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1.
Actas Dermosifiliogr ; 103(1): 44-50, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22464597

RESUMEN

BACKGROUND: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. OBJECTIVES: To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. MATERIAL AND METHODS: A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. RESULTS: At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). CONCLUSIONS: The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.


Asunto(s)
Melanoma/genética , Proteínas de Neoplasias/genética , Neoplasias Inducidas por Radiación/genética , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Luz Solar/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Humanos , Masculino , Melanoma/epidemiología , Melanoma/etiología , Melanoma/patología , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/patología , Nevo Pigmentado/epidemiología , Nevo Pigmentado/genética , Fenotipo , Receptor de Melanocortina Tipo 1/fisiología , Análisis de Secuencia de ADN , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , España/epidemiología , Quemadura Solar/epidemiología , Adulto Joven
2.
Actas dermo-sifiliogr. (Ed. impr.) ; 103(1): 44-50, ene.-feb. 2012.
Artículo en Español | IBECS | ID: ibc-101175

RESUMEN

Introducción: El receptor de la melanocortina-1 (MC1R) es un importante determinante del riesgo de melanoma debido a su función en la producción de melanina en respuesta a la exposición solar. Objetivos: Analizar las características fenotípicas e histológicas de los pacientes con melanoma cutáneo portadores de mutaciones del MC1R asociadas a riesgo de melanoma y la influencia de la exposición solar en la aparición del melanoma. Material y métodos: Se incluyeron 224 pacientes diagnosticados de melanoma atendidos en el Servicio de Dermatología del Hospital General Universitario Gregorio Marañón (septiembre de 2004 -diciembre de 2009). Se realizó la secuenciación genómica del ADN del MC1R mediante PCR. Resultados: El 58% presentaba al menos una de las siguientes variantes de MC1R (V60L, V92M, I155T, R160W, D294H, R163Q). Estos pacientes presentaban antecedentes de quemaduras solares (p=0,018), melanomas localizados en áreas de exposición solar intermitente (p=0,019), con predominio del tipo histológico de extensión superficial. Estas asociaciones fueron especialmente significativas en los portadores de las variantes R160W y D294H. Los portadores de R160W presentaron además melanomas asociados a nevus melanocíticos (p=0,028). Conclusión: Los resultados obtenidos sugieren que puede existir una relación entre la expresión de determinadas variantes de MC1R y los hábitos de exposición solar, antecedentes de quemadura y tipo de piel del paciente, así como una mayor frecuencia de melanomas de extensión superficial y melanomas asociados a nevus en portadores de ciertas mutaciones de MC1R (AU)


Background: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. Objectives: To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. Material and methods: A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. Results: At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=0.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=0.028). Conclusions: The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R (AU)


Asunto(s)
Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Melanoma/epidemiología , Melanoma/fisiopatología , Quemadura Solar/complicaciones , Receptor de Melanocortina Tipo 1/genética , Receptor de Melanocortina Tipo 1/inmunología , Neoplasias Cutáneas/diagnóstico , Genómica/métodos , Secuencia de ADN Inestable/genética , Secuencia de ADN Inestable/fisiología , Nevo/diagnóstico , Radiación Solar/efectos adversos , Quemadura Solar/inmunología , Quemadura Solar/patología , Melanoma/genética , Melanoma/inmunología , Hospitales Universitarios/economía , Hospitales Universitarios
3.
Actas Dermosifiliogr ; 103(1): 44-50, 2012.
Artículo en Español | MEDLINE | ID: mdl-21737053

RESUMEN

BACKGROUND: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. OBJECTIVES: To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. MATERIAL AND METHODS: A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. RESULTS: At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). CONCLUSIONS: The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.


Asunto(s)
Melanoma/genética , Melanoma/patología , Mutación , Polimorfismo Genético , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto Joven
4.
Hum Mutat ; 29(9): 1161-7, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18563784

RESUMEN

Human pigmentation appears to be one of the strongest risk factors for malignant melanoma (MM). In humans, there is a long list of genes known to be involved in rare pigmentary disorders such as albinism. These genes explain most of the variation in pigmentation phenotypes seen in human populations, and they do this by regulating the level of synthesis, chemical composition, packaging, and distribution of melanin. This Spanish case-control study included 131 consecutive melanoma patients and 245 control subjects frequency-matched for sex and age. A total of 23 SNPs in six candidate genes (ASP, OCA2, TYR, TYRP1, SILV, and SLC45A) belonging to the pigmentation pathway were genotyped. We found that the variant allele of c.1122C>G, p.Phe374Leu (NCBI dbSNP rs16891982) in SLC45A2 (membrane associated transporter previously known as MATP) was associated with protection from MM (OR, 0.41; 95% CI, 0.24-0.70; P=0.008 after adjustment for multiple testing). This association was validated by the consistent link observed with dark hair, dark skin, dark eye color, and the presence of solar lentigins and childhood sunburns. This is the first time SLC45A2 has been described as a melanoma susceptibility gene in a light-skinned population.


