Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Reconstitución Inmune , Piel/inmunología , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Estudios Prospectivos , Inmunología del Trasplante , Trasplante HomólogoRESUMEN
BACKGROUND: Gene expression profiling of melanoma and nevic tissue has demonstrated that pleiotrophin (PTN) is significantly overexpressed in human melanomas. METHODS: To further evaluate PTN expression in melanocytic lesions, protein immunohistochemistry was performed on the spectrum of melanocytic lesions. RESULTS: Melanocytic nevi were consistently negative (n=58). In contrast, the great majority of metastatic melanomas were positive (33/34, 97%). The analysis of 34 primary melanomas demonstrated PTN positivity in 20 lesions while 14 lesions were negative. Within the primary melanomas, PTN immunoreactivity was associated with metastasis (p=0.0004) and decreased melanoma-related survival (p=0.0444). Univariate analysis of PTN immunoreactivity predicted an increased risk for metastasis (relative risk 9.1, p=0.003). CONCLUSIONS: The results of this study confirm previous gene profiling data showing differential PTN expression between melanocytic nevi and melanomas. In addition, lesional PTN expression is associated with metastatic potential and may be a prognostic factor for melanomas.
Asunto(s)
Proteínas Portadoras/biosíntesis , Citocinas/biosíntesis , Melanoma/metabolismo , Metástasis de la Neoplasia/patología , Nevo Pigmentado/metabolismo , Neoplasias Cutáneas/metabolismo , Adulto , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Melanoma/mortalidad , Melanoma/patología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de SupervivenciaRESUMEN
The earliest events within the peripheral mammalian nervous system that cause herpes simplex virus type 1 (HSV-1) to reactivate from latency are unknown but are highly likely to include altered regulation of cellular transcription factors. Using gene array analysis, we have examined the changes that occur in cellular mRNA levels in mouse trigeminal ganglia following explantation, a stimulus that results in HSV-1 reactivation from latency. We have detected both increased and decreased expression levels of particular cellular transcripts, which include RNAs encoding neuronal factors, transcription factors, and factors involved in the cell cycle. Among the transcription factors that are upregulated is Bcl-3, a coactivator for NFkappaB. We have confirmed these increases in Bcl-3 transcription levels using reverse transcription-PCR and S1 nuclease protection assays. In addition, we have shown Bcl-3 upregulation at the protein level. Importantly, Bcl-3 RNA levels were found to increase specifically in neuronal cells within the trigeminal ganglia. We discuss a potential role for this factor in upregulating ICP0 transcription, which is an important viral event for initiation of HSV-1 reactivation.
Asunto(s)
Herpesvirus Humano 1/fisiología , Sistema Nervioso Periférico/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Activación Viral , Animales , Proteínas del Linfoma 3 de Células B , Western Blotting , Femenino , Perfilación de la Expresión Génica , Herpesvirus Humano 1/genética , Hibridación in Situ , Ratones , Ratones Endogámicos BALB C , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/análisis , Factores de Tiempo , Factores de Transcripción , Regulación hacia Arriba , Latencia del VirusRESUMEN
We report a case of an aggressive digital papillary adenocarcinoma (ADPA) on the right thumb of a 48-year-old white man. Histologic evaluation of the initial biopsy demonstrated features consistent with those proposed for aggressive digital papillary adenoma; however, re-excision of the remaining lesion revealed histologic features consistent with aggressive digital papillary adenocarcinoma. These tumors have a high rate of local recurrence and can metastasize, occasionally resulting in mortality. Our case demonstrates that even if the histologic criteria of aggressive digital papillary adenocarcinoma are met, the lesion may still represent an aggressive digital papillary adenocarcinoma (ADPAca). In agreement with a recent study by Duke et al., this case supports the idea that aggressive digital papillary lesions should be classified as aggressive digital papillary adenocarcinoma.
