Murine Embryonic Craniofacial Tissue

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    Saurabh Singh

    2005-01-01

    Full Text Available During the early stages of embryogenesis, pluripotent neural crest cells (NCC are known to migrate from the neural folds to populate multiple target sites in the embryo where they differentiate into various derivatives, including cartilage, bone, connective tissue, melanocytes, glia, and neurons of the peripheral nervous system. The ability to obtain pure NCC populations is essential to enable molecular analyses of neural crest induction, migration, and/or differentiation. Crossing Wnt1-Cre and Z/EG transgenic mouse lines resulted in offspring in which the Wnt1-Cre transgene activated permanent EGFP expression only in NCC. The present report demonstrates a flow cytometric method to sort and isolate populations of EGFP-labeled NCC. The identity of the sorted neural crest cells was confirmed by assaying expression of known marker genes by TaqMan Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR. The molecular strategy described in this report provides a means to extract intact RNA from a pure population of NCC thus enabling analysis of gene expression in a defined population of embryonic precursor cells critical to development.

  19. 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

    Science.gov (United States)

    2015-10-01

    variants of the MC1R, R151C, R160W, and D294H, are strongly associated with red hair color, fair skin , and poor tanning ability. Expression of any two of...susceptibility, and reveal common pathways, such as NER and antioxidant pathways, that are affected by both p16 and MC1R. To investigate our hypothesis...established primary cultures of melanocytes, keratinocytes and fibroblasts form skin biopsies of patients from melanoma-prone families, who are heterozygous

  20. Biphasic pro-melanogenic and pro-apoptotic effects of all-trans-retinoic acid (ATRA) on human melanocytes: time-course study.

    Science.gov (United States)

    Baldea, Ioana; Costin, Gertrude-Emilia; Shellman, Yiqun; Kechris, Katerina; Olteanu, Elena Diana; Filip, Adriana; Cosgarea, Maria Rodica; Norris, David Albert; Birlea, Stanca Ariana

    2013-11-01

    The effects of retinoids on melanogenesis and their mechanism as depigmenting agents in topical therapy have not been fully elucidated. Conflicting data about their impact on melanogenic pathways have been reported. To investigate the effects of all-trans-retinoic acid (ATRA) on normal human melanocytes from Caucasian subjects. We assessed ATRA's cytotoxicity by measuring viability with a cell proliferation assay, and apoptotic effects using Annexin V and γ-H2AX markers. ATRA's melanogenic activity was investigated based on spectrophotometric measurement of melanin content and tyrosinase enzymatic activity. Tyrosinase expression was assessed by Western blotting. We tested the antioxidant activity of superoxide dismutase (SOD) and catalase (CAT) in melanocytes using a spectrophotometric assay. Of the concentrations tested in this 72h time-course study, the 1.0μM ATRA had a well-defined two-stage pro-melanogenic and pro-apoptotic effect on melanocytes. In the first 6h, treated cells showed significant increase (p≤0.01) of melanin content, tyrosinase, SOD, and CAT activities compared to the controls. While overall tyrosinase expression was not affected by ATRA, all other tested parameters decreased progressively beyond the short-term point of 6h. ATRA treatment of over 6h induced melanocyte apoptosis, as shown by the time-dependent decrease in cell viability, coupled with significant increase in Annexin V positive cells and nuclear accumulation of γ-H2AX foci. The results obtained using this testing platform show a biphasic ATRA action: immediate pro-melanogenic effect and longer-term exposure pro-apoptotic activity. These data qualify ATRA as a potent tool to better understand the mechanisms that regulate the pigmentary system. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  1. Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3.

    Science.gov (United States)

    Swope, Viki B; Jameson, Joshua A; McFarland, Kevin L; Supp, Dorothy M; Miller, William E; McGraw, Dennis W; Patel, Mira A; Nix, Matthew A; Millhauser, Glenn L; Babcock, George F; Abdel-Malek, Zalfa A

    2012-09-01

    The melanocortin 1 receptor (MC1R), a G(s) protein-coupled receptor, has an important role in human pigmentation. We investigated the regulation of expression and activity of the MC1R in primary human melanocyte cultures. Human β-defensin 3 (HBD3) acted as an antagonist for MC1R, inhibiting the α-melanocortin (α-melanocyte-stimulating hormone (α-MSH))-induced increase in the activities of adenylate cyclase and tyrosinase, the rate-limiting enzyme for melanogenesis. α-Melanocortin and forskolin, which activate adenylate cyclase, and 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C, increased, whereas exposure to UV radiation reduced, MC1R gene and membrane protein expression. Brief treatment with α-MSH resulted in MC1R desensitization, whereas continuous treatment up to 3 hours caused a steady rise in cAMP, suggesting receptor recycling. Pretreatment with agouti signaling protein or HBD3 prohibited responsiveness to α-MSH, but not forskolin, suggesting receptor desensitization by these antagonists. Melanocytes from different donors expressed different levels of the G protein-coupled receptor kinases (GRKs) 2, 3, 5, and 6, as well as β-arrestin 1. Therefore, in addition to the MC1R genotype, regulation of MC1R expression and activity is expected to affect human pigmentation and the responses to UV.