Asunto(s)
Antígenos de Neoplasias/genética , Melanoma/genética , Proteínas de Transporte de Membrana/genética , Pigmentación/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , España/epidemiología
5.
Carcinogenesis ; 27(9): 1930-7, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16679306

RESUMEN

Several components of the Fanconi anaemia (FA) family of proteins allow the formation of the DNA repair complex foci formed by proteins such as BRCA1/2 and RAD51. Because the genes that participate in the DNA repair pathway have been described as low-penetrance breast cancer susceptibility genes, we postulated that variants in FA genes could also be associated with sporadic breast cancer risk. We studied seven SNPs in FANCA, FANCL and FANCD2 in a total of 897 consecutive and non-related sporadic breast cancer cases and 1033 unaffected controls from the Spanish population. We observed a statistically significant association with sporadic breast cancer for the variant rs2272125 (L1366L) located on FANCD2 (OR per allele=1.35; 95% C.I. 1.09-1.67; P=0.005). Both haplotype and diplotype analyses confirmed this association, where one haplotype and pooled diplotypes carrying it were associated with more than 4-fold risk (P=0.007 and P=0.006, respectively). Screening for potential causal variants in FANCD2 was performed, detecting one in the putative promoter region, which is located in a phylogenetically conserved motif with consensus binding sites for some transcriptional factors, suggesting a functional implication. Our data indicate that a relationship between FANCD2 and sporadic breast cancer risk may exist.


Asunto(s)
Neoplasias de la Mama/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/fisiología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Animales , Secuencia de Bases , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Riesgo , España
6.
Int J Cancer ; 119(2): 467-71, 2006 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-16477637

RESUMEN

Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI = 0.58-0.97; p = 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European-American population.


Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Adulto , Anciano , Estudios de Casos y Controles , Sondas de ADN , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Medición de Riesgo , Factores de Riesgo , España/epidemiología
7.
Talanta ; 51(1): 123-9, 2000 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-18967844

RESUMEN

A new micelle-mediated phase separation of metal ions to preconcentrate trace levels of lead as a prior step to its determination by flame atomic spectroscopy has been developed. The methodology is based on the cloud point extraction of lead with PONPE 7.5 in the absence of chelating agent. The chemical variables affecting the sensitivity of the extractive-spectrometric procedure were evaluated in detail, optimised and successfully applied to the determination of lead in saliva samples. Under the optimal conditions, a %E higher than 99.9 was achieved. The proposed method showed linear calibration within the range: 0.6-4 mug ml(-1) Pb(II). The sensitivity was 0.053 mug ml(-1). The method has been applied to the determination of lead in human saliva. The nature of the extracting species as well as the location of lead in the micelle were studied. The analytical performance of the proposed method clearly satisfies the typical requirements for control processes.

8.
Analyst ; 123(9): 1803-7, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10071379

RESUMEN

An extraction methodology based on cloud point phase separation of non-ionic surfactants has been developed for the preconcentration of ppb amounts of gadolinium in urine as a prior step to its determination by an absorptiometric procedure. A method based on the formation of complexes with 2-(3,5-dichloro-2-pyridylazo)-5-dimethylaminophenol was used for the extraction of Gd(III) in the surfactant-rich phase of non-ionic surfactant polyethyleneglycolmono-p-nonylphenylether (PONPE 7.5). The variables affecting the combined preconcentration-absorptiometric method have been evaluated and optimised. The extraction efficiency, linearity, and the limit of detection (LOD) of the method were determined. The optimised procedure was applied to determine total and free Gd(III) contents in real urine samples of patients after the NMR imaging diagnostic examination with contrast agent.


