RESUMEN
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases.
Asunto(s)
Diagnóstico por Imagen/métodos , Neoplasias Hematológicas/diagnóstico por imagen , Trastornos Mieloproliferativos/diagnóstico por imagen , HumanosRESUMEN
OBJECTIVE: We aimed to examine the general health and intestinal physiology of young and old non-human primates with comparable life histories and dietary environments. DESIGN: Vervet monkeys (Chlorcebus aethiops sabaeus) in stable and comparable social and nutritional environments were selected for evaluation. Health phenotype, circulating cytokines and biomarkers of microbial translocation (MT) were measured (n=26-44). Subsets of monkeys additionally had their intestinal motility, intestinal permeability, and fecal microbiomes characterized. These outcomes document age-related intestinal changes present in the absence of nutritional stressors, which are all known to affect gastrointestinal motility, microbiome, and MT. RESULTS: We found that old monkeys have greater systemic inflammation and poor intestinal barrier function as compared to young monkeys. Old monkeys have dramatically reduced intestinal motility, and all changes in motility and MT are present without large differences in fecal microbiomes. CONCLUSION: We conclude that deteriorating intestinal function is a feature of normal aging and could represent the source of inflammatory burden yet to be explained by disease or diet in normal aging human primate populations. Intestinal changes were seen independent of dietary influences and aging within a consistent environment appears to avoid major microbiome shifts. Our data suggests interventions to promote intestinal motility and mucosal barrier function have the potential to support better health with aging.
Asunto(s)
Envejecimiento/fisiología , Chlorocebus aethiops/fisiología , Microbioma Gastrointestinal , Motilidad Gastrointestinal/fisiología , Inflamación/fisiopatología , Mucosa Intestinal/fisiología , Uniones Estrechas/fisiología , Animales , Biomarcadores/sangre , Citocinas/sangre , Dieta , Femenino , Humanos , MasculinoRESUMEN
Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.
Asunto(s)
Enfermedades de los Perros/terapia , Terapia Genética/métodos , Inmunoterapia Adoptiva/métodos , Linfoma/terapia , Linfoma/veterinaria , ARN Neoplásico/genética , Animales , Células Presentadoras de Antígenos/inmunología , Secuencia de Bases , Antígenos CD40/inmunología , Línea Celular Tumoral , Células Cultivadas , Enfermedades de los Perros/inmunología , Perros , Humanos , Inmunofenotipificación , Activación de Linfocitos , Linfoma/inmunología , Datos de Secuencia Molecular , Receptores CCR7/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología , TransfecciónRESUMEN
Arteriovenous malformations remain a difficult clinical problem. There is very little understanding of the underlying pathogenesis of these lesions, and therapy frequently involves considerable risks with suboptimal outcomes. Recently, a comprehensive description of the angiosomes of the head and neck was completed in the authors' unit. It was noticed that the location of several clinically observed arteriovenous malformations in the head and neck seemed to correspond to the anatomic location of the choke anastomotic zones linking the angiosomes. Therefore, selective clinical angiograms were compared with those from the authors' previously performed fresh cadaver injection studies, in which they defined the angiosomes of the head and neck. In each patient, the location of the arteriovenous malformation corresponded directly to the choke vessel anastomotic zone linking two or more adjacent angiosomes. Clinical and pathologic ramifications of this observation are discussed.
Asunto(s)
Malformaciones Arteriovenosas/patología , Cabeza/irrigación sanguínea , Cuello/irrigación sanguínea , Piel/irrigación sanguínea , Adolescente , Adulto , Angiografía , Arterias/anatomía & histología , Arterias/patología , Malformaciones Arteriovenosas/diagnóstico por imagen , Malformaciones Arteriovenosas/terapia , Niño , Preescolar , Embolización Terapéutica/efectos adversos , Femenino , Humanos , Masculino , Radiografía Intervencional , Venas/anatomía & histología , Venas/patologíaRESUMEN
BACKGROUND: Breast conservation therapy (BCT) offers equivalent survival to modified radical mastectomy in patients with early-stage (I and IIa) breast cancer, but is utilized in less than 50% of eligible patients. While patient demographics have been linked to BCT rates, we suspected that physician influence was a major factor. The purpose of this study was to compare BCT at three affiliated centers staffed by similarly trained surgeons yet serving widely disparate populations, in order to assess the importance of physician influence on the utilization of BCT. METHODS: Tumor registry data were reviewed from 1993 through 1997 at affiliated city/county (CH), university (UH), and private hospitals (PH). Data were analyzed for clinical stage, treatment, and age of patient. RESULTS: The utilization of BCT for stage I and IIa breast cancer is similar at the three hospitals: 45% of patients at CH, 55% of patient at UH, and 57% of patients at PH (P>0.05). Rates of BCT were similar across all patient age groups at all sites. CONCLUSIONS: Similar BCT utilization rates can be achieved despite widely disparate patient populations. The three affiliated hospitals are staffed by surgeons with similar training, and all offer a multidisciplinary approach to breast cancer care. This suggests that physician influence may override patients' socioeconomic issues in providing optimal breast cancer therapy.