  2. Evaluation of the MPATH-Dx Classification Scheme for Diagnosis of Cutaneous Melanocytic Neoplasms: Results from the International Melanoma Pathology Study Group

    Science.gov (United States)

    Lott, Jason P.; Elmore, Joann; Zhao, Ge A.; Knezevich, Stevan R.; Frederick, Paul D.; Reisch, Lisa M.; Chu, Emily Y.; Cook, Martin G.; Duncan, Lyn M.; Elenitsas, Rosalie; Gerami, Pedram; Landman, Gilles; Lowe, Lori; Messina, Jane L.; Mihm, Martin C.; van den Oord, Joost J.; Rabkin, Michael S.; Schmidt, Birgitta; Shea, Christopher R.; Yun, Sook Jung; Xu, George X.; Piepkorn, Michael W.; Elder, David E.; Barnhill, Raymond L.

    2016-01-01

    Background Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. Objective To evaluate the Melanoma Pathology Assessment and Treatment Hierarchy (MPATH-Dx) scheme, a five-category classification system for melanocytic lesions. Methods Participants (n=16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when provided, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Inter-rater agreement [95% CI] and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. Results Most participants were dermatopathologists (n=12), age ≥50 years (n=12), male (n=9), US-based (n=11), and primary academic faculty (n=14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement following MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 [0.68, 0.71] and 0.72 [0.71, 0.73], respectively, while correlation between MPATH-Dx categorization and treatment suggestions was 0.91. Limitations Small sample size of experienced pathologists in a testing situation. Conclusion Varying diagnostic nomenclature can be consistently classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care. PMID:27189823

  3. MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes

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    Pengchao Wang

    2016-06-01

    Full Text Available MicroRNAs (miRNAs play an important role in regulating almost all biological processes. miRNAs bind to the 3′ untranslated region (UTR of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3′ UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF and Tyrosinase (TYR were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5.

  4. Effect of Novel Marine Nutraceuticals on IL-1α-Mediated TNF-α Release from UVB-Irradiated Human Melanocyte-Derived Cells

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    Visalini Muthusamy

    2011-01-01

    Full Text Available UV-induced inflammation and reactive oxygen species formation are involved in the development of melanoma. Natural products like 5β-scymnol and CO2-supercritical fluid extract (CO2-SFE of mussel oil contain anti-inflammatory and antioxidant properties that may aid in reducing the deleterious effects of UV radiation. Therefore, their effect on the release of the proinflammatory cytokine, tumour necrosis factor-α (TNF-α, from UVB-irradiated human melanocytic cells was examined. Human epidermal melanocytes (HEM and MM96L melanoma cells were exposed to UVB radiation and IL-1α. Cell viability and TNF-α levels were determined 24 hours after-irradiation while p38 mitogen-activated protein kinase (MAPK activation was observed at 15 min after-irradiation. When α-tocopherol, CO2-SFE mussel oil, and 5β-scymnol were added to the UVB-irradiated HEM cells treated with IL-1α, TNF-α levels fell by 53%, 65%, and 76%, respectively, while no inhibition was evident in MM96L cells. This effect was not due to inhibition of the intracellular p38 MAPK signalling pathway. These compounds may be useful in preventing inflammation-induced damage to normal melanocytes.

  5. A modified fluorimetric host cell reactivation assay to determine the repair capacity of primary keratinocytes, melanocytes and fibroblasts

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    Gebhard Daniel

    2010-06-01

    Full Text Available Abstract Background The Host Cell Reactivation Assay (HCRA is widely used to identify circumstances and substances affecting the repair capacity of cells, however, it is restricted by the transfection procedure used and the sensitivity of the detection method. Primary skin cells are particularly difficult to transfect, and therefore sensitive methods are needed to detect any variations due to the cell-type or inter-individual differences or changes induced by diverse substances. A sensitive and repeatable method to detect the repair capacity of skin cells would be useful in two different aspects: On the one hand, to identify substances influencing the repair capacity in a positive manner (these substances could be promising ingredients for cosmetic products and on the other hand, to exclude the negative effects of substances on the repair capacity (this could serve as one step further towards replacing or at least reducing animal testing. Results In this paper, we present a rapid and sensitive assay to determine the repair capacity of primary keratinocytes, melanocytes and fibroblasts based on two wave-length Green Fluorescent Protein (GFP and DsRed reporter technology in order to test different substances and their potential to influence the DNA repair capacity. For the detection of plasmid restoration, we used FACS technology, which, in comparison to luminometer technology, is highly sensitive and allows single cell based analysis. The usefulness of this assay and studying the repair capacity is demonstrated by the evidence that DNA repair is repressed by Cyclosporin A in fibroblasts. Conclusions The methodology described in this paper determines the DNA repair capacity in different types of human skin cells. The described transfection protocol is suitable for the transfection of melanocytes, keratinocytes and fibroblasts, reaching efficacies suitable for the detection of the restored plasmids by FACS technology. Therefore the repair capacity

