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Ernst Gustav Jung - One of the best experts on this subject based on the ideXlab platform.
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DNA repair synthesis following irradiation with 254-nm and 312-nm ultraviolet light is not diminished in fibroblasts from patients with Dysplastic Nevus Syndrome
Journal of Cancer Research and Clinical Oncology, 1995Co-Authors: Heinz Walter Thielmann, Odilia Popanda, Lutz Edler, Axel Böing, Ernst Gustav JungAbstract:The DNA excision repair capacity of 23 primary fibroblast lines from patients with Dysplastic Nevus Syndrome was investigated and DNA repair synthesis (“unscheduled DNA synthesis”) was determined after UV exposure. Seventeen fibroblast lines from normal donors served as controls. The dose/response experiments included up to ten dose levels and two wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial “sunlamp” radiation centering around 312-nm light). For each dose level, silver grains over fibroblast nuclei were counted by visual inspection. Twelve cell lines were also evaluated for both UV wavelength ranges using a new semi-automatic image analyzing system. This system included components for rapid sequential identification of both fibroblast nuclei and silver grains sited above them. Silver grains over 100 nuclei were determined for each UV dose level. Dose/response curves were established and analyzed by linear regression. As a quantitative term for assessing DNA excision repair capacity of a cell line we calculated the linear increase ( G _0) in the number of grains per nucleus, when the UV dose was multiplied by the factor e (i.e. 2.72). The sensitivity of grain detection and resolution ofoverlapping grains was approximately threefold better in visual than in automatic counting, especially when there were more than 70 grains over nuclei. The time recуired for visual conting, however, was tenfold that of automatic counting. The varianceweighted mean G _0 ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 79.1 (±1.8-grains/nucleus, that of fibroblast lines from normal donors was 74.2 (±1.7) grains/nucleus. This difference revealed a slightly better repair capability for cell lines from patients but was at the borderline of detection and, therefore, should not be overinterpreted. From the experimental accuracy achieved by determination of the varianceweighted means of the two groups, we would have been able to detect a difference of 7 and more grains [> 2 x (σ_normal + σ_patients)]. The variance-weighted mean G _o ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 76.4 (±1.4) grains/nucleus, whereas that of fibroblast lines from normal donors was only 66.6 (±1.8) grains/nucleus. This difference was statistically significant and, contrary to expectation, revealed better, not worse post-UV DNA repair capability in cell lines from patients that in those from normal donors. From the experimental accuracy achieved by determination of the variance-weighted means of the two groups, we would have been able to detect a difference of 6.4 or more grains [> 2 x (σ_normal + σ_patients)]. Variation between cell lines belonging to the same group was expressed by the standard deviation. On average, the standard deviation was in the range 18.2–21.1 grains/nucleus. This variation did not reflect experimental inaccuracy but different responses of individual cell lines to UV irradiation. On the basis of our data, we consider the hypothesis that patients with Dysplastic Nevus Syndrome are prone to melanoma development because of a general defect in post-UV DNA repair to be improbable.
Ulrik Ringborg - One of the best experts on this subject based on the ideXlab platform.
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ARTICLES Screening of Germline Mutations in the CDKN2A and CDKN2B Genes in Swedish Families With Hereditary Cutaneous Melanoma
2015Co-Authors: Anton Platz, Johan Hansson, Eva Månsson-brahme, Stig Linder, E Lundqvist, P Sevigny, Ulrik RingborgAbstract:nomas occur in families in which several members are af-fected. The familial predisposition to this disease is often associated with Dysplastic Nevus Syndrome, a condition in which afflicted family members have multiple Dysplastic nevi (atypical moles). The chromosome region 9p21 and markers on chromosomes 1p and 6p have been linked to melanoma susceptibility. The tumor suppressor genes CDKN2A and CDKN2B have been mapped to the 9p21 re-gion, and genetic analyses have revealed the presence of germline CDKN2A alterations in melanoma families. The reported frequencies of such alterations, however, vary among these families. Purpose: The present investigation was carried out to determine the frequencies of CDKN2A and CDKN2B germline gene mutations among members in a population-based cohort of Swedish melanoma families (i.e.
