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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental evidence indicates a relationship between cholesterol alpha-epoxide and skin cancer, and exposure of skin fibroblasts to ultraviolet radiation enduces formation of significant levels of this oxide. Colon cancer is also etiologically linked to cholesterol oxidation products. Higher than normal levels of cholestanetriol have been found in patients with colon cancer and also in those with precancerous disorders such as adenomatous polyps and ulcerative colitis. Higher than normal levels of cholesterol alpha-epoxide have been found in breast fluid aspirates of women with benign breast disease, with or without atypical hyperplasia of the epithelium, and this may be a factor in the increased incidence of breast cancer associated with hyperplasia. Similarly, the observed increased levels of cholesterol alpha and beta-epoxides in prostatic fluid of men with benign prostatic hypertrophy may be associated with subsequent development of prostate cancer. Cholesterol alpha-epoxide has been found to be mutagenic to fibroblasts in culture and to induce morphological transformation in hamster embryo cells and in mouse C3H cells. 25-Hydroxycholesterol and 20 alpha-hydroxycholesterol are potent suppressors of generation and proliferation of tumor-specific cytotoxic T lymphocytes. Although investigations into the role of cholesterol oxidation products in cancer are still in the early stages, evidence to date indicates a potentially significant role in the induction of some types of cancer.
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PMID:Cholesterol oxides and carcinogenesis. 206 46

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
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PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

Administration of alpha-difluoromethylornithine (DFMO) to mice was found to inhibit both the cutaneous carcinogenesis and the immunosuppression induced by ultraviolet B (UVB) irradiation. BALB/cAnNTacfBR mice were given 1% F2MeOrn in their drinking water throughout the experiment. After 3 weeks, mice received UVB irradiation consisting of five 30-min exposures per week to banks of six FS40 Westinghouse sunlamps. In the photocarcinogenesis study, mice received a total dose of approximately 1273 kJ m-2. Skin cancer incidence in UV-irradiated mice was 38% 28 weeks after the first UV exposure; DFMO reduced this incidence to 9% (P = 0.025, log-rank test). Although DFMO has been demonstrated to be chemopreventive of chemical carcinogenesis, this is the first report that it is effective against cancers induced by a physical carcinogen. The immunosuppression induced by UVB irradiation prevents the host from rejecting antigenic, syngeneic UV-induced tumors, which normal mice can reject. The level of immunosuppression in UV-irradiated mice treated with DFMO was measured by a passive-transfer assay. Splenocytes from UV-irradiated mice to naive mice prevented the recipients from rejecting 20/24 UV-induced tumor challenges, whereas splenocytes from UV-irradiated mice treated with DFMO did not prevent recipients from rejecting such challenges (2/24 grew). The difference between these values was significant (P less than 0.001, two-sample test for binomial proportions). Phenotypic analysis of splenocytes used in the passive transfer, using a biotin-avidin-immunoperoxidase technique, revealed that DFMO treatment prevented the reduction of Ia expression normally seen in UV-irradiated mice. Thus, administration of DFMO reduced skin carcinogenesis and immunosuppression induced by UVB irradiation.
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PMID:Prevention by alpha-difluoromethylornithine of skin carcinogenesis and immunosuppression induced by ultraviolet irradiation. 206 55

UV radiation is a potent DNA damaging agent and a known inducer of skin cancer in experimental animals. There is excellent scientific evidence to indicate that most non-melanoma human skin cancers are induced by repeated exposure to sunlight. UV radiation is unique in that it induces DNA damage that differs from the lesions induced by any other carcinogen. The prevalence of skin cancer on sun-exposed body sites in individuals with the inherited disorder XP suggests that defective repair of UV-induced DNA damage can lead to cancer induction. Carcinogenesis in the skin, as elsewhere, is a multistep process in which a series of genetic and epigenetic events leads to the emergence of a clone of cells that have escaped normal growth control mechanisms. The principal candidates that are involved in these events are oncogenes and tumor suppressor genes. Oncogenes display a positive effect on transformation, whereas tumor suppressor genes have an essentially negative effect, blocking transformation. Activated ras oncogenes have been identified in human skin cancers. In most cases, the mutations in the ras oncogenes have been localized to pyrimidine-rich sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. The finding that activation of ras oncogenes in benign and self-regressing keratoacanthomas in both humans and in animals indicates that they play a role in the early stages of carcinogenesis (Corominas et al., 1989; Kumar et al., 1990). Since cancers do not arise immediately after exposure to physical or chemical carcinogens, ras oncogenes must remain latent for long periods of time. Tumor growth and progression into the more malignant stages may require additional events involving activation of other oncogenes or deletion of growth suppressor genes. In addition, amplification of proto-oncogenes or other genes may also be involved in tumor induction or progression. In contrast to the few studies that implicate the involvement of oncogenes in UV carcinogenesis, the role of tumor suppressor genes in UV carcinogenesis is unknown. Since cancer-prone individuals, particularly XP patients, lack one or more repair pathways, one can speculate that DNA repair enzymes would confer susceptibility to both spontaneous and environmentally induced cancers. Another potential candidate that can function as a tumor suppressor gene is the normal c-Ha-ras gene. Spandidos and Wilkie (1988) have shown that the normal c-Ha-ras gene can suppress transformation induced by the mutated ras gene.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular mechanisms of ultraviolet radiation carcinogenesis. 208