  6. The Response of microRNAs to Solar UVR in Skin-Resident Melanocytes Differs between Melanoma Patients and Healthy Persons.

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    Jingfeng Sha

    Full Text Available The conversion of melanocytes into cutaneous melanoma is largely dictated by the effects of solar ultraviolet radiation (UVR. Yet to be described, however, is exactly how these cells are affected by intense solar UVR while residing in their natural microenvironment, and whether their response differs in persons with a history of melanoma when compared to that of healthy individuals. By using laser capture microdissection (LCM to isolate a pure population of melanocytes from a small area of skin that had been intermittingly exposed or un-exposed to physiological doses of solar UVR, we can now report for the first time that the majority of UV-responsive microRNAs (miRNAs in the melanocytes of a group of women with a history of melanoma are down-regulated when compared to those in the melanocytes of healthy controls. Among the miRNAs that were commonly and significantly down-regulated in each of these women were miR-193b (P<0.003, miR-342-3p (P<0.003, miR186 (P<0.007, miR-130a (P<0.007, and miR-146a (P<0.007. To identify genes potentially released from inhibition by these repressed UV-miRNAs, we analyzed databases (e.g., DIANA-TarBase containing experimentally validated microRNA-gene interactions. In the end, this enabled us to construct UV-miRNA-gene regulatory networks consisting of individual genes with a probable gain-of-function being intersected not by one, but by several down-regulated UV-miRNAs. Most striking, however, was that these networks typified well-known regulatory modules involved in controlling the epithelial-to-mesenchymal transition and processes associated with the regulation of immune-evasion. We speculate that these pathways become activated by UVR resulting in miRNA down regulation only in melanocytes susceptible to melanoma, and that these changes could be partially responsible for empowering these cells toward tumor progression.

  7. Conducting Polymers for Neural Prosthetic and Neural Interface Applications

    Science.gov (United States)

    2015-01-01

    Neural interfacing devices are an artificial mechanism for restoring or supplementing the function of the nervous system lost as a result of injury or disease. Conducting polymers (CPs) are gaining significant attention due to their capacity to meet the performance criteria of a number of neuronal therapies including recording and stimulating neural activity, the regeneration of neural tissue and the delivery of bioactive molecules for mediating device-tissue interactions. CPs form a flexible platform technology that enables the development of tailored materials for a range of neuronal diagnostic and treatment therapies. In this review the application of CPs for neural prostheses and other neural interfacing devices are discussed, with a specific focus on neural recording, neural stimulation, neural regeneration, and therapeutic drug delivery. PMID:26414302

  8. Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: A new subtype of albinism classified as {open_quotes}OCA3{close_quotes}

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    Boissy, R.E.; Zhao, H.; Austin, L.M.; Boissy, Y.L.; Zhao, Y. [Univ. of Cincinnati College of Medicine, OH (United States)] [and others

    1996-06-01

    Most types of human oculocutaneous albinism (OCA) result from mutations in the gene for tyrosinase (OCA1) or the P protein (OCA2), although other types of OCA have been described but have not been mapped to specific loci. Melanocytes were cultured from an African-American with OCA, who exhibited the phenotype of Brown OCA, and his normal fraternal twin. Melanocytes cultured from the patient with OCA and the normal twin appeared brown versus black, respectively. Melanocytes from both the patient with OCA and the normal twin demonstrated equal amounts of NP-40-soluble melanin; however, melanocytes from the patient with OCA contained only 7% of the amount of insoluble melanin found from the normal twin. Tyrosinase-related protein-1 (TRP-1) was not detected in the OCA melanocytes by use of various anti-TRP-1 probes. Furthermore, transcripts for TRP-1 were absent in cultured OCA melanocytes. The affected twin was homozygous for a single-bp deletion in exon 6, removing an A in codon 368 and leading to a premature stop at codon 384. Tyrosine hydroxylase activity of the OCA melanocytes was comparable to controls when assayed in cell lysates but was only 30% of controls when assayed in intact cells. We conclude that this mutation of the human TRP-1 gene affects its interaction with tyrosinase, resulting in dysregulation of tyrosinase activity, promotes the synthesis of brown versus black melanin, and is responsible for a third genetic type of OCA in humans, which we classify as {open_quotes}OCA3.{close_quotes} 69 refs., 7 figs., 3 tabs.