Asunto(s)
Adenocarcinoma Papilar/patología , Neoplasias de las Glándulas Sudoríparas/patología , Adenocarcinoma Papilar/química , Adenocarcinoma Papilar/cirugía , Adenoma/diagnóstico , Antígeno Carcinoembrionario/análisis , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Queratinas/análisis , Masculino , Persona de Mediana Edad , Proteínas S100/análisis , Neoplasias de las Glándulas Sudoríparas/química , Neoplasias de las Glándulas Sudoríparas/cirugía , Pulgar/patologíaRESUMEN
Annular erythema of Sjögren's syndrome (AE-SS) is believed to be the Asian counterpart of subacute cutaneous lupus erythematosus (SCLE) in white persons. We report the second case of a white person with AE-SS, diagnosed by clinical and serologic findings, as well as the absence of histologic criteria for SCLE. The diagnosis of AE-SS was established by symptoms of xerophthalmia and xerostomia, as well as by examination of skin and salivary gland biopsy specimens. Evaluation showed the presence of anti-Ro(SS-A) and anti-La(SS-B) autoantibody, with the presence of anti-Ro(SS-A) antibody against the 60-kd, but not the 52-kd, epitope, a pattern frequently seen in both the Asians with AE-SS and in white patients with SCLE. Both skin and sicca symptoms were alleviated with combination antimalarial therapy, which included hydroxychloroquine and quinacrine. This case demonstrates that AE-SS can occur in white patients and that the autoantibody profile is similar to that described in Asians with this disease.
Asunto(s)
Eritema/etiología , Síndrome de Sjögren/complicaciones , Anciano , Autoanticuerpos/análisis , Biopsia , Diagnóstico Diferencial , Eritema/inmunología , Femenino , Humanos , Glándulas Salivales/patología , Piel/patología , Población BlancaRESUMEN
Scleromyxedema is a rare systemic disorder characterized by cutaneous sclerosis and papulosis, accompanied by deposition of mucin in the skin and other organs. We describe a case of scleromyxedema in a 62-year-old man. The cutaneous symptoms of the disorder were preceded by episodes of acute central nervous system dysfunction that included mental confusion, hemiparesis, tremor, and migraine. As the cutaneous symptoms progressed, the patient experienced persistent confusion and difficulty concentrating. Therapy with melphalan and plasmapheresis led to complete resolution of the cutaneous symptoms as well as near-resolution of the neurologic symptoms. This is the first report to describe the successful treatment of the cutaneous symptoms of scleromyxedema accompanied by reversal of chronic neurologic dysfunction.
Asunto(s)
Enfermedades del Sistema Nervioso Central/terapia , Erupciones Liquenoides/terapia , Mixedema/terapia , Esclerodermia Sistémica/terapia , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/diagnóstico , Humanos , Erupciones Liquenoides/complicaciones , Erupciones Liquenoides/diagnóstico , Masculino , Persona de Mediana Edad , Mixedema/complicaciones , Mixedema/diagnóstico , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnósticoRESUMEN
We previously demonstrated that precancers (actinic keratoses and dysplasias) and squamous cell carcinomas (SCCs) develop in one quarter of human neonatal foreskins grafted onto recombinase-activating gene-1-knockout mice treated once with 7,12-dimethylbenz[a]anthracene (DMBA) followed by chronic intermediate-range ultraviolet (UV) B light irradiation. The goals of this study were to determine if a longer UVB exposure followed by further observation would increase the number of precancers and invasive cancers and to evaluate whether this model results in changes in p53 expression and cell proliferation similar to those seen in sun-damaged normal skin, actinic keratoses, and SCCs. The treatment consisted of a single dose of DMBA followed by 500 J/m2 UVB radiation administered three times weekly for at least 5 mo. Histologic changes (cysts, hyperplasias, precancers, and/or invasive cancers) were seen in 24 of 25 treated xenografts but not in controls. Ten of 25 grafts (40%) had two or more histological changes, and two human SCCs developed. After seven or more months of UV exposure and a total time from DMBA treatment to killing of 12-18 mo, 83% (15 of 18) of specimens developed squamous precancer or SCC of human origin, and 44% (eight of 18) developed melanocytic hyperplasia or melanoma. The change from moderate dysplasias to SCC required longer UV exposure (median, 11 mo), and 5 mo more observation than did the development of mild dysplasias (median UV exposure, 7 mo; median DMBA to death time, 12 mo). There was a direct correlation between both p53 expression and cell proliferation and the degree of histologic alteration both in squamous epithelial and melanocytic cells.
