Dysplastic nevus--risk factor or disguise for melanoma

Dysplastic nevus is an acquired or hereditary nevus that clinically seems atypical and pathohistologically dysplastic. The term of dysplastic nevus has changed through history and even until now the dermatologists and pathologists have not found the same conclusion for name and definition of dysplastic nevus. Epidemiology of dysplastic nevus is different depending on geographic lattitude, being three times higher in Australia than in Great Britain. Genetic factors play a role in etiology of dysplastic nevus but are still not well defined. UV radiation is indisputable main etiological factor in developing dysplastic nevus. Many studies confirm that children who have been using sun protection creams with SPF have less dysplastic nevi than those who did not. Nevus with geographic shape and muddy borders, dominately macular, red to brown colored and has 5 mm or more in diameter is clinically dysplastic nevus. ABCDE rules count for dysplastic nevus as well as for melanoma but prefferable diagnostic criteria for dysplastic nevus would be "ugly duckling sign". Pathohistologic analysis is the key in confirming the diagnosis of dysplastic nevus. Great experience and knowledge in dermatopathology field is essential for pathologists to make a distinction between dysplastic nevus and melanoma in situ. Likewise great experience in dermatooncology field is essential in differentiating dysplastic nevus from other nevi. Surgical excision is the only therapy that should be done for dysplastic nevus. Regular follow up is highly recommended for patients with dysplastic nevus and syndroma naevi dysplastic. Education about sun protection measures and self-examination techniques is essential for all patients with dysplastic nevi and their family.     

Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data

Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus-prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.     

The dysplastic nevus: recognition and management

The recognition of atypical or dysplastic nevomelanocytic nevi potentially provides clinicians with another means of identifying individuals at increased risk for cutaneous malignant melanoma. However, a great deal of controversy still surrounds these lesions, their significance, and the clinical and histologic criteria needed for their diagnosis at present. In general, dysplastic nevi tend to be asymmetrical and larger (greater than 5 mm) than ordinary acquired nevi, have a macular component, irregular and ill-defined borders, and haphazard (variegate) coloration. A clinical diagnosis of dysplastic nevi must be confirmed by histopathology, since not all clinically atypical nevi are dysplastic. While precise histopathologic criteria for dysplastic nevi are lacking, most authorities agree that an abnormal nevomelanocytic proliferative pattern as manifested by increased numbers of basilar melanocytes and/or abnormal junctional nevomelanocytic nesting in the setting of lentiginous epidermal hyperplasia, variable degrees of nevomelanocytic nuclear atypia, and a lymphocytic host response are consistent with a histologic diagnosis of dysplastic nevi. Current data for individuals with dysplastic nevi and a family history of cutaneous malignant melanoma (at least two family members with cutaneous malignant melanoma) indicate a relative risk for cutaneous malignant melanoma about 148 times that of the general population. In comparison, cutaneous malignant melanoma risk seems lower for individuals with familial dysplastic nevi (but without familial cutaneous malignant melanoma) and "sporadic" dysplastic nevi. With respect to progression to melanoma, probably the vast majority of dysplastic nevi remain stable or possibly regress. Management of individuals with histologically confirmed dysplastic nevi involves periodic skin examinations. Regional overview and life-size photography are helpful in following these patients. Patients should also be instructed in the examination of their own skin. While a definite relationship between sun exposure and dysplastic nevi remains unproved, the use of sunscreens and avoidance of unnecessary sun exposure are advised. Examination of family members for atypical melanocytic lesions is also recommended.     

Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation?