  9. Alpha-melanocyte-stimulating hormone attenuates behavioral effects of corticotropin-releasing factor in isolated guinea pig pups.

    Science.gov (United States)

    Schiml-Webb, Patricia A; Miller, Emily; Deak, Terrence; Hennessy, Michael B

    2009-07-01

    During a 3-hr period of social isolation in a novel environment, guinea pig pups exhibit an initial active phase of behavioral responsiveness, characterized primarily by vocalizing, which is then followed by a stage of passive responsiveness in which pups display a distinctive crouch, eye-closing, and extensive piloerection. Prior treatment of pups with alpha-melanocyte-stimulating hormone (alpha-MSH) reduces each of the passive behaviors. The onset of passive responding during separation can be accelerated with peripheral injection of corticotropin-releasing factor (CRF). To examine whether CRF produces its effects through a mechanism similar to that of prolonged separation, we examined the effect of administering alpha-MSH to pups injected with CRF. As expected, CRF markedly enhanced passive responding during a 60-min period of separation. alpha-MSH delivered by either intracerebroventricular infusion or intraperitoneal injection significantly reduced each of the passive behavioral responses without significantly affecting active behavior. These findings, together with previous results indicating that it is the anti-inflammatory property of alpha-MSH that is responsible for its behavioral effects during prolonged separation, suggest that peripheral CRF speeds the induction of passive responding through a mechanism involving enhanced proinflammatory activity.

  10. Human breast cancer cell lines co-express neuronal, epithelial, and melanocytic differentiation markers in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Qingbei Zhang

    Full Text Available Differentiation programs are aberrant in cancer cells allowing them to express differentiation markers in addition to their tissue of origin. In the present study, we demonstrate the multi-lineage differentiation potential of breast cancer cell lines to express multiple neuronal/glial lineage-specific markers as well as mammary epithelial and melanocytic-specific markers. Multilineage expression was detected in luminal (MCF-7 and SKBR3 and basal (MDA-MB-231 types of human breast cancer cell lines. We also observed comparable co-expression of these three cell lineage markers in MDA-MB-435 cells in vitro, in MDA-MB-435 primary tumors derived from parental and single cell clones and in lung metastases in vivo. Furthermore, ectoderm multi-lineage transdifferentiation was also found in human melanoma (Ul-MeL and glioblastoma cell lines (U87 and D54. These observations indicate that aberrant multi-lineage transdifferentiation or lineage infidelity may be a wide spread phenomenon in cancer.

  11. NRG1/ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation

    Science.gov (United States)

    Buac, Kristina; Xu, Mai; Cronin, Julie; Weeraratna, Ashani T.; Hewitt, Stephen M.; Pavan, William J.

    2010-01-01

    Summary Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared to nevi or metastatic lesions. NRG1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. PMID:19659570

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

    Science.gov (United States)

    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.

  13. Recent advances in the understanding of how neuropeptide Y and α-melanocyte stimulating hormone function in adipose physiology

    Science.gov (United States)

    Shipp, Steven L.; Cline, Mark A.; Gilbert, Elizabeth R.

    2016-01-01

    ABSTRACT Communication between the brain and the adipose tissue has been the focus of many studies in recent years, with the “brain-fat axis” identified as a system that orchestrates the assimilation and usage of energy to maintain body mass and adequate fat stores. It is now well-known that appetite-regulating peptides that were studied as neurotransmitters in the central nervous system can act both on the hypothalamus to regulate feeding behavior and also on the adipose tissue to modulate the storage of energy. Energy balance is thus partly controlled by factors that can alter both energy intake and storage/expenditure. Two such factors involved in these processes are neuropeptide Y (NPY) and α-melanocyte stimulating hormone (α-MSH). NPY, an orexigenic factor, is associated with promoting adipogenesis in both mammals and chickens, while α-MSH, an anorexigenic factor, stimulates lipolysis in rodents. There is also evidence of interaction between the 2 peptides. This review aims to summarize recent advances in the study of NPY and α-MSH regarding their role in adipose tissue physiology, with an emphasis on the cellular and molecular mechanisms. A greater understanding of the brain-fat axis and regulation of adiposity by bioactive peptides may provide insights on strategies to prevent or treat obesity and also enhance nutrient utilization efficiency in agriculturally-important species. PMID:27994947

  14. Acquired melanocytic naevus phenotypes and MC1R genotypes in Han Chinese: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Xiaohong Li