The rejection of murine UV-induced skin cancers by normal mice is a striking example of powerful immune surveillance of the normal host against malignant cells. In this study, we show that UV-induced regressor tumors regularly grew progressively and killed mice that were depleted of CD8+ T-cells. Depletion of CD4+ T-cells had no effect, suggesting that CD8+ but not CD4+ T-cells were required for this immune surveillance. To determine whether change in major histocompatibility complex (MHC) class I expression was a frequent event that caused low immunogenicity of tumors or facilitated escape from immune destruction, recently isolated murine tumors of varying degrees of immunogenicity, including highly immunogenic UV-induced regressor, less immunogenic UV-induced progressor, and poorly immunogenic spontaneous progressor tumors, were compared. There was no correlation between the ability of a tumor to grow progressively in a normal immunocompetent host and the level of constitutive class I expression or the level of expression induced in vitro by gamma interferon. (Only 1 of more than 20 progressor tumors analyzed showed complete loss of a MHC class I molecule.) Some progressor variants showed loss of a unique tumor-specific cytotoxic T-lymphocyte-defined antigen, consistent with earlier evidence of antigen loss providing a mechanism for tumor escape. However, most of the host-selected progressor variants retained both MHC class I antigens and the unique tumor antigens that we could detect with cytotoxic T-lymphocyte clones, suggesting that mechanisms other than loss of MHC class I or of the unique target antigen may be involved in escape of some tumors from a highly effective CD8-dependent host surveillance.
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PMID:Major histocompatibility complex class I and unique antigen expression by murine tumors that escaped from CD8+ T-cell-dependent surveillance. 211 81

Mice heterozygous for repeated epilation mutation (Er) have cutaneous abnormalities that result in repeated loss of hair. Skin papillomas and carcinomas occur spontaneously in such Er/+ mice. BALB/c mice are generally resistant to induced skin cancers. We investigated whether Er/+ heterozygous mice of BALB/c genetic background exhibit increased susceptibility to spontaneous and induced skin tumors. Although none of the Er/+ CXB(N5) mice spontaneously developed skin tumors, they exhibited increased sensitivity to the development of skin papillomas induced by an initiation-promotion regimen. Er/+ mice developed papillomas after 20 micrograms DMBA initiation in the absence of TPA promotion, but the same dose of DMBA was subtumorigenic in +/+ (sibling) mice. Although 15 weeks of TPA promotion resulted in similar tumor susceptibilities, tumor latencies and tumor frequencies in the 2 groups of initiated mice, the papillomas were qualitatively different. Er/+ mice developed more papillomas of the delayed promoter-independent type, which occur after termination of promotion. In contrast, +/+ mice developed more promoter-dependent papillomas, which regress after termination of promotion. Therefore Er/+ mice had a significantly higher number of papillomas than +/+ mice at the termination of the experiment. These results suggest that Er-mutation-induced skin defects not only lead to the repeated loss of hair, but also influence the mode of development of skin papillomas from carcinogen-initiated cells.
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PMID:Increased sensitivity to two-stage skin carcinogenesis of mice heterozygous for the repeated epilation mutation (Er). 212 51