Asunto(s)
Neoplasias de la Mama/cirugía , Mastectomía Segmentaria/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Colorado/epidemiología , Femenino , Hospitales de Condado , Hospitales Privados , Hospitales Universitarios , Humanos , Escisión del Ganglio Linfático , Persona de Mediana Edad , Estadificación de Neoplasias , Educación del Paciente como Asunto , Radioterapia Adyuvante , Factores SocioeconómicosAsunto(s)
Prestación Integrada de Atención de Salud , Industria Farmacéutica , Seguro de Servicios Farmacéuticos , Programas Controlados de Atención en Salud , Leyes Antitrust , Conflicto de Intereses , Prestación Integrada de Atención de Salud/legislación & jurisprudencia , Industria Farmacéutica/legislación & jurisprudencia , Humanos , Revisión de Utilización de Seguros , Programas Controlados de Atención en Salud/legislación & jurisprudencia , Servicios Farmacéuticos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents. However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with Li-Fraumeni syndrome (LFS) and 18 strains from normal volunteers. The families include three that are classical LFS families, but in whom no TP53 mutation has been found. In the families with mutations, increased longevity and resistance to low-dose-rate ionizing radiation showed a statistically significant association with the presence of TP53 mutations. However, not all heterozygotes had increased longevity or were radioresistant, and fibroblasts from cancer-affected members of LFS families without TP53 mutations showed no significant increase in either of these end points. In contrast, all mutation-carrying strains showed evidence of genomic instability, expressed as aneuploidy, and accumulated structural chromosome aberrations in up to 100% of cells, usually accompanied by loss of the wild-type TP53 allele, immediately before senescence. Levels of aneuploidy higher than in normal cells were also observed in fibroblasts from families without TP53 mutations, suggesting that chromosome instability is a major factor in determining the cancer proneness of these families.
Asunto(s)
Aberraciones Cromosómicas , Fibroblastos/ultraestructura , Síndrome de Li-Fraumeni/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Fibroblastos/efectos de la radiación , Genes p53 , Mutación de Línea Germinal , Heterocigoto , Humanos , Síndrome de Li-Fraumeni/patología , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
PURPOSE: To investigate whether the good discrimination we previously observed between ataxia-telangiectasia (A-T) heterozygotes and normal donors for induction of chromosome aberrations by X-rays in G2 lymphocytes is also seen in G2 fibroblasts. Also to investigate the G2 radiosensitivity of a patient with the cancer-prone Li-Fraumeni syndrome (LFS) whose fibroblasts are resistant to the lethal effects of radiation. MATERIALS AND METHODS: Fibroblasts were exposed to 0.5 Gy X-rays and harvested for metaphase analysis 90 min later. RESULTS: Four A-T heterozygote cell strains were all more sensitive than seven normal controls. The LFS strain with a germline TP53 mutation was twice as sensitive as the mean control value. CONCLUSIONS: Although chromosomal, radiosensitivity is seen in A-T heterozygotes and LFS cells, the former are radiosensitive and the latter radioresistant to cell killing. Repair defects may predominate in A-T heterozygotes, inadequate genome surveillance in LFS cells.
Asunto(s)
Ataxia Telangiectasia/patología , Cromosomas Humanos/efectos de la radiación , Fibroblastos/ultraestructura , Fase G2/efectos de la radiación , Síndrome de Li-Fraumeni/patología , Tolerancia a Radiación/fisiología , Ataxia Telangiectasia/genética , Aberraciones Cromosómicas , Fibroblastos/efectos de la radiación , Heterocigoto , Humanos , Síndrome de Li-Fraumeni/genéticaRESUMEN
We report the cytogenetic findings in a case of Pleuro-Pulmonary Blastoma of Childhood Type II. This is a rare intrathoracic tumour that can occur in the lungs with up to 25% of cases being extra pulmonary.
Asunto(s)
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Blastoma Pulmonar/genética , Blastoma Pulmonar/patología , Preescolar , Femenino , HumanosRESUMEN
A 6 month old boy presented with bilateral Wilms' tumour. Cytogenetic analysis of the lymphocytes from the patient showed a de novo balanced translocation t(5;6)(q21;q21), which was also present in the tumour material as the sole cytogenetic abnormality. To facilitate the identification of the translocation breakpoints, we have established a lymphoblastoid cell line (MA214L) from the patient which maintains the translocation in culture. We have used Genethon microsatellite markers as sequence tagged sites (STSs) to isolate yeast artificial chromosome (YAC) clones to 5q and 6q from human genomic libraries. Using fluorescence in situ hybridisation (FISH) on metaphase preparations of MA214L, we have physically defined the translocation breakpoints between YAC clones on each chromosome arm. The genetic distance separating the flanking YACs on 6q21 is 3 cM, while that on 5q21 is 4 cM. To date this is the first report of these chromosomal regions being implicated in Wilms' tumourigenesis.