    2017-12-01

    Full Text Available Background Early detection and treatment are the most important elements in reducing the incidence of melanoma deaths. Acquired melanocytic naevi (AMN are well-known precursors of melanoma but most of our knowledge on the clinico-dermoscopic phenotypes of AMN is based on studies in European-background populations, particularly American and Australian populations. There has been little research in Chinese Han populations on clinico-dermoscopic variability of naevi or how naevi are affected by melanoma-linked variants of the melanocortin 1 receptor (MC1R gene. Methods Clinical and dermoscopic features of 448 AMN in 115 patients from the Han ethnic group in mainland China were described. Germline polymorphisms in MC1R were determined for 98 of these patients. Results AMN were predominantly found on the head and neck. Dermoscopic patterns observed were nonspecific, reticular, globular, and parallel furrow, with most AMN having a nonspecific pattern. There were no associations between MC1R polymorphisms and clinical or dermoscopic features of AMN. Discussion Our results provide evidence that AMN in the Han population in China have similar dermoscopic patterns to those in European populations, but are present in much lower numbers. As there were no associations between clinical or dermoscopic features of AMN and MC1R polymorphisms, further studies should focus on candidate gene associations with AMN features and the risk of melanoma, with larger sample sizes and comparisons to AMN in other populations.

  15. A multicentre pilot study investigating high-definition optical coherence tomography in the differentiation of cutaneous melanoma and melanocytic naevi.

    Science.gov (United States)

    Gambichler, T; Schmid-Wendtner, M H; Plura, I; Kampilafkos, P; Stücker, M; Berking, C; Maier, T

    2015-03-01

    High-definition optical coherence tomography scanners have recently been developed. To assess the diagnostic performance of HD-OCT in the differentiation of benign melanocytic skin lesions (MSL) and cutaneous melanoma (CM). Patients with MSL were assessed by HD-OCT. All diagnoses were histopathologically confirmed. One blinded observer evaluated both slice and en-face HD-OCT images and diagnosed MLS on the basis of an algorithm adopted from reflectance confocal microscopy, recent HD-OCT reports, and conventional OCT. A total of 93 MSL were studied comprising 66 benign MSL and 27 CM. The sensitivity of HD-OCT was 74.1% [95% confidence interval (CI) 53.7-88.8%)], specificity was 92.4% (95% CI 83.2-97.5%). The positive predictive value was 80%, the negative predictive value 89.7%. The performance of HD-OCT depended on tumour thickness and the presence of borderline lesions indicated by high false negative rates in very thin melanomas and high false positive rates in dysplastic naevi. In the distinction of MSL, HD-OCT applied in an investigator blinded fashion has a moderate diagnostic performance. The diagnostic performance of HD-OCT of MSL should be reassessed in other clinical settings. © 2014 European Academy of Dermatology and Venereology.

  16. Long-term follow-up of patients undergoing autologous noncultured melanocyte-keratinocyte transplantation for vitiligo and other leukodermas.

    Science.gov (United States)

    Silpa-Archa, Narumol; Griffith, James L; Huggins, Richard H; Henderson, Marsha D; Kerr, Holly A; Jacobsen, Gordon; Mulekar, Sanjeev V; Lim, Henry W; Hamzavi, Iltefat H

    2017-08-01

    Persistence of pigmentation after a melanocyte-keratinocyte transplantation procedure (MKTP) is an important consideration for efficacy. We sought to determine long-term repigmentation of MKTP in vitiligo and other leukodermas. A retrospective review of electronic medical records was conducted for all MKTPs performed at Henry Ford Hospital between January 2009 and April 2014. Repigmentation was assessed by a 5-point grading scale (poor to excellent) and Vitiligo Area Scoring Index (VASI). One hundred patients had MKTP performed at 236 anatomically-based lesions (ABLs); 63 patients with 157 ABLs had long-term data available (12-72 months; median, 24 months). Segmental vitiligo, nonsegmental vitiligo, and physical leukoderma demonstrated improvement in VASI scores: -75.6 ± 24.6%, -59.2 ± 36.6%, and -32.4 ± 33.5%, respectively. In vitiligo, at 24, 48, and 72 months after MKTP, 53%, 64%, and 53% of ABLs, respectively, maintained >75% repigmentation. Skin phototype, age, and anatomic location of ABLs had no significant effect on the outcome of treatment. Limitations of the study include the retrospective design with uncontrolled, postoperative adjuvant treatments and inconsistent compliance to scheduled follow-up evaluations. MKTP provides satisfactory long-term repigmentation in the majority of appropriately selected patients with leukoderma. MKTP can maintain repigmentation for at least 72 months. Copyright © 2017. Published by Elsevier Inc.