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Monitoring of Kindreds With Hereditary Predisposition for Cutaneous Melanoma and Dysplastic Nevus Syndrome: Results of a Swedish Preventive Program
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2007Co-Authors: Johan Hansson, Mia Bergenmar, Ulrik Ringborg, Per-ake Hofer, Goeran Lundell, Eva Månsson-brahme, Ingrid Synnerstad, Annika Ternesten Bratel, Ann-marie Wennberg, Inger RosdahlAbstract:Purpose To evaluate a program initiated in 1987 by the Swedish Melanoma Study Group aiming to provide preventive surveillance to kindreds with hereditary cutaneous melanoma and Dysplastic Nevus Syndrome. Patients and Methods Overall, 2,080 individuals belonging to 280 melanoma families were followed for 14 years between 1987 and 2001 at 12 participating centers. Data were registered in a central database. Results Among 1,912 skin lesions excised during follow-up, 41 melanomas were removed in 32 individuals. Of these, 15 (37%) were in situ melanomas and 26 (63%) invasive melanomas. The median tumor thickness of invasive melanomas was 0.5 mm. Ulceration was absent in 24 of 26 invasive melanomas (92%) and 12 (46%) lacked vertical growth phase. Compared with melanomas in the general Swedish population, the melanomas identified in these kindreds during follow-up had better prognostic characteristics. All melanomas except one were diagnosed in families with two or more first-degree relatives with melanoma. Diag...
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screening of germline mutations in the cdkn2a and cdkn2b genes in swedish families with hereditary cutaneous melanoma
Journal of the National Cancer Institute, 1997Co-Authors: Anton Platz, Johan Hansson, Eva Manssonbrahme, B Lagerlof, Stig Linder, E Lundqvist, P Sevigny, M Inganas, Ulrik RingborgAbstract:Background: Approximately 10% of human cutaneous melanomas occur in families in which several members are affected. The familial predisposition to this disease is often associated with Dysplastic Nevus Syndrome, a condition in which afflicted family members have multiple Dysplastic nevi (atypical moles). The chromosome region 9p21 and markers on chromosomes 1p and 6p have been linked to melanoma susceptibility. The tumor suppressor genes CDKN2A and CDKN2B have been mapped to the 9p21 region, and genetic analyses have revealed the presence of germline CDKN2A alterations in melanoma families. The reported frequencies of such alterations, however, vary among these families. Purpose: The present investigation was carried out to determine the frequencies of CDKN2A and CDKN2B germline gene mutations among members in a population-based cohort of Swedish melanoma families (i.e., melanoma kindreds). Methods: DNA was prepared from blood samples obtained from 181 individuals belonging to 100 melanoma kindreds. The polymerase chain reaction (PCR) technique, followed by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses, were used to identify the types and frequencies of mutations in exons 1, 1b, 2, and 3 of the CDKN2A gene and in exons 1 and 2 of the CDKN2B gene. Results: CDKN2A gene aberrations were independently identified by both SSCP and nucleotide-sequence analyses. Nucleotide-sequence analysis identified a single point mutation leading to a substitution of leucine for proline in codon 48 of exon 1 in a family with a history of melanoma and several other cancers. A second abnormality, leading to an insertion of an extra arginine residue at codon number 113 of exon 2, was seen in four separate families. The CDKN2A exon-3 coding region had the wild-type sequence in all samples. No germline mutations were found in the alternative exon 1b of the CDKN2A gene or in exons 1 and 2 of the CDKN2B gene. Conclusions: The present investigation demonstrates that CDKN2A germline gene mutations were observed in 7.8% of the 64 Swedish melanoma kindreds that each included at least two firstdegree relatives with melanoma and Dysplastic Nevus Syndrome. No CDKN2A exon 1b or CDKN2B mutations were identified. The critical genes responsible for the inheritance of a susceptibility to develop melanoma among family members in this population have yet to be identified. [J Natl Cancer Inst 1997;89:697-702]
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prevalence of primary acquired melanosis and nevi of the conjunctiva and uvea in the Dysplastic Nevus Syndrome a case control study
Ophthalmology, 1995Co-Authors: Stefan Seregard, Eva Af Trampe, Eva Manssonbrahme, Erik Kock, Mia Bergenmar, Ulrik RingborgAbstract:Purpose: To investigate whether conjunctival and uveal nevi and primary acquired melanosis are more common in individuals with the Dysplastic Nevus Syndrome than in control subjects derived from the general population. Methods: Power calculations were used to determine the sample size. After invitation, 162 individuals with the Dysplastic Nevus Syndrome and 119 control subjects, matched for sex and age but otherwise randomized from the Stockholm county census file, were entered into the study. All individuals were examined in a masked fashion by the same ophthalmologist, and the presence of conjunctival and uveal melanocytic lesions and the iris color, skin type, and hair color of each individual were recorded. Contingency tables and odds ratios were used for statistical evaluation. Results: The proportions of individuals with the Dysplastic Nevus Syndrome featuring primary acquired melanosis of the conjunctiva, or nevi of the iris and choroid were not significantly different from those of control subjects. However, individuals with the Dysplastic Nevus Syndrome appeared to have a more sun-sensitive skin type and a reddish or blond hair color more often than control subjects. Conclusion: In contrast to previous reports, this study suggests that ocular melanocytic lesions are no more common in individuals with the Dysplastic Nevus Syndrome than in the general population. Therefore, this work does not provide support that periodic ophthalmic surveillance of individuals with the Dysplastic Nevus Syndrome for the purpose of detecting conjunctival or uveal melanomas, or their precursors, is meaningful.