Asunto(s)
Cromosomas Humanos Par 5 , Cromosomas Humanos Par 6 , Translocación Genética , Tumor de Wilms/genética , Fragilidad Cromosómica , Mapeo Cromosómico , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Lactante , MasculinoRESUMEN
Comparative genomic hybridisation has been used to map copy number changes in nine cases of ductal carcinoma in situ of the breast obtained from wax-embedded archive material. A wide variety of abnormalities were detected including gain of regions of 1q, 17q, 19q, 20p and 20q and loss on 13q, 14q, 17p, 16q and 22q. Amplification of areas on 10p, 8q and 20q were also observed. Chromosomal alterations were more frequent in higher grade DCIS and closely resemble those previously detected in invasive breast cancer using the same technique. These data provide strong molecular support for the view that DCIS is a precursor lesion of invasive breast carcinoma.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma in Situ/genética , Carcinoma Ductal de Mama/genética , Amplificación de Genes/genética , Eliminación de Gen , Anciano , Femenino , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Hibridación de Ácido Nucleico/métodos , Estudios RetrospectivosRESUMEN
We report here the cytogenetic analysis of a neuroblastoma from a 6-month-old male. Both conventional GTG banded analysis and fluorescence in situ hybridization were performed. The tumour was found to have a der(17)t(1;17)(p34;q21).
Asunto(s)
Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 1/genética , Neuroblastoma/genética , Neoplasias Retroperitoneales/genética , Translocación Genética/genética , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 17/ultraestructura , Resultado Fatal , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Neuroblastoma/patología , Neoplasias Retroperitoneales/patologíaRESUMEN
We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.
Asunto(s)
Codón/genética , Genes p53/genética , Síndrome de Li-Fraumeni/genética , Mutación Puntual/genética , Adulto , Alelos , Secuencia de Bases , Femenino , Genotipo , Humanos , Cariotipificación , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: The budding yeast Saccharomyces cerevisiae can bud in two spatially programmed patterns: axial or bipolar. In the axial budding pattern, cells polarize and divide adjacent to the previous site of cell separation, in response to a cell-division remnant, which includes Bud3p, Bud4p and septin proteins. This paper investigates the role of an additional component of the cell-division remnant, Bud10p, in axial budding. RESULTS: The sequence of Bud10p predicts a protein that contains a single trans-membrane domain but lacks similarity to known proteins. Subcellular fractionations confirm that Bud10p is associated with membranes. Bud10p accumulates as a patch at the bud site prior to bud formation, and then persists at the mother-bud neck as the bud grows. Towards the end of the cell cycle, the localization of Bud10p refines to a tight double ring which splits at cytokinesis into two single rings, one in each progeny cell. Each single ring remains until a new concentration of Bud10p forms at the developing axial bud site, immediately adjacent to the old ring. Certain aspects of Bud10p localization are dependent upon BUD3, suggesting a close functional interaction between Bud10p and Bud3p. CONCLUSIONS: Bud10p is the first example of a transmembrane protein that controls cell polarization during budding. Because Bud10p contains a large extracellular domain, it is possible that Bud10p functions in a manner analogous to an extracellular matrix receptor. Clusters of Bud10p at the mother-bud neck formed in response to Bud3p (and possibly to an extracellular cue, such as a component of the cell wall), might facilitate the docking of downstream components that direct polarization of the cytoskeleton.
Asunto(s)
Polaridad Celular/fisiología , Proteínas Fúngicas/fisiología , Proteínas de la Membrana/fisiología , Receptores de Superficie Celular/fisiología , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/citología , Secuencia de Aminoácidos , Secuencia de Bases , Cartilla de ADN , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas de la Membrana/química , Datos de Secuencia Molecular , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genéticaRESUMEN
The gene loci CDK4, GLI, CHOP and MDM2 have been mapped to the q13-q15 region of chromosome 12. Using fluorescence in situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, we have more precisely mapped and ordered these loci, together with a number of Genethon microsatellite markers. GLI and CHOP localize to 12q13.3-14.1, CDK4 to 12q14 and MDM2 to 12q14.3-q15, and the gene order is cen-GLI/CHOP-CDK4-MDM2. The Genethon microsatellites D12S80 and D12S83 flank MDM2.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Cromosomas Humanos Par 12 , Quinasas Ciclina-Dependientes , Proteínas de Unión al ADN/genética , Proteínas Nucleares , Proteínas Oncogénicas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Mapeo Cromosómico , Quinasa 4 Dependiente de la Ciclina , Marcadores Genéticos/genética , Humanos , Hibridación Fluorescente in Situ , Proteínas Proto-Oncogénicas c-mdm2 , Transactivadores , Factor de Transcripción CHOP , Proteína con Dedos de Zinc GLI1RESUMEN
The three loci NRAS, NGFB, and CD2 map to human chromosome band 1p13. Using fluorescence in situ hybridisation (FISH) to simultaneously DAPI-banded metaphase chromosomes, we have further refined the localisation of these three genes to specific subbands. NRAS localises to subband 1p13.2 and CD2 and NGFB to 1p13.1. Also, with the use of multicolour FISH, we have determined the order and orientation of the three loci in relation to the centromere. The order is cen-CD2-NGFB-NRAS.