Asunto(s)
Medios de Contraste/metabolismo , Gadolinio/metabolismo , Gadolinio/orina , Humanos , Espectroscopía de Resonancia Magnética
9.
Exp Hematol ; 23(9): 978-85, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7635184

RESUMEN

The exact mechanism of immunosuppression by thalidomide is poorly understood. A common denominator in the pathogenesis of graft-vs.-host disease, graft rejection, reactional lepromatous leprosy, and autoimmune disorders modulated by thalidomide is the activation of T lymphocytes culminating in the synthesis of interleukin-2 (IL-2), the expression of high-affinity IL-2 receptors, and the induction of proliferation. We investigated the effect of thalidomide on the production of IL-2 by the human leukemia cell line Jurkat through induction of IL-2 gene enhancer activity and through the presence of IL-2 in supernatants. beta-galactosidase activity, encoded by a reporter lac z construct and controlled by a transcription factor in thalidomide-treated PMA- and ionomycin-stimulated Jurkat cells, was similar (97 +/- 1.33%; p > 0.1) to non-thalidomide-treated controls at all drug concentrations tested. IL-2 enhancer-driven beta-galactose activity of thalidomide-treated and stimulated cells was also similar to that of untreated controls (p > 0.2). The IL-2 production of activated nontransfected Jurkat cells was gauged by using the IL-2-dependent cell line HT-2 as a readout and by ELISA. Jurkat cells were subcloned by limiting dilution. Bulk cultures and three subclones (J.5.2.5., J.5.2.9., and J.5.3.8.) were assayed at 6, 12, and 24 hours after PHA/PMA-induced stimulation. No inhibitory effect on the IL-2 production by thalidomide could be detected at any of the drug concentrations tested (5-30 micrograms/mL), whereas 10 to 100 ng/mL of cyclosporine inhibited the IL-2 production by 95 to 100%. In addition, we observed neither inhibition of IL-2-dependent proliferation of HT-2 nor inhibition of PHA-induced proliferation of peripheral mononuclear cells by thalidomide at all drug concentrations used (5-30 micrograms/mL). These results do not support the possibility of a modulatory effect on the immune response by thalidomide via IL-2 production and IL-2 response.


Asunto(s)
Interleucina-2/biosíntesis , Linfocitos/inmunología , Talidomida/farmacología , Células Cultivadas , Células Clonales , Relación Dosis-Respuesta a Droga , Elementos de Facilitación Genéticos , Ensayo de Inmunoadsorción Enzimática , Humanos , Interleucina-2/análisis , Ionomicina/farmacología , Cinética , Leucemia , Activación de Linfocitos , Linfocitos/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Transfección , Células Tumorales Cultivadas , beta-Galactosidasa/análisis , beta-Galactosidasa/biosíntesis
10.
Blood ; 84(8): 2802-10, 1994 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-7522644

RESUMEN

Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1-11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin-5 gene.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Antígenos de Histocompatibilidad Clase II/metabolismo , Fragmentos de Péptidos/uso terapéutico , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Trasplante de Médula Ósea , Femenino , Antígenos H-2/análisis , Antígenos H-2/inmunología , Histocompatibilidad , Interleucina-5/genética , Ratones , Datos de Secuencia Molecular , Proteína Básica de Mielina/química , Proteína Básica de Mielina/uso terapéutico , Ovalbúmina/química , Ovalbúmina/uso terapéutico , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos Nucleicos , Bazo/trasplante , Linfocitos T/inmunología
11.
Exp Hematol ; 21(13): 1673-9, 1993 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7694868

RESUMEN

Cytokine-induced killer (CIK) cells are highly efficient cytotoxic effector cells capable of lysing tumor cell targets. Cultures of human CIK cells have been shown to have enhanced cytotoxicity and to proliferate more rapidly than lymphokine activated killer (LAK) cells by both in vitro and in vivo studies. In this report, we have further characterized the phenotype of CIK cells and explored the molecular structures involved in CIK-mediated cell lysis of tumor target cells. The dominant cell phenotype in CIK cell cultures expresses the alpha, beta T cell receptor (TCR-alpha/beta). In addition, CD56 is expressed on the main effector cell on a per-cell basis. Interestingly, the total number of CD56+ cells increases more than 1000-fold during the generation of CIK cells, mainly due to expansion of CD56+ cells coexpressing CD3. The higher lytic activity of CIK cells as compared to LAK cells is mainly due to the higher proliferation of CD3+CD56+ cells and to the cytotoxic activity of TCR-alpha/beta+ cells in CIK cell cultures. CIK-mediated cellular lysis is non-major histocompatibility antigen (MHC) restricted. The cytotoxic effect of CIK cells against tumor targets is blocked by antibodies directed against lymphocyte function-associated antigen (LFA-1) and its counter receptor, intercellular adhesion molecule-1 (ICAM-1).


Asunto(s)
Citocinas/farmacología , Citotoxicidad Inmunológica , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Animales , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Complejo CD3/análisis , Antígeno CD56 , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Linfoma de Células B , Ratones , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/análisis , Células Tumorales Cultivadas
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