  17. The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi.

    Science.gov (United States)

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

    2012-10-01

    Although several studies have shown a dysregulation of microRNA (miRNA) expression profiles in cutaneous melanoma, there has been little research on the miRNA machinery itself. In this study, we investigated the mRNA expression profiles of different miRNA machinery components in primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic nevi (BMN). Patients with PCMM (n = 7), CMMM (n = 6) and BMN (n = 7) were included in the study. Punch biopsies were harvested from the centers of tumors (lesional) and from BMN (control). In contrast to previous reports exploring specific clusters of miRNAs in PCMM, the present study investigates mRNA expression levels of Dicer, Drosha, Exp5, DGCR8 and the RISC components PACT, argonaute-1, argonaute-2, TARBP1, TARBP2, MTDH and SND1, which were detected by TaqMan real-time reverse transcription polymerase chain reaction (RT-PCR). Argonaute-1, TARBP2 and SND1 expression levels were significantly higher in BMN compared to PCMM (p  0.05). The results of this study show that the miRNA machinery components argonaute-1, TARBP2 and SND1 are dysregulated in PCMM and CMMM compared to BMN and may play a role in the process of malignant transformation.

  18. The effects of acute and chronic alpha melanocyte stimulating hormone (alphaMSH) on cardiovascular dynamics in conscious rats.

    Science.gov (United States)

    Hill, Crystal; Dunbar, Joseph C

    2002-09-01

    Alpha melanocyte stimulating hormone (alphaMSH) has been demonstrated to have regulatory functions in the periphery and central nervous system (CNS). alphaMSH plays a central role in the regulation of metabolic balance such as decreasing food intake, increasing sympathetic outflow and hypothalamic/pituitary function. Our laboratory has investigated the actions of alphaMSH on sympathetic and cardiovascular dynamics using anesthetized animals. In this study we determined both the acute and chronic effects of alphaMSH on cardiovascular and metabolic dynamics in conscious unrestrained rats. Animals were each implanted with a radio-telemetry transmitter for recording of cardiovascular parameters and subsequently instrumented with intracerebroventricular (ICV) cannulas. The acute ICV administration of alphaMSH significantly increased the mean arterial pressure (MAP) and heart rate (HR) when compared to artificial cerebrospinal fluid (ACSF) controls. On the other hand chronic alphaMSH infusion resulted in an initial increase in MAP and HR lasting for 2 days followed by a decrease in MAP. Chronic alphaMSH administration decreased physical activity and food intake but not weight gain. We conclude that in the conscious unrestrained animal the acute administration of alphaMSH increased MAP and HR, however, chronic infusion is associated with decreased MAP, physical activity and food intake.

  19. Biomarkers as Key Contributors in Treating Malignant Melanoma Metastases

    Directory of Open Access Journals (Sweden)

    Camila Ferreira de Souza

    2012-01-01

    Full Text Available Melanoma is a human neurocristopathy associated with developmental defects in the neural crest-derived epidermal melanocytes. At the present time, at least three hypotheses were identified that may explain melanoma aetiology, as follows: (1 a model of linear progression from differentiated melanocytes to metastatic cancer cells (2 a model involving the appearance of melanoma stem-like cells, and (3 an epigenetic progenitor model of cancer. Treating metastatic melanoma is one of the most serious challenges in the 21st century. This is justified because of a subpopulation of cells presenting a remarkable molecular heterogeneity, which is able to explain the drug resistance and the growing mortality rates worldwide. Fortunately, there are now evidences sustaining the importance of genetic, epigenetic, and metabolomic alterations as biomarkers for classification, staging, and better management of melanoma patients. To illustrate some fascinating insights in this field, the genes BRAFV600E and CTLA4 have been recognized as bona fide targets to benefit melanoma patients. Our research attempts to carefully evaluate data from the literature in order to highlight the link between a molecular disease model and the key contribution of biomarkers in treating malignant melanoma metastases.

  20. Hyperbolic Hopfield neural networks.

    Science.gov (United States)

    Kobayashi, M

    2013-02-01

    In recent years, several neural networks using Clifford algebra have been studied. Clifford algebra is also called geometric algebra. Complex-valued Hopfield neural networks (CHNNs) are the most popular neural networks using Clifford algebra. The aim of this brief is to construct hyperbolic HNNs (HHNNs) as an analog of CHNNs. Hyperbolic algebra is a Clifford algebra based on Lorentzian geometry. In this brief, a hyperbolic neuron is defined in a manner analogous to a phasor neuron, which is a typical complex-valued neuron model. HHNNs share common concepts with CHNNs, such as the angle and energy. However, HHNNs and CHNNs are different in several aspects. The states of hyperbolic neurons do not form a circle, and, therefore, the start and end states are not identical. In the quantized version, unlike complex-valued neurons, hyperbolic neurons have an infinite number of states.

