RESUMEN
PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
Asunto(s)
Ataxia Telangiectasia , Melanoma , Proteínas de la Ataxia Telangiectasia Mutada/genética , Australia , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Melanoma/genéticaRESUMEN
The sensitivity of soil carbon to warming is a major uncertainty in projections of carbon dioxide concentration and climate. Experimental studies overwhelmingly indicate increased soil organic carbon (SOC) decomposition at higher temperatures, resulting in increased carbon dioxide emissions from soils. However, recent findings have been cited as evidence against increased soil carbon emissions in a warmer world. In soil warming experiments, the initially increased carbon dioxide efflux returns to pre-warming rates within one to three years, and apparent carbon pool turnover times are insensitive to temperature. It has already been suggested that the apparent lack of temperature dependence could be an artefact due to neglecting the extreme heterogeneity of soil carbon, but no explicit model has yet been presented that can reconcile all the above findings. Here we present a simple three-pool model that partitions SOC into components with different intrinsic turnover rates. Using this model, we show that the results of all the soil-warming experiments are compatible with long-term temperature sensitivity of SOC turnover: they can be explained by rapid depletion of labile SOC combined with the negligible response of non-labile SOC on experimental timescales. Furthermore, we present evidence that non-labile SOC is more sensitive to temperature than labile SOC, implying that the long-term positive feedback of soil decomposition in a warming world may be even stronger than predicted by global models.
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Carbono/metabolismo , Efecto Invernadero , Suelo/análisis , Temperatura , Atmósfera/química , Brasil , Dióxido de Carbono/metabolismo , Modelos Teóricos , Microbiología del Suelo , Factores de Tiempo , Árboles/fisiologíaRESUMEN
The inferior olive (IO) is a required component of neural circuits controlling the classical conditioning of eyeblink responses. Previous reports indicated that lesioning or inactivating the IO abolishes conditioned eyeblinks (CRs), but there was disagreement regarding the timing of the CR performance deficit. As a result, it was not clear whether IO inactivation produces unlearning of CRs or a non-specific dysfunction of cerebellar circuits. Since most of these studies used methods that could block unrelated axons passing through the IO region, additional experiments are required to further elucidate IO function, using inactivating agents that act selectively on cell bodies. In the present study, the IO was inactivated using the glutamate receptor antagonist DGG and the GABA-A receptor agonist muscimol in rabbits performing well-learned CRs. Effects of inactivating the IO on CR expression and on neuronal activity in the anterior cerebellar interposed nucleus (IN) were examined. We found that either blocking excitatory glutamate inputs or activating inhibitory GABA inputs to the IO abolished CRs. This effect occurred with variable delay following drug injections. Additional experiments, in which post-injection testing was delayed to allow for drug diffusion, revealed invariably immediate suppression of CRs. This demonstrated that suppressing IO activity using DGG or muscimol does not induce unlearning of CRs. Single-unit recording during DGG injections revealed that CR suppression was paralleled by a dramatic suppression of IN neuronal activity. We concluded that inactivating the rostral parts of the IO complex abolishes CRs by producing a tonic malfunction of cerebellar eyeblink conditioning circuits.
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Cerebelo/fisiología , Condicionamiento Palpebral/fisiología , Extinción Psicológica/fisiología , Vías Nerviosas/fisiología , Núcleo Olivar/fisiología , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Cerebelo/citología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Condicionamiento Palpebral/efectos de los fármacos , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Extinción Psicológica/efectos de los fármacos , Agonistas del GABA/farmacología , Masculino , Muscimol/farmacología , Vías Nerviosas/citología , Vías Nerviosas/efectos de los fármacos , Neuronas/fisiología , Conejos , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/fisiologíaRESUMEN
Mutations in the CDKN2A (p16INK4a) tumour suppressor gene on chromosome 9p21 are associated with inherited predisposition to melanoma, yet some 9p-linking hereditary melanoma families show no mutations in this gene. Splicing of CDKN2A exons 2 and 3 to an alternative first exon produces a transcript (p16beta) encoding a protein with cell cycle regulatory properties. We have analysed allele-specific expression levels of both the p16INK4a and p16beta transcripts in B-lymphoblastoid cells from 18 members of hereditary melanoma kindreds including four unrelated control individuals. In 15 of the 18 individuals examined, steady-state levels of each transcript either originated equally from each parental chromosome, or one parental chromosome was dominant for both transcripts. However, in three affected members of two 9p-linking hereditary melanoma kindreds, without exonic CDKN2A mutations, this pattern of coordinate expression was disrupted. In these individuals there was underexpression of the p16beta transcript, relative to the p16INK4a transcript, from the chromosome segregating with disease susceptibility. Loss of coordinate expression of the p16INK4a and p16beta transcripts may be an alternative genetic basis for melanoma susceptibility in certain 9p-linking kindreds.