Exposure to ultraviolet radiation (UVR) is associated with both adverse and beneficial health effects. While many of the adverse effects of excessive exposure are well known, the adverse effects of insufficient UVR exposure are less clear-cut, but may include a heightened risk of several cancers and autoimmune disorders as well as of bone diseases such as rickets, osteomalacia and osteoporosis. Although some of the postulated beneficial effects of UVR exposure may occur through the maintenance of adequate levels of vitamin D, it is not clear that this can account for all of these effects. We briefly review the epidemiological literature with respect to vitamin D, UVR exposure and autoimmune diseases. We further outline alternative pathways, whereby UVR could alter the risk of development of some cancers and autoimmune disorders, independent of effects on vitamin D synthesis. Recognition of the beneficial effects of UVR exposure has led to a reconsideration of sun avoidance policies. It is important to recognize that all of the beneficial effects of UVR exposure may not occur only through UVR-induced vitamin D synthesis. Thus maintaining current sun avoidance policies while supplementing food with vitamin D may not be sufficient to avoid the risks of insufficient exposure to UVR.     

Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study

Human leukocyte antigen (HLA) class II associations with two subtypes of vitiligo: vitiligo vulgaris and halo nevi associated with vitiligo were investigated. In previous studies associations between vitiligo and HLA antigens have been reported but these two subtypes have never been taken into account. However from a clinical and histological point of view, a difference in (auto)-immune pathogenesis can be expected. This difference might be reflected in an association with different HLA alleles. Seventy-six unrelated Dutch Caucasians, 40 with vitiligo vulgaris and 36 with halo nevi associated with vitiligo were included. A panel of randomly chosen HLA typed healthy Dutch blood donors (n = 2400) served as control population. HLA-DR and -DQ typing was carried out on blood samples by amplifying genomic DNA using polymerase chain reaction followed by dot blot hybridization with sequence specific oligonucleotides. The main outcome measures were odds ratio (OR), uncorrected P-value (P(u)) and corrected P-value. There were distinct differences in the clinical manifestations between vitiligo vulgaris and halo nevi associated with vitiligo with respect to precipitating factors, extent and progress of the disease and the association with other auto-immune diseases in the two subtypes and their respective first degree family members. Our stratification reveals differences in HLA class II between both subtypes and between subtypes and controls. A case-control association study showed a significant positive association of HLA-DR4 (OR = 2.787, P(u) = 0.0022) and DR53 (OR = 2.249, P(u) = 0.0153) and a negative association of HLA-DR3 (OR = 0.195, P(u) = 0.0024) with vitiligo vulgaris. The group with halo nevi associated with vitiligo did not show these associations, but had a significant negative association with HLA-DR11 (OR = 0.083, P(u) = 0.0067). In conclusion, the differences in HLA association within clinical subtypes of vitiligo support our suggestion that vitiligo vulgaris and halo nevi associated with vitiligo have distinct pathogenic mechanisms.     

A determinant for directionality of organelle transport in Drosophila embryos

BACKGROUND: Motor-driven transport along microtubules is a primary cellular mechanism for moving and positioning organelles. Many cargoes move bidirectionally by using both minus and plus end-directed motors. How such cargoes undergo controlled net transport is unresolved. RESULTS: Using a combination of genetics, molecular biology, and biophysics, we have identified Halo, a novel regulator of lipid droplet transport in early Drosophila embryos. In embryos lacking Halo, net transport of lipid droplets, but not that of other cargoes, is specifically altered; net transport is minus-end directed at developmental stages when it is normally plus-end directed. This reversal is due to an altered balance of motion at the level of individual organelles; without Halo, travel distances and stall forces are reduced for plus-end and increased for minus-end motion. During development, halo mRNA is highly upregulated just as net plus-end transport is initiated (phase II), and its levels drop precipitously shortly before transport becomes minus-end directed (phase III). Exogenously provided Halo prevents the switch to net minus-end transport in phase III in wild-type embryos and induces net plus-end transport during phase II in halo mutant embryos. This mechanism of regulation is likely to be of general importance because the Drosophila genome encodes a family of related proteins with similar sequences, each transiently expressed in distinct domains. CONCLUSIONS: We conclude that Halo acts as a directionality determinant for embryonic droplet transport and is the first member of a new class of transport regulators.     