  1. Neural Semantic Encoders.

    Science.gov (United States)

    Munkhdalai, Tsendsuren; Yu, Hong

    2017-04-01

    We present a memory augmented neural network for natural language understanding: Neural Semantic Encoders. NSE is equipped with a novel memory update rule and has a variable sized encoding memory that evolves over time and maintains the understanding of input sequences through read, compose and write operations. NSE can also access multiple and shared memories. In this paper, we demonstrated the effectiveness and the flexibility of NSE on five different natural language tasks: natural language inference, question answering, sentence classification, document sentiment analysis and machine translation where NSE achieved state-of-the-art performance when evaluated on publically available benchmarks. For example, our shared-memory model showed an encouraging result on neural machine translation, improving an attention-based baseline by approximately 1.0 BLEU.

  2. The neural crest and neural crest cells: discovery and significance ...

    Indian Academy of Sciences (India)

    In this paper I provide a brief overview of the major phases of investigation into the neural crest and the major players involved, discuss how the origin of the neural crest relates to the origin of the nervous system in vertebrate embryos, discuss the impact on the germ-layer theory of the discovery of the neural crest and of ...

  3. Introduction to Artificial Neural Networks

    DEFF Research Database (Denmark)

    Larsen, Jan

    1999-01-01

    The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks.......The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks....

  4. Deconvolution using a neural network

    Energy Technology Data Exchange (ETDEWEB)

    Lehman, S.K.

    1990-11-15

    Viewing one dimensional deconvolution as a matrix inversion problem, we compare a neural network backpropagation matrix inverse with LMS, and pseudo-inverse. This is a largely an exercise in understanding how our neural network code works. 1 ref.

  5. Relação entre o nevo melanocítico congênito pequeno e melanoma cutâneo Small congenital melanocytic nevus and the risk of developing melanoma

    Directory of Open Access Journals (Sweden)

    Marcus Maia

    2003-04-01

    Full Text Available FUNDAMENTOS: O risco da ocorrência, de Melanoma Cutâneo (MC, no Nevo Melanocítico Congênito Pequeno (NMCP (BACKGROUND: There have been few studies, even recently, into the risk of occurrence of cutaneous melanoma in small congenital melanocytic nevi < 3 cm. There is no consensus regarding the management of these lesions. OBJECTIVES: The purpose of the study was to evaluate the frequency with which small congenital melanocytic nevi transform into cutaneous melanoma and discuss this in relation to the literature, focussing on the practical management. PATIENT AND METHODS: From a total of 204 patients with cutaneous melanoma, the authors selected those whose disease was derived from small congenital melanocytic nevi. The inclusion criterion was clinical, based on patient records. RESULTS: Malignant transformation of small congenital melanocytic nevi was found in 44/204 patients (21.6% with confidence interval (CI of 12.2 to 28%.. No cases occurred before 20 years of age and there was no preferential age range for the transformation. CONCLUSION: Small congenital melanocytic nevi are a precursor lesion of cutaneous melanoma; the transformation most probably does not occur before puberty; while the risk of transformation after puberty seems to occur homogeneously throughout life. Suggestion: The excision should be performed at the onset of puberty.

  6. Neural Network Ensembles

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Salamon, Peter

    1990-01-01

    We propose several means for improving the performance an training of neural networks for classification. We use crossvalidation as a tool for optimizing network parameters and architecture. We show further that the remaining generalization error can be reduced by invoking ensembles of similar...... networks....

  7. Neural systems for control

    National Research Council Canada - National Science Library

    Omidvar, Omid; Elliott, David L

    1997-01-01

    ... is reprinted with permission from A. Barto, "Reinforcement Learning," Handbook of Brain Theory and Neural Networks, M.A. Arbib, ed.. The MIT Press, Cambridge, MA, pp. 804-809, 1995. Chapter 4, Figures 4-5 and 7-9 and Tables 2-5, are reprinted with permission, from S. Cho, "Map Formation in Proprioceptive Cortex," International Jour...

  8. Neural Tube Defects

    Science.gov (United States)

    ... pregnancies each year in the United States. A baby’s neural tube normally develops into the brain and spinal cord. ... fluid in the brain. This is called hydrocephalus. Babies with this condition are treated with surgery to insert a tube (called a shunt) into the brain. The shunt ...

  9. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

    Science.gov (United States)

    Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-07-20

    The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

  10. Neural Stem Cells and Its Derivatives as a New Material for Melanin Inhibition.

    Science.gov (United States)

    Hwang, Insik; Hong, Sunghoi

    2017-12-22

    The pigment molecule, melanin, is produced from melanosomes of melanocytes through melanogenesis, which is a complex process involving a combination of chemical and enzymatically catalyzed reactions. The synthesis of melanin is primarily influenced by tyrosinase (TYR), which has attracted interest as a target molecule for the regulation of pigmentation or depigmentation in skin. Thus, direct inhibitors of TYR activity have been sought from various natural and synthetic materials. However, due to issues with these inhibitors, such as weak or permanent ability for depigmentation, allergy, irritant dermatitis and rapid oxidation, in vitro and in vivo, the development of new materials that inhibit melanin production is essential. A conditioned medium (CM) derived from stem cells contains many cell-secreted factors, such as cytokines, chemokines, growth factors and extracellular vesicles including exosomes. In addition, the secreted factors could negatively regulate melanin production through stimulation of a microenvironment of skin tissue in a paracrine manner, which allows the neural stem cell CM to be explored as a new material for skin depigmentation. In this review, we will summarize the current knowledge regulating depigmentation, and discuss the potential of neural stem cells and their derivatives, as a new material for skin depigmentation.