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Proteínas Portadoras/genética , Melanoma/genética , Mutación , Transcripción Genética , Empalme Alternativo , Linfocitos B/patología , Secuencia de Bases , Proteínas Portadoras/metabolismo , Cromosomas Humanos Par 9 , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Polimorfismo Genético , Análisis de Secuencia de ADNRESUMEN
Recent studies have implicated chromosome 9p21-22 as a location for a gene involved in cutaneous melanoma (CM). Deletion mapping in 35 matched tumour-constitutional DNA pairs from metastatic melanomas (including one melanoma cell line) and one dysplastic naevus has been performed using six short tandem repeat polymorphic (STRP) markers (D9S157-D9S162-IFNA-D9S171-DS9126-D9S10 4 ) which span approximately 19 cM across the 9p21-22 region. Both heterozygous and homozygous deletions were observed across the region in melanomas from both sporadic and familial cases. Overall 57% (20/35) of the samples displayed some form of loss. A deletion map identifies two areas of common loss either side of the interferon gene cluster. Familial CM has previously been shown to link to the more proximal of these regions. The deleted region distal to IFNA has not been previously described in melanoma. The results imply the involvement of more than one tumour suppressor gene on 9p in CM.
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Cromosomas Humanos Par 9 , Eliminación de Gen , Melanoma/genética , Neoplasias Cutáneas/genética , Mapeo Cromosómico/métodos , Genes Supresores , Heterocigoto , Homocigoto , HumanosRESUMEN
CDKN2 has been implicated as a melanoma susceptibility gene in some kindreds with a family history of this disease. Mutation analysis of CDKN2 in 17 familial melanoma Australian kindreds revealed a paucity of exon mutations and none of the previously described disease-related mutations. One novel germline mutation was found in exon one, Arg24Pro, which segregates with melanoma in 1/17 kindreds. Two previously described polymorphisms, Ala148Thr and a base change at nucleotide 540 were detected and one novel polymorphism in the untranslated region of exon 3 (nucleotide 580) was also found. Together with other recent reports, these findings provide support for CDKN2 as a susceptibility locus for familial melanoma but suggest that other loci are involved in some hereditary melanoma kindreds.
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Proteínas Portadoras/genética , Melanoma/genética , Australia , Secuencia de Bases , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Cartilla de ADN , Exones , Femenino , Eliminación de Gen , Mutación de Línea Germinal , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Mutación PuntualRESUMEN
Cytogenetic and allelic deletion studies have indicated that the loss of distal chromosome 10q may be a frequent and early event in melanoma tumorigenesis. We have studied nine polymorphic markers spanning 56 cM of this region in 27 advanced melanomas and find that half exhibited loss of the entire region, but none had more limited deletions. Because all these tumors had a codeletion of 9p, the 10q deletion event is likely to impair a pathway other than the cyclin-dependent kinase-mediated phosphorylation of the retinoblastoma protein.
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Deleción Cromosómica , Cromosomas Humanos Par 10 , Melanoma/secundario , Neoplasias Cutáneas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Humanos , Melanoma/genéticaRESUMEN
Nitrogen (N) limits plant growth in many terrestrial ecosystems, potentially constraining terrestrial ecosystem response to elevated CO2. In this study, elevated CO2 stimulated gross N mineralization and plant N uptake in two annual grasslands. In contrast to other studies that have invoked increased C input to soil as the mechanism altering soil N cycling in response to elevated CO2, increased soil moisture, due to decreased plant transpiration in elevated CO2, best explains the changes we observed. This study suggests that atmospheric CO2 concentration may influence ecosystem biogeochemistry through plant control of soil moisture.
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Solitary or multifocal pulmonary pseudolymphoma developed in two men and two women between 59 and 76 years of age. The lesions were detected incidentally in three patients and following a respiratory infection in the fourth. Follow-up radiographs and chest CT revealed gradual expansion of the opacities without cavitation, calcification, or pleural involvement. Histopathologic sections from open lung biopsies or resected segments showed dense alveolar and peribronchial infiltration by numerous mature lymphocytes and plasma cells surrounding reactive lymphoid follicles with true germinal centers. Their benign nature was confirmed by immunofluorescent studies showing polyclonal cell populations. No recurrence or malignant change occurred during 4- to 9-year periods of observation. The clinical and radiologic features of pulmonary pseudolymphoma are presented with a brief review of 54 previously reported cases.