荧光晕法在细胞染色质结构状态检测中的应用

荧光晕法是近年来发展起来的定量检测细胞染色质结构状态的方法,由于其简易、直观、灵敏、快速,已被广泛用于放射生物学及肿瘤细胞生物学研究中。我们依据文献报道建立了此法,并对其进行了改良,进一步优化了操作步骤。并用该法检测了两种相同来源(具有相似遗传背景)、具不同辐射敏感性的细胞株的染色质结构状态,发现辐射敏感株SX-9具有更松散的染色质结构,可能与两者的辐射敏感性差异有关,为研究染色质结构状态与辐射敏感性的关系提供了佐证。     

Genetics of melanocytic nevi

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

The challenge resulting from positive and negative effects of sunlight: how much solar UV exposure is appropriate to balance between risks of vitamin D deficiency and skin cancer?

There is no doubt that solar ultraviolet (UV) exposure is the most important environmental risk factor for the development of non-melanoma skin cancer. Therefore, sun protection is of particular importance to prevent these malignancies, especially in risk groups. However, 90% of all requisite vitamin D has to be formed in the skin through the action of the sun-a serious problem, for a connection between vitamin D deficiency and a broad variety of independent diseases including various types of cancer, bone diseases, autoimmune diseases, hypertension and cardiovascular disease has now been clearly indicated in a large number of epidemiologic and laboratory studies. An important link that improved our understanding of these new findings was the discovery that the biologically active vitamin D metabolite 1,25(OH)(2)D is not exclusively produced in the kidney, but in many other tissues such as prostate, colon, skin and osteoblasts. Extra-renally produced 1,25(OH)(2)D is now considered to be an autocrine or paracrine hormone, regulating various cellular functions including cell growth. We and others have shown that strict sun protection causes vitamin D deficiency in risk groups. In the light of new scientific findings that convincingly demonstrate an association of vitamin D deficiency with a variety of severe diseases including various cancers, the detection and treatment of vitamin D deficiency in sun-deprived risk groups is of high importance. It has to be emphasized that in groups that are at high risk of developing vitamin D deficiency (e.g., nursing home residents or patients under immunosuppressive therapy), vitamin D status has to be monitored. Vitamin D deficiency should be treated, e.g., by giving vitamin D orally. Dermatologists and other clinicians have to recognize that there is convincing evidence that the protective effect of less intense solar UV radiation outweighs its mutagenic effects. Although further work is necessary to define an adequate vitamin D status and adequate guidelines for solar UV exposure, it is at present mandatory that public health campaigns and recommendations of dermatologists on sun protection consider these facts. Well-balanced recommendations on sun protection have to ensure an adequate vitamin D status, thereby protecting people against adverse effects of strict sun protection without significantly increasing the risk of developing UV-induced skin cancer.     

First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi

Segmental vitiligo is often ascribed to the neurogenic theory of melanocyte destruction, although data about the initial etiopathological events are scarce. Clinical, histopathological and T-cell phenotypic analyses were performed during the early onset of a segmental vitiligo lesion in a patient with associated halo nevi. Histopathological analysis revealed a lymphocytic infiltrate, mainly composed of CD8⁺ T-cells and some CD4⁺ T-cells around the dermo–epidermal junction. Flow cytometry analysis of resident T-cells revealed a clear enrichment of pro-inflammatory IFN-γ producing CD8⁺ T-cells in lesional skin compared to the non-lesional skin. Using human leukocyte antigen-peptide tetramers (MART-1, tyrosinase, gp100), increased numbers of T cells, recognizing melanocyte antigens were found in segmental vitiligo lesional skin, as compared with the non-lesional skin and the blood. Our findings indicate that a CD8⁺ melanocyte specific T cell-mediated immune response, as observed in generalized vitiligo, also plays a role in segmental vitiligo with associated halo nevi.     