Lutz Edler - One of the best experts on this subject based on the ideXlab platform.
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DNA repair synthesis following irradiation with 254-nm and 312-nm ultraviolet light is not diminished in fibroblasts from patients with Dysplastic Nevus Syndrome
Journal of Cancer Research and Clinical Oncology, 1995Co-Authors: Heinz Walter Thielmann, Odilia Popanda, Lutz Edler, Axel Böing, Ernst Gustav JungAbstract:The DNA excision repair capacity of 23 primary fibroblast lines from patients with Dysplastic Nevus Syndrome was investigated and DNA repair synthesis (“unscheduled DNA synthesis”) was determined after UV exposure. Seventeen fibroblast lines from normal donors served as controls. The dose/response experiments included up to ten dose levels and two wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial “sunlamp” radiation centering around 312-nm light). For each dose level, silver grains over fibroblast nuclei were counted by visual inspection. Twelve cell lines were also evaluated for both UV wavelength ranges using a new semi-automatic image analyzing system. This system included components for rapid sequential identification of both fibroblast nuclei and silver grains sited above them. Silver grains over 100 nuclei were determined for each UV dose level. Dose/response curves were established and analyzed by linear regression. As a quantitative term for assessing DNA excision repair capacity of a cell line we calculated the linear increase ( G _0) in the number of grains per nucleus, when the UV dose was multiplied by the factor e (i.e. 2.72). The sensitivity of grain detection and resolution ofoverlapping grains was approximately threefold better in visual than in automatic counting, especially when there were more than 70 grains over nuclei. The time recуired for visual conting, however, was tenfold that of automatic counting. The varianceweighted mean G _0 ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 79.1 (±1.8-grains/nucleus, that of fibroblast lines from normal donors was 74.2 (±1.7) grains/nucleus. This difference revealed a slightly better repair capability for cell lines from patients but was at the borderline of detection and, therefore, should not be overinterpreted. From the experimental accuracy achieved by determination of the varianceweighted means of the two groups, we would have been able to detect a difference of 7 and more grains [> 2 x (σ_normal + σ_patients)]. The variance-weighted mean G _o ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 76.4 (±1.4) grains/nucleus, whereas that of fibroblast lines from normal donors was only 66.6 (±1.8) grains/nucleus. This difference was statistically significant and, contrary to expectation, revealed better, not worse post-UV DNA repair capability in cell lines from patients that in those from normal donors. From the experimental accuracy achieved by determination of the variance-weighted means of the two groups, we would have been able to detect a difference of 6.4 or more grains [> 2 x (σ_normal + σ_patients)]. Variation between cell lines belonging to the same group was expressed by the standard deviation. On average, the standard deviation was in the range 18.2–21.1 grains/nucleus. This variation did not reflect experimental inaccuracy but different responses of individual cell lines to UV irradiation. On the basis of our data, we consider the hypothesis that patients with Dysplastic Nevus Syndrome are prone to melanoma development because of a general defect in post-UV DNA repair to be improbable.
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fibroblasts derived from patients with Dysplastic Nevus Syndrome are not more sensitive towards 254 nm and 312 nm ultraviolet light than fibroblasts from normal donors
Journal of Cancer Research and Clinical Oncology, 1991Co-Authors: Heinz Walter Thielmann, Lutz Edler, Angelika Brucker, Ernst G. JungAbstract:DNA repair capacity of 18 fibroblast strains from patients with Dysplastic Nevus Syndrome, 5 of them with malignant melanoma, was investigated and their colony-forming ability (D 0) after UV exposure was determined as a measurement of this. Seventeen fibroblast strains from normal donors served as controls. The dose/ response experiments included up to 11 dose levels and two UV wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial “sunlamp” radiation centering around 312-nm light). The exponential segments of the dose/response curves were analysed by linear regression and the negative reciprocals of the regression coefficients,D 0, were calculated for each cell strain and each wavelength range. When comparingD 0 values of individual cell strains from patients with and without melanomas with the mean value for all normal donors, only 4 out of 18 showed increased sensitivity towards UV-B. This difference, however, was not statistically significant. On the contrary, weighted-meanD 0 values for fibroblast strains from patients with and without melanoma were found to be slightly but significantly higher than those for normal donors (significance level: 5%), indicating that cell strains from these patients were less sensitive to UV light (UV-C and UV-B) of both wavelength. This result, which on the basis of current literature data is somewhat unexpected, holds true within the limits of experimental accuracy of ±12%.