Asunto(s)
Antígenos CD/genética , Antígenos CD2/genética , Cromosomas Humanos Par 1 , Genes ras , Factores de Crecimiento Nervioso/genética , Secuencia de Bases , Núcleo Celular/ultraestructura , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Cartilla de ADN , Exones , Humanos , Hibridación Fluorescente in Situ , Interfase , Masculino , Metafase , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Reacción en Cadena de la PolimerasaRESUMEN
The helix-loop-helix (HLH) family of transcription factors plays a central role in the regulation of cell growth, differentiation and tumourigenesis. Members of the Id (inhibitor of DNA binding) class of these nuclear proteins are able to heterodimerise with and thereby antagonise the functions of other transcription factors of this family. We report here on the genomic organisation of the human Id3 (HLH 1R21/heir1) gene. Comparison with the two other mammalian Id genes, Id1 and Id2, reveals a highly conserved protein coding gene organisation consistent with evolution from a common, ancestral Id-like gene. In addition, by using a yeast artificial chromosome (YAC) clone of Id3, we have fine-scale mapped the gene to chromosome band 1p36.1 by fluorescence in situ hybridisation (FISH) and, using the same FISH technique, we have detected heterogeneity in tumour-associated 1p36 chromosome translocations.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 1 , Proteínas de Neoplasias , Factores de Transcripción/genética , Adenocarcinoma/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Evolución Biológica , Neoplasias de la Mama/genética , Mapeo Cromosómico , Secuencia de Consenso , Secuencia Conservada , Secuencias Hélice-Asa-Hélice , Humanos , Hibridación Fluorescente in Situ , Proteínas Inhibidoras de la Diferenciación , Leucemia/genética , Neoplasias Pulmonares/genética , Linfocitos/citología , Linfocitos/fisiología , Mamíferos , Datos de Secuencia Molecular , Mapeo Restrictivo , Homología de Secuencia de Aminoácido , Translocación Genética , Células Tumorales CultivadasRESUMEN
An NlaIV polymorphism in the 5' untranslated region of the MDM2 gene is described. MDM2 was sublocalised by fluorescence in situ hybridisation with a yeast artificial chromosome probe to 12q14.3-12q15. We demonstrate the use of the polymorphism to assess allelic imbalance in breast tumours.
Asunto(s)
Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Polimorfismo Genético , Proteínas Proto-Oncogénicas , Alelos , Secuencia de Bases , Neoplasias de la Mama/genética , Cartilla de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-mdm2 , Saccharomyces cerevisiae/genéticaRESUMEN
We have determined the cDNA sequence of a human B cell specific, immediate early gene, designated 1R20, which is inducible in response to several B cell activation signals. The cDNA sequence predicts a 196 amino acid open reading frame comprising numerous highly basic residues and the predicted structure contains several potential alpha helical domains together with eight consensus protein phosphorylation sites. The 1R20 gene has been localised by fluorescence in situ hybridisation to chromosome band 1q31, a region known to be implicated in the pathogenesis of haemopoietic malignancies.
Asunto(s)
Linfocitos B/ultraestructura , Cromosomas Humanos Par 1 , Genes Inmediatos-Precoces , Proteínas Inmediatas-Precoces/genética , Fosfoproteínas/genética , Proteínas RGS , Secuencia de Aminoácidos , Linfocitos B/efectos de los fármacos , Secuencia de Bases , Sitios de Unión , Secuencia Conservada , ADN Complementario/química , Humanos , Proteínas Inmediatas-Precoces/química , Linfoma de Células B/genética , Datos de Secuencia Molecular , Fosfoproteínas/químicaRESUMEN
The expression frequency of aphidicolin-induced fragile sites was examined in familial breast cancer patients to determine whether this parameter could be used as a marker of genetic susceptibility in at-risk individuals. No difference was found in expression frequency between the breast cancer patients and a group of normal individuals (p = 0.61). This indicates that the expression frequency of aphidicolin-induced fragile sites is not a suitable marker for assessing genetic susceptibility in familial breast cancer.