Asunto(s)
Carcinoma de Células Escamosas/etiología , Melanocitos/efectos de la radiación , Neoplasias Inducidas por Radiación/etiología , Lesiones Precancerosas/etiología , Neoplasias Cutáneas/etiología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , 9,10-Dimetil-1,2-benzantraceno , Adulto , Animales , Antígenos Nucleares , Biomarcadores de Tumor/análisis , Carcinógenos , Carcinoma de Células Escamosas/patología , División Celular/fisiología , Modelos Animales de Enfermedad , Células Epiteliales/efectos de la radiación , Proteínas de Homeodominio/genética , Humanos , Masculino , Melanocitos/patología , Ratones , Neoplasias Inducidas por Radiación/patología , Proteínas Nucleares/biosíntesis , Lesiones Precancerosas/patología , Piel/patología , Neoplasias Cutáneas/patología , Trasplante de Piel , Factores de Tiempo , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
A direct causal relationship between ultraviolet (UV) light in the B range and melanoma development has not been demonstrated in humans; this study aims to establish causality. A total of 158 RAG-1 mice, grafted with human newborn foreskin, were separated into four groups and observed for a median of 10 months: 1) no treatment, 2) a single treatment with 7,12-dimethyl(a)benzanthracene (DMBA), 3) UVB irradiation at 500 J/m2 alone, three times weekly, and 4) a combination of DMBA and UVB. Twenty-three percent of 40 normal human skin grafts treated with UVB only and 38% of 48 grafts treated with the combination of DMBA and UVB developed solar lentigines within 5 to 10 months of treatment. Melanocytic hyperplasia was found in 73% of all UVB-treated xenografts. Histological melanocytic changes resembling lentigo and lentigo maligna were seen in several skin grafts treated with both DMBA and UVB. In one graft of an animal treated with a combination of DMBA and UVB, a human malignant melanoma, nodular type, developed. This experimental system demonstrates that chronic UVB irradiation with or without an initiating carcinogen can induce human melanocytic lesions, including melanoma.
Asunto(s)
Melanocitos/efectos de la radiación , Melanoma/patología , Neoplasias Inducidas por Radiación/patología , Neoplasias Cutáneas/patología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Carcinógenos/toxicidad , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , ADN de Neoplasias/análisis , Humanos , Hiperplasia , Hibridación in Situ , Recién Nacido , Masculino , Melanocitos/efectos de los fármacos , Melanocitos/patología , Melanoma/etiología , Ratones , Ratones Noqueados , Ratones SCID , Neoplasias Inducidas por Radiación/etiología , Inmunodeficiencia Combinada Grave/patología , Piel/efectos de los fármacos , Piel/patología , Neoplasias Cutáneas/etiología , Trasplante de Piel , Trasplante HeterólogoRESUMEN
Risk markers for cancer are genetic or behavioral attributes that are statistically associated with increased incidence of cancer. Risk may be assessed either in case-control studies, or in cohort studies in which individuals with particular attributes are followed and cancer risk is determined by direct observation. Both of these methods have been used to determine the major risk markers for melanoma. The single most important risk marker is the presence on the skin of dysplastic nevi. Dysplastic nevi may be regarded as intermediate lesions of tumor progression, in that approximately 30% of melanomas arise in association with a precursor nevus, which is most commonly dysplastic. However, paradoxically, because they are vastly more numerous than melanoma, most dysplastic nevi are stable lesions that do not progress. Additional important melanoma risk factors include a family and/or personal history of melanoma. A third major category of risk markers includes indicators of acute and chronic exposure to the sun, including freckles, actinic skin damage, and a history of sunburn. Evaluation of these markers in oncological patients and their first-degree relatives can identify a population of individuals whose risk for melanoma ranges from several-fold to more than 100-fold greater than that of random population members. Efforts directed at early diagnosis in these individuals can result in recognition of melanomas in their early, curable stages.
Asunto(s)
Síndrome del Nevo Displásico/epidemiología , Melanoma/epidemiología , Neoplasias Cutáneas/epidemiología , Proteínas Portadoras/genética , Estudios de Casos y Controles , Transformación Celular Neoplásica , Estudios de Cohortes , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Síndrome del Nevo Displásico/genética , Síndrome del Nevo Displásico/patología , Salud de la Familia , Predisposición Genética a la Enfermedad , Humanos , Melanoma/genética , Melanoma/patología , Nevo Pigmentado/epidemiología , Nevo Pigmentado/genética , Nevo Pigmentado/patología , Factores de Riesgo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Quemadura SolarRESUMEN
The quantitation of effort both within and among surgical pathology laboratories is data which is being increasingly sought by physician managers, hospital administrators and managed care organizations. Simple measurement of case numbers fails to adequately represent the work of a laboratory. The complexity of the cases reviewed is likely to explain a significant portion of the variance in the time required to bring a case to final diagnosis. Measures which adequately reflect complexity in surgical pathology cases have not been developed. We have studied a variety of extractable report features and correlated these with the time required for case sign-out. Numbers of slides reviewed and total lines of factual data provided were strong correlates of the time required to complete case review, report construction and verification. Such data suggests that models can be constructed based on data that can be gleaned from case reports and records which will relate such data to actual work time.