Ernst G. Jung - One of the best experts on this subject based on the ideXlab platform.
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fibroblasts derived from patients with Dysplastic Nevus Syndrome are not more sensitive towards 254 nm and 312 nm ultraviolet light than fibroblasts from normal donors
Journal of Cancer Research and Clinical Oncology, 1991Co-Authors: Heinz Walter Thielmann, Lutz Edler, Angelika Brucker, Ernst G. JungAbstract:DNA repair capacity of 18 fibroblast strains from patients with Dysplastic Nevus Syndrome, 5 of them with malignant melanoma, was investigated and their colony-forming ability (D 0) after UV exposure was determined as a measurement of this. Seventeen fibroblast strains from normal donors served as controls. The dose/ response experiments included up to 11 dose levels and two UV wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial “sunlamp” radiation centering around 312-nm light). The exponential segments of the dose/response curves were analysed by linear regression and the negative reciprocals of the regression coefficients,D 0, were calculated for each cell strain and each wavelength range. When comparingD 0 values of individual cell strains from patients with and without melanomas with the mean value for all normal donors, only 4 out of 18 showed increased sensitivity towards UV-B. This difference, however, was not statistically significant. On the contrary, weighted-meanD 0 values for fibroblast strains from patients with and without melanoma were found to be slightly but significantly higher than those for normal donors (significance level: 5%), indicating that cell strains from these patients were less sensitive to UV light (UV-C and UV-B) of both wavelength. This result, which on the basis of current literature data is somewhat unexpected, holds true within the limits of experimental accuracy of ±12%.
Heinz Walter Thielmann - One of the best experts on this subject based on the ideXlab platform.
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DNA repair synthesis following irradiation with 254-nm and 312-nm ultraviolet light is not diminished in fibroblasts from patients with Dysplastic Nevus Syndrome
Journal of Cancer Research and Clinical Oncology, 1995Co-Authors: Heinz Walter Thielmann, Odilia Popanda, Lutz Edler, Axel Böing, Ernst Gustav JungAbstract:The DNA excision repair capacity of 23 primary fibroblast lines from patients with Dysplastic Nevus Syndrome was investigated and DNA repair synthesis (“unscheduled DNA synthesis”) was determined after UV exposure. Seventeen fibroblast lines from normal donors served as controls. The dose/response experiments included up to ten dose levels and two wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial “sunlamp” radiation centering around 312-nm light). For each dose level, silver grains over fibroblast nuclei were counted by visual inspection. Twelve cell lines were also evaluated for both UV wavelength ranges using a new semi-automatic image analyzing system. This system included components for rapid sequential identification of both fibroblast nuclei and silver grains sited above them. Silver grains over 100 nuclei were determined for each UV dose level. Dose/response curves were established and analyzed by linear regression. As a quantitative term for assessing DNA excision repair capacity of a cell line we calculated the linear increase ( G _0) in the number of grains per nucleus, when the UV dose was multiplied by the factor e (i.e. 2.72). The sensitivity of grain detection and resolution ofoverlapping grains was approximately threefold better in visual than in automatic counting, especially when there were more than 70 grains over nuclei. The time recуired for visual conting, however, was tenfold that of automatic counting. The varianceweighted mean G _0 ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 79.1 (±1.8-grains/nucleus, that of fibroblast lines from normal donors was 74.2 (±1.7) grains/nucleus. This difference revealed a slightly better repair capability for cell lines from patients but was at the borderline of detection and, therefore, should not be overinterpreted. From the experimental accuracy achieved by determination of the varianceweighted means of the two groups, we would have been able to detect a difference of 7 and more grains [> 2 x (σ_normal + σ_patients)]. The variance-weighted mean G _o ^v,w of all fibroblast lines from patients with Dysplastic Nevus Syndrome was found to be 76.4 (±1.4) grains/nucleus, whereas that of fibroblast lines from normal donors was only 66.6 (±1.8) grains/nucleus. This difference was statistically significant and, contrary to expectation, revealed better, not worse post-UV DNA repair capability in cell lines from patients that in those from normal donors. From the experimental accuracy achieved by determination of the variance-weighted means of the two groups, we would have been able to detect a difference of 6.4 or more grains [> 2 x (σ_normal + σ_patients)]. Variation between cell lines belonging to the same group was expressed by the standard deviation. On average, the standard deviation was in the range 18.2–21.1 grains/nucleus. This variation did not reflect experimental inaccuracy but different responses of individual cell lines to UV irradiation. On the basis of our data, we consider the hypothesis that patients with Dysplastic Nevus Syndrome are prone to melanoma development because of a general defect in post-UV DNA repair to be improbable.