Studies over the past two decades have established that exposure to ultraviolet radiation (UVR) has profound effects on immunity. Most of this work was done in animal models with limited data from human studies. Exposure to UVR inhibits the induction of contact hypersensitivity in mice systemically at high doses and locally at low doses, associated with the appearance of transferable T suppressor cells. In some strains of mice, chronic UVR exposure results in the occurrence of highly immunogenic cutaneous malignancies which are rejected upon transplantation to syngeneic recipients. However, within the primary host the tumor is protected from destruction, at least in part, by the appearance of T suppressor cells. Syngeneic animals exposed to large doses of UVR also permit the growth of these transplanted tumors and this phenomenon also results, at least in part, from the presence of suppressor cells. Interestingly, these suppressor cells appear to recognize UVR-induced regressor tumors as a class within a given mouse strain, suggesting that they recognize shared determinants. The mechanisms of these examples of UVR-induced immunosuppression are not completely clear, but perhaps relate to changes in Langerhans cell function and/or epidermal cell release of cytokines induced by UVR. Exposure to UVR in vitro alters the ability of epidermal cells and Langerhans cells to present some antigens. Keratinocytes alter their secretion of specific cytokines after exposure to UVR and are induced to produce immunosuppressive factors. Immunosuppressed patients also have increased rates of skin cancer, suggesting immunologic involvement in regulation of cutaneous oncogenesis in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ultraviolet radiation effects on immunologic function. 215 Sep 17

Exposure to ultraviolet (UV) radiation has been well correlated with skin cancer incidence. Long wave UV radiation (320-400 nm, UVA) is a major component of natural sunlight and cosmetic tanning 'salon' light, and has been shown not only to damage DNA and to act as a complete carcinogen, but also to promote ultraviolet B (280-320 nm, UVB) carcinogenesis. The mechanism by which the latter occurs is unknown, but it is believed to be related to the inflammation and irritation which results from UV exposure. In order to examine the possibility that UVA stimulates the same signalling pathway as do the phorbol esters, a class of much more thoroughly characterized skin tumor promoters, we exposed cells in culture to UVA radiation and measured cellular responses related to protein kinase C (PKC) activation. The data presented here demonstrate that a low, physiologic dose of UVA inhibits epidermal growth factor binding and increases PKC activity in cultured mammalian fibroblasts. The increase in cytosolic activity is not completely translocated to the membrane, and can be partially suppressed by puromycin and cycloheximide but not by actinomycin D. These observations are the first evidence to suggest that a protein which has been strongly linked to chemical tumor promotion may also be a critical mediator for UV-induced promotion. The response of cells to UVA is also unique, in that it does not cause a 12-O-tetradecanoyl phorbol-13-acetate-like rapid redistribution of PKC activity followed by down regulation.
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PMID:Induction of protein kinase C activity by ultraviolet radiation. 215 38

The human gene ERCC-3 specifically corrects the defect in an early step of the DNA excision repair pathway of UV-sensitive rodent mutants of complementation group 3. The predicted 782 amino acid ERCC-3 protein harbors putative nucleotide, chromatin, and helix-turn-helix DNA binding domains and seven consecutive motifs conserved between two superfamilies of DNA and RNA helicases, strongly suggesting that it is a DNA repair helicase. ERCC-3-deficient rodent mutants phenotypically resemble the human repair syndrome xeroderma pigmentosum (XP). ERCC-3 specifically corrects the excision defect in one of the eight XP complementation groups, XP-B. The sole XP-B patient presents an exceptional conjunction of two rare repair disorders: XP and Cockayne's syndrome. This patient's DNA contains a C----A transversion in the splice acceptor sequence of the last intron of the only ERCC-3 allele that is detectably expressed, leading to a 4 bp insertion in the mRNA and an inactivating frameshift in the C-terminus of the protein. Because XP is associated with predisposition to skin cancer, ERCC-3 can be considered a tumor-preventing gene.
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PMID:A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome. 216 79

This article discusses some of the pitfalls and disadvantages of Mohs micrographic surgery for the excision of skin cancer. These include (1) frozen section quality; (2) interpretation of frozen sections; (3) holes in fragmented tissue margins; (4) tissue orientation problems; (5) excessively narrow or wide margins; (6) transection of the tumor itself; (7) problems with multifocal tumor; and (8) the tedious, time-consuming nature of the procedure. Despite these problems, the importance of the procedure in the treatment of cutaneous neoplasms should not be underestimated.
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PMID:Pitfalls of Mohs micrographic surgery. 218 Sep 98


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