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Neoplasias Pulmonares , Linfoma , Anciano , Biopsia con Aguja , Diagnóstico Diferencial , Femenino , Células Gigantes/patología , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Linfocitos/patología , Linfoma/diagnóstico por imagen , Linfoma/patología , Masculino , Persona de Mediana Edad , Células Plasmáticas/patología , Tomografía Computarizada por Rayos XRESUMEN
Osteoporosis has recently become a concern in both the medical and lay communities. Osteoporosis may be defined as a decrease in bone mass with maintenance of normal bone composition. The increase in bone fragility results in an increased incidence of fractures. The disease most commonly affects postmenopausal women, particularly Caucasians. It is estimated that 1.2 million fractures per year can be attributed to osteoporosis. These fractures cost the health care system approximately $18.1 billion per year. Given the magnitude of the health and attendant financial problems, osteoporosis deserves the attention of clinicians and researchers. This article will deal with the pathophysiologic processes, techniques for bone mineral determination, therapeutic regimens and the advisability of mass screening. The relationship between bone mineral content and fracture risk has not been clearly defined. If every American woman between the ages of 40 and 54 years were given a single bone mineral screening examination, the cost would be approximately $187.5 million/year. At this price and in the absence of accepted treatment programs, it does not seem prudent for radiologists or other physicians to recommend expensive mass screening.
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Osteoporosis , Anciano , Femenino , Humanos , Osteoporosis/diagnóstico por imagen , Osteoporosis/economía , Radiografía , Problemas Sociales , Estados UnidosRESUMEN
BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.
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Genes p16 , Heterocigoto , Melanoma/genética , Mutación , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Adulto , Australia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Europa (Continente) , Femenino , Color del Cabello , Humanos , Masculino , Nevo/complicaciones , Nevo/genética , América del Norte , Fenotipo , Medición de Riesgo , Factores de Riesgo , Pigmentación de la Piel , Quemadura Solar/complicaciones , Población Blanca/genéticaRESUMEN
Each uroradiologic procedure performed in the pre- and postoperative evaluation of the child undergoing undiversion contributes unique information. Function and anatomy of both the upper and lower urinary tracts must be carefully assessed. If the immediate postoperative studies show that the undiversion has been successful, the patient should be monitored yearly with excretory urography. If urinary tract symptoms develop, a more extensive radiographic evaluation (voiding cystourethrography, excretory urography, scintigraphy) may be warranted.
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Complicaciones Posoperatorias/diagnóstico por imagen , Derivación Urinaria/métodos , Niño , Humanos , Cuidados Preoperatorios , UrografíaRESUMEN
Between January and March 1986, 117 wives of insulation workers exposed to asbestos were screened by means of chest radiography, pulmonary function testing, and a detailed questionnaire. The final study group included 93 women over 40 years of age. Eighteen of these (19.4%) demonstrated pleural changes consistent with asbestos exposure, including pleural plaque (88.9%), diaphragm plaque (27.8%), pleural calcification (16.6%), and diffuse pleural thickening (5.5%). In statistical correlation between the groups with normal and abnormal radiographs, the only factor that proved significant was the year of first exposure (the duration of the latent period). Finally, radiographs of the husbands were compared for 17 of the 18 wives with radiographic abnormalities. Fourteen of the husbands (82%) demonstrated more severe radiographic changes than their wives.
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Asbestosis/genética , Pulmón/diagnóstico por imagen , Enfermedades Pleurales/genética , Adulto , Asbestosis/diagnóstico por imagen , Exposición a Riesgos Ambientales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Pleurales/diagnóstico por imagen , Radiografía , Pruebas de Función Respiratoria , FumarRESUMEN
Hypertension was noted in 2 children thought to have a solitary kidney after multiple radiological studies. Aggressive diagnostic evaluation allowed for detection of occult contralateral renal tissue. Surgical removal of this parenchyma resulted in a return to normal blood pressure.