The Physiological Role of Boron on Health

Environmental factors have been implicated in the etiology of autism spectrum disorder (ASD); however, the role of heavy metals has not been fully defined. This study investigated whether blood levels of mercury, arsenic, cadmium, and lead of children with ASD significantly differ from those of age- and sex-matched controls. One hundred eighty unrelated children with ASD and 184 healthy controls were recruited. Data showed that the children with ASD had significantly (p < 0.001) higher levels of mercury and arsenic and a lower level of cadmium. The levels of lead did not differ significantly between the groups. The results of this study are consistent with numerous previous studies, supporting an important role for heavy metal exposure, particularly mercury, in the etiology of ASD. It is desirable to continue future research into the relationship between ASD and heavy metal exposure.     

Arthritis susceptibility and the gut microbiome

Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology though both genetic and environmental factors have been suggested to be involved in its pathogenesis. While infections and other environmental factors (e.g. smoking) have been studied extensively and show some association, a direct link between all the factors has been difficult to prove. With the recent advances in technology, it has become possible to sequence the commensals that are residing in our gut. The gut microbiome may provide the missing link to this puzzle and help solve the mystery of many leaky gut syndromes. The gut commensals are involved in maintaining host immune homeostasis and function suggesting that they might be critical in altering the immune system, which leads to autoimmune diseases like RA. Mouse models support the role of the gut microbiota in predisposition to RA. If that is true, the power of gut-derived commensal can be harnessed to our benefit by generating a biomarker profile along with genetic factors to define individuals at risk and by altering the gut microbial composition using various means.     

Genetic and environmental factors in cutaneous malignant melanoma

Cutaneous malignant melanoma (CMM) is an interesting example of multifactorial disease, where both genetic and environmental factors are involved and interact. Major risk factors include a personal and familial history of melanoma, cutaneous and pigmentary characteristics, sun exposure and reactions to sun exposure. Phenotypic risk factors are likely to be genetically determined. Two high-risk melanoma susceptibility genes-CDKN2A and CDK4-have been identified to date, with a third gene p14(ARF) also being suspected of playing a role. Other high-risk genes are anticipated by the existence of 9p21-unlinked families. A low-risk melanoma-susceptibility gene-MC1R-has also been identified. Current studies aim to identify other susceptibility genes as well as to determine the respective contributions and interactions of the various genetic and environmental factors of CMM and associated phenotypes.     

Solar spectral lines ("solar halo")--healing or harmful for the retina?

The sungazing method has been known for thousands of years as healing method based on chromotherapeutic principle. Our examinations on the island of Rab show that it is acceptable only if applied 10 min before the sunset. Gazing has to be directed towards the green-yellow part of the spectrum, since the remaining part of the sun halo contains harmful energy. However, authors suggest that it would be preferable to use spectacles with medical filters transmitting wavelight of green-yellow colour, especially for treatment of macular degeneration.     

Distribution of immune cells in the epididymis of the aging Brown Norway rat is segment-specific and related to the luminal content.

Remarkable changes occur during aging in the testis and epididymis of the Brown Norway rat. A dramatic increase in the number of halo cells, which are present in the epididymal epithelium and originate from the immune system, is found in animals of increasing age. Halo cells have been postulated to be either lymphocytes or monocytes. We hypothesized that halo cells are a mixture of different immune cells and that their relative composition changes with age. To verify this hypothesis, markers for helper T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, and monocytes-macrophages were used to identify the major categories of immune cells in the epididymides of Brown Norway rats ranging in age from 3 to 24 mo. The numbers of immunocompetent cells in the epididymis were determined in relation to age, epididymal segment, and luminal content. We found that monocytes, helper T lymphocytes, and cytotoxic T lymphocytes belong to the population of halo cells. In addition, a segment-specific increase with age in the number of these immune cells was noted. Finally, we report a segment-specific recruitment of cytotoxic T lymphocytes and monocytes-macrophages in the epididymal epithelium of aged rats whose epididymal lumen contained few spermatozoa. We postulate that accumulation of damaged epithelial cells and antigens of germ cell origin, leaking through a dysfunctional blood-epididymis barrier, may contribute to the active recruitment of immune cells with age.     