Asunto(s)
Patología Quirúrgica/estadística & datos numéricos , Carga de Trabajo , Análisis de Varianza , Femenino , Humanos , Masculino , Análisis y Desempeño de Tareas , Factores de TiempoRESUMEN
MARCKS is a protein kinase C (PKC) substrate which binds calcium/calmodulin and actin, and which has been implicated in cell motility, phagocytosis, membrane traffic, and mitogenesis. MARCKS cycles on and off the membrane via a myristoyl electrostatic switch (McLaughlin, S., and Aderem, A.(1995) Trends Biochem. Sci. 20, 272-276). Here we define the molecular determinants of the myristoyl-electrostatic switch. Mutation of the N-terminal glycine results in a nonmyristoylated form of MARCKS which does not bind membranes and is poorly phosphorylated. This indicates that myristic acid targets MARCKS to the membrane, where it is efficiently phosphorylated by PKC. A chimeric protein in which the N terminus of MARCKS is replaced by a sequence, which is doubly palmitoylated, is phosphorylated by PKC but not released from the membrane. Thus two palmitic acid moieties confer sufficient membrane binding energy to render the second, electrostatic membrane binding site superfluous. Mutation of the PKC phosphorylation sites results in a mutant which does not translocate from the membrane to the cytosol. A mutant in which the intervening sequence between the myristoyl moiety and the basic effector domain is deleted, is not displaced from the membrane by PKC dependent phosphorylation, fulfilling a theoretical prediction of the model. In addition to the nonspecific membrane binding interactions conferred by the myristoyl-electrostatic switch, indirect immunofluorescence microscopy demonstrates that specific protein-protein interactions also specify the intracellular localization of MARCKS.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Proteínas/química , Animales , Secuencia de Bases , Cartilla de ADN/genética , Electroquímica , Humanos , Inmunohistoquímica , Técnicas In Vitro , Datos de Secuencia Molecular , Estructura Molecular , Mutagénesis Sitio-Dirigida , Ácido Mirístico , Ácidos Mirísticos/química , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Proteína Quinasa C/metabolismo , Proteínas/genética , Proteínas/metabolismo , Especificidad por SustratoRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) pneumonia in immunocompromised patients, especially bone marrow transplant recipients, is associated with high mortality. Early diagnosis in these cases is important because antiviral therapy with ribavirin is effective in reducing mortality. CASE: A 45-year-old male with multiple myeloma who underwent autologous peripheral stem cell transplantation subsequently developed bilateral pulmonary infiltrates. A bronchoalveolar lavage specimen demonstrated the cytologic changes associated with RSV pneumonia. Infection with RSV was confirmed by indirect immunofluorescence, enzyme immunoassay and, later, on histology and electron microscopy at autopsy. CONCLUSION: Recognition of the cytologic changes associated with RSV pneumonia in immunodeficient patients can be life saving since this would initiate confirmatory immunologic studies and therapy.
Asunto(s)
Líquido del Lavado Bronquioalveolar/virología , Neumonía Viral/patología , Infecciones por Virus Sincitial Respiratorio/patología , Eosinófilos/patología , Resultado Fatal , Humanos , Cuerpos de Inclusión/patología , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/ultraestructura , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Neumonía Viral/diagnóstico , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Trasplante de Células MadreRESUMEN
We have isolated and characterized a cDNA clone encoding the murine macrophage 68-kDa protein kinase C substrate, which is homologous to the 80- to 87-kDa protein identified by the acronym MARCKS (myristoylated alanine-rich C kinase substrate). The murine MARCKS cDNA clone encodes an acidic protein of 309 amino acids with a calculated molecular weight of 29,661. Transfection of the murine MARCKS gene into TK-L fibroblasts produced a myristoylated protein kinase C substrate that migrated on SDS/PAGE with an apparent molecular mass of 68 kDa. Peptide mapping studies indicated that MARCKS produced by the transfected gene was indistinguishable from the endogenous murine macrophage protein. Comparison of the murine macrophage sequence with the previously published chicken and bovine brain sequences revealed two conserved domains: an N-terminal membrane-binding domain and a phosphorylation domain that also contains calmodulin and actin binding sites. In murine peritoneal macrophages, bacterial lipopolysaccharide increased MARCKS mRNA levels by greater than 30-fold. Multiple MARCKS transcripts were observed and could be accounted for by differential polyadenylylation and incomplete processing. Genomic Southern blot analysis suggested a single MARCKS gene per haploid genome.