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Hipertensión Renal/etiología , Riñón/anomalías , Niño , Femenino , Humanos , Hipertensión Renal/cirugía , Lactante , Riñón/diagnóstico por imagen , Riñón/patología , Masculino , Compuestos Organometálicos , Ácido Pentético , Cintigrafía , Pentetato de Tecnecio Tc 99m , UrografíaRESUMEN
We explored how responses of two populations variable in grazing tolerance provide feedbacks to nutrient supply by controlling carbon supply to soil heterotrophs. The study focused on differences in production and carbon and nitrogen allocation patterns between the two populations. The grazing-tolerant population, or on-colony population, is found on intensively grazed prairie dog colonies, and a grazing-intolerant population, the off-colony population, is found in uncolonized grasslands. Equations describing the production and allocation responses to defoliation for the two ecotypes described were incorporated into CENTURY, a nutrientcycling simulation model. Simulations showed an increase in plant production that paralleled increases in net nitrogen mineralization. Production was greater with grazing and was maintained at higher grazing intensities for the on-colony than the off-colony population. Differences between the populations provided important controls over nitrogen losses. Feedbacks between plant responses to grazing and nitrogen cycling accounted for increased nitrogen availability with grazing. These feedbacks were more important determinants of ecosystem function than were fertilization effects of urine and feces deposition. The simulation results suggest that ecosystem function may be sensitive to physiological differences in population responses to periodic disturbances like herbivory.
RESUMEN
The INK4a/ARF locus encodes two cell cycle regulatory proteins, the cyclin-dependent kinase inhibitor, p16(INK4a), and the p53 activator, p14(ARF). Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Many of these mutations specifically impair p16(INK4a), whereas mutations uniquely targeting p14(ARF) are rare. Nevertheless, the importance of p14(ARF) has not been excluded because more than 40% of INK4a/ARF alterations affect p16(INK4a) and p14(ARF). We now report that p14(ARF) is functionally impaired in melanoma kindreds carrying INK4a/ARF mutations. Of the seven INK4a/ARF mutations tested, three altered the subcellular distribution of p14(ARF) and diminished the ability of p14(ARF) to activate the p53 pathway. This work establishes the importance of p14(ARF) in melanoma predisposition.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Predisposición Genética a la Enfermedad , Melanoma/genética , Mutación Missense , Proteína p14ARF Supresora de Tumor/genética , Secuencia de Aminoácidos , Secuencia de Bases , Inhibidor p16 de la Quinasa Dependiente de Ciclina/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , ADN de Neoplasias , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Datos de Secuencia Molecular , Fracciones Subcelulares/metabolismo , Células Tumorales Cultivadas , Proteína p14ARF Supresora de Tumor/química , Proteína p14ARF Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
CDKN2A (9p21) and CDK4 (12q13) have been identified as melanoma susceptibility genes in certain familial melanoma (FM) kindreds. There remain other FM families, however, for which there is little or no evidence for linkage of melanoma to these loci. Other loci may be involved in susceptibility to this malignancy. Chromosome 6 is deleted or rearranged in 66% of melanomas and has been targeted by several studies in an attempt to identify chromosomal regions associated with initiation or progression of melanoma. Previous studies of familial melanoma and chromosome arm 6p reported evidence suggestive of linkage for markers flanking the HLA complex. We have carried out genetic linkage analysis in 14 Australian familial melanoma kindreds using 16 short tandem repeat polymorphism (STRP) markers spanning 6p23-6q27. Analysis by maximum likelihood and non-parametric (affected pedigree member) techniques showed no evidence of linkage of melanoma in this family set to chromosome 6 (two-point Zmax = 0.5 at theta = 0.2 for D6S285). Lod scores > 1.0 were obtained for the loci D6S285, D6S105, D6S265, D6S292, and D6S311 in three individual kindreds but these were insufficiently strong for formal heterogeneity testing to confirm that a chromosome 6-linked subset of families exists. These data imply little or no role for a major chromosome 6 melanoma susceptibility locus; however the possibility of such a locus remains open and warrants further investigation.