Sun exposure and skin cancer,and the puzzle of cutaneous melanoma: A perspective on Fears et al. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. American Journal of Epidemiology 1977; 105: 420–427

Sunlight has been known as an important cause of skin cancer since around the turn of the 20th Century. A 1977 landmark paper of US scientists Fears, Scotto, and Schneiderman advanced a novel hypothesis whereby cutaneous melanoma was primarily caused by intermittent sun exposure (i.e. periodic, brief episodes of exposure to high-intensity ultraviolet radiation) while the keratinocyte cancers, squamous cell carcinoma and basal cell carcinoma, were primarily caused by progressive accumulation of sun exposure. With respect to cutaneous melanoma, this became known as the intermittent exposure hypothesis. The hypothesis stemmed from analysis of measured ambient ultraviolet radiation and age-specific incidence rates of melanoma and keratinocyte cancers collected as an extension to the US Third National Cancer Survey in several US States. In this perspective paper, we put this novel hypothesis into the context of knowledge at the time, and describe subsequent epidemiological and molecular research into melanoma that elaborated the intermittent exposure hypothesis and ultimately replaced it with a dual pathway hypothesis. Our present understanding is of two distinct biological pathways by which cutaneous melanoma might develop; a nevus prone pathway initiated by early sun exposure and promoted by intermittent sun exposure or possibly host factors; and a chronic sun exposure pathway in sun sensitive people who progressively accumulate sun exposure to the sites of future melanomas.     

Does sunlight have a beneficial influence on certain cancers?

Apperly [1941. The relation of solar radiation to cancer mortality in North America. Cancer Research 1, 191-195] first proposed that increased mortality from cancer in the north than in the south of the USA might be due to the south to north decrease in ambient solar radiation. This inverse association between ambient solar radiation and cancer mortality has been subsequently reported for cancers of the colon, breast, ovary and prostate. While the evidence that sunlight might be related to lower incidence or more favourable outcomes from cancer came initially from ecological studies, case-control and cohort studies have now shown a similar association of sun exposure with risks of colon, breast and prostate cancers in individuals, and other studies in individuals have found that serum and dietary vitamin D levels are associated with reduced risks of colorectal cancer and, less certainly, prostate cancer. Studies in individuals have recently also suggested an effect of sun exposure to reduce risk of non-Hodgkin lymphoma and to increase survival after a diagnosis of melanoma. Data on variation in survival from cancer by season of diagnosis suggest that sun exposure may also improve outcome from cancers of the breast, colon and prostate and Hodgkin lymphoma.     

Locomotor activity rhythm and sun compass orientation in the sandhopper <Emphasis Type="Italic">Talitrus </Emphasis><Emphasis Type="Italic">saltator</Emphasis> are related

The sandhopper Talitrus saltator has an endogenous activity rhythm with a circadian periodicity. It is well known for its ability to compensate for the apparent movement of the sun during its migrations along the sea–land axis of the beach. Both chronometric mechanisms are entrained by the natural LD photoperiod. Using actographic recordings and tests of solar orientation of individuals kept under an LD 12:12 clock-shifted cycle, after 1–13 days of treatment, we demonstrate that the timing mechanism of activity rhythm and the chronometric mechanism underlying the sun compass are the same.     

Heat shock proteins in autoimmune diseases

Heat shock proteins (hsp's) are among the most conserved proteins in evolution. They have been identified as important pathogen-related antigens as well as autoantigens suitable for construction of novel vaccines. The high evolutionary homology of hsp's has raised the question about the safety of such vaccines. Experimental and clinical observations have confirmed that hsp proteins are involved in the regulation of some autoimmune disease such as autoimmune arthritis, type 1 diabetes mellitus, atherosclerosis, multiple sclerosis, and other autoimmune reactions. It has been shown in experimental animals that some hsp proteins (especially hsp60, hsp70, and hsp10) can either induce or prevent autoimmune reactions depending on the circumstances. This article discusses the involvement of hsp proteins in the etiology of autoimmune diseases and it presents promising experimental data on the effects of immunization with hsp proteins in the prevention and therapy of autoimmune diseases.