  11. Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers.

    Directory of Open Access Journals (Sweden)

    Judit Váradi

    Full Text Available Alpha-melanocyte-stimulating hormone (α-MSH is a potent anti-inflammatory peptide with cytoprotective effect in various tissues. The present investigation demonstrates the ability of α-MSH to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. The barrier integrity was assessed by measuring transepithelial electric resistance (TEER and permeability for marker molecules. Caco-2 monolayers were evaluated by immunohistochemistry for expression of melanocortin-1 receptor and tight junction proteins ZO-1 and claudin-4. The activation of nuclear factor kappa beta (NF-κB was detected by fluorescence microscopy and inflammatory cytokine expression was assessed by flow cytometric bead array cytokine assay. Exposure of Caco-2 monolayers to proinflammatory cytokines lowered TEER and increased permeability for fluorescein and albumin, which was accompanied by changes in ZO-1 and claudin-4 immunostaining. α-MSH was able to prevent inflammation-associated decrease of TEER in a dose-dependent manner and reduce the increased permeability for paracellular marker fluorescein. Further immunohistochemistry analysis revealed proinflammatory cytokine induced translocation of the NF-κB p65 subunit into Caco-2 cell nuclei, which was inhibited by α-MSH. As a result the IL-6 and IL-8 production of Caco-2 monolayers were also decreased with different patterns by the addition of α-MSH to the culture medium. In conclusion, Caco-2 cells showed a positive immunostaining for melanocortin-1 receptor and α-MSH protected Caco-2 cells against inflammatory barrier dysfunction and inflammatory activation induced by tumor necrosis factor-α and interleukin-1β cytokines.

  12. Expression of cyclins A and E in melanocytic skin lesions and its correlation with some clinicopathologic features

    Directory of Open Access Journals (Sweden)

    Ana Alekseenko

    2012-07-01

    Full Text Available Cyclins play a fundamental role in the cell cycle. Recent studies have focused on their role in the development of various malignancies. The objective of this study was to evaluate and compare the expression of cyclins A and E in common nevi, dysplastic nevi and malignant melanomas, and to investigate the relationship between cyclin expression and some pathological parameters such as tumor thickness, ulceration, regression, and mitotic rate, as well as several clinical and phenotypic parameters such as skin phototype, hair and eye color, number of nevi, personal or family melanoma history, and personal history of nonmelanoma skin cancer (NMSC. A total of 102 melanocytic skin lesions, including 30 common nevi, 38 dysplastic nevi and 34 melanomas, were examined. Expression of cyclins was detected by immunohistochemistry and quantified as a percentage of immunostained cell nuclei in each sample. Significant differences in expression of both cyclins were found between all lesion types: the median percentage of cyclin A-positive nuclei was 8.2% in melanomas, 3.4% in dysplastic nevi, and 0.95% in common nevi (p < 0.001. The corresponding percentages for cyclin E were 9.5%, 4.25% and 1.44% (p < 0.001. Expression of both cyclins was significantly higher among patients with a personal history of NMSC. Cyclin A was also significantly overexpressed in patients with a high total nevus count (TNC compared to moderate and low TNC. Expression of cyclins did not significantly correlate with the other clinicopathologic features investigated. These findings indicate the possible involvement of cyclins A and E in the pathogenesis of malignant melanoma. Our results also show a potential diagnostic significance of these cyclins as markers allowing discrimination between dysplastic nevi and melanoma.

  13. Effects of alpha-melanocyte-stimulating hormone on mitochondrial energy metabolism in rats of different age-groups.

    Science.gov (United States)

    Feichtinger, René G; Pétervári, Erika; Zopf, Michaela; Vidali, Silvia; Aminzadeh-Gohari, Sepideh; Mayr, Johannes A; Kofler, Barbara; Balaskó, Márta

    2017-08-01

    Hypothalamic alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis. Its anorexigenic and hypermetabolic effects show characteristic age-related alterations that may be part of the mechanism of middle-aged obesity and geriatric anorexia/cachexia seen in humans and other mammals. We aimed to investigate the role of α-MSH in mitochondrial energy metabolism during the course of aging in a rodent model. To determine th