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Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Melanoma/genética , Alelos , Australia , ADN/aislamiento & purificación , Heterogeneidad Genética , Genotipo , Haplotipos , Humanos , Funciones de Verosimilitud , Escala de Lod , Linaje , Polimorfismo Genético , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Mutation analysis of two genes involved in melanoma susceptibility (CDKN2A/p16(INK4a) and CDK4) was undertaken in 131 probands with a family history of melanoma. Screening of all three exons of CDKN2A and exon 2 of CDK4 by single-strand conformation polymorphism (SSCP) analysis and/or direct sequencing identified a total of 10 different CDKN2A germline mutations, including 6 not previously described in the germline. All but one has been previously proven to, or is likely to, affect the structure and function of p16(INK4a). The incidence of CDKN2A mutation was 8.4% (11/131), but was significantly higher in families with three or more cases of melanoma (10/66, 15.1%) than in those in which only two relatives were affected (1/65, 1.5%). The incidence of CDKN2A mutation was also higher in families with three or more cases of melanoma and at least one member with multiple primary melanomas (6/19, 31.6%) than in similar families without multiple primary melanomas (4/47, 8.5%). One novel CDK4 variant of uncertain significance was found in a kindred that also carries a CDKN2A mutation. Genes Chromosomes Cancer 25:339-348, 1999.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Quinasas Ciclina-Dependientes/genética , Mutación de Línea Germinal , Melanoma/genética , Neoplasias Primarias Múltiples/genética , Proteínas Proto-Oncogénicas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Análisis por Conglomerados , Quinasa 4 Dependiente de la Ciclina , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
A microtitre adhesion assay has been developed to define parameters affecting the adherence of washed platelets to laminin. Adherence was optimally supported by Mg2+ and was inhibited by Ca2+ and by anti-laminin Fab fragments, but significant adhesion (75-90% of control) was found both in heparinized plasma containing physiological levels of bivalent cations and in plasma anti-coagulated with EGTA. Adherence was unaffected by platelet activation with ADP but was decreased by 50% by treatment with alpha-thrombin (1 unit/ml, 5 min). Adherence was unaffected by monospecific polyclonal antibodies to glycoprotein (GP) Ib and GPIV, and was normal with platelets from two patients with Glanzmann's thrombasthaenia, indicating that GPIb, the GPIIb/IIIa complex and GPIV are not involved in platelet-laminin interaction. Affinity chromatography of Triton-solubilized membranes on laminin-Sepharose followed by elution with 0.2 M-glycine/HCl (pH 2.85) identified a major band with a molecular mass of 67 kDa in the reduced and of 53 kDa in the unreduced form. This protein gave a positive reaction on Western blotting with a monospecific polyclonal antibody raised against the high-affinity laminin receptor isolated from human breast carcinoma tissue. The adhesion of platelets to laminin was inhibited by two monoclonal IgM antibodies specific to the LR-1 domain of the 67 kDa receptor. The binding protein was surface-oriented, as shown by flow cytofluorimetry and by the fact that it could be iodinated in intact platelets, but it was not labelled by the periodate-borotritide procedure, suggesting that it did not contain terminal sialic acid. The laminin-derived peptides Tyr-Ile-Gly-Ser-Arg and Cys-Asp-Pro-Gly-Tyr-Ile-Gly-Ser-Arg-NH2, which constitute a complementary binding domain in laminin for the 67 kDa receptor, themselves supported platelet adhesion, bound to the receptor and inhibited the adhesion of platelets to laminin. In addition, Fab fragments of anti-Tyr-Ile-Gly-Ser-Arg antibody inhibited platelet adhesion to laminin. These results demonstrate that the high-affinity 67 kDa laminin receptor previously identified in a range of normal and transformed cells and its complementary Tyr-Ile-Gly-Ser-Arg binding domain play an important role in the interaction of platelets with laminin.
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Plaquetas/inmunología , Laminina/sangre , Adhesividad Plaquetaria , Receptores Inmunológicos/metabolismo , Secuencia de Aminoácidos , Cromatografía de Afinidad , Citometría de Flujo , Humanos , Cinética , Laminina/inmunología , Datos de Secuencia Molecular , Peso Molecular , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Adhesividad Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/fisiología , Receptores Inmunológicos/aislamiento & purificación , Receptores de LamininaRESUMEN
Malignant melanoma occurs as a familial cancer in 5%-10% of cases where it segregates in a manner consistent with autosomal dominant inheritance. Evidence from cytogenetics, fine-mapping studies of deletions in melanomas, and recent linkage studies supports the location of a human melanoma predisposition gene on the short arm of chromosome 9. We have carried out linkage analysis using the 9p markers IFNA and D9S126 in 26 Australian melanoma kindreds. Multipoint analysis gave a peak lod score of 4.43, 15 cM centromeric to D9S126, although a lod score of 4.13 was also found 15 cM telomeric of IFNA. These data confirm the existence of a melanoma susceptibility gene on 9p and indicate that this locus most probably lies outside of the IFNA-D9S126 interval. No significant heterogeneity was found between families, when either pairwise or multipoint data were analyzed using HOMOG.