RESUMEN
The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.
Asunto(s)
Linfoma de Burkitt/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Adolescente , Adulto , Linfoma de Burkitt/patología , Niño , Preescolar , Femenino , Expresión Génica , Genes de Inmunoglobulinas , Genes myc , Humanos , Hibridación Fluorescente in Situ/métodos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Translocación Genética , Adulto JovenAsunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Tamizaje Masivo , Receptor ErbB-2/metabolismo , TrastuzumabRESUMEN
From the literature that was initially searched by electronic databases using the keywords quality, quality control and quality assurance in combination with clinical trials, surgery, pathology, radiotherapy, chemotherapy and data management, a comprehensive review is given on what quality assurance means, the various methods used for quality assurance in different aspects of clinical trials and the impact of this quality assurance on outcome and every day practice.
Asunto(s)
Ensayos Clínicos como Asunto/normas , Garantía de la Calidad de Atención de Salud , Protocolos Clínicos/normas , Humanos , Oncología Médica/métodos , Oncología Médica/normas , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/radioterapia , Control de Calidad , Resultado del TratamientoRESUMEN
In families at risk for hereditary non-polyposis colorectal cancer (HNPCC) that do not fulfill all clinical criteria for HNPCC, additional evidence is sought by testing cancer specimens for microsatellite instability (MSI). We investigated whether the location of a colorectal cancer (CRC) predicts the result of MSI-testing in these families. One hundred and seven patients suspected for HNPCC were offered MSI-testing. MSI-testing was positive in 6/7 patients with endometrial carcinoma and in 22/100 patients with CRC. Only one out of 22 (4%) rectal cancers was MSI-positive, and in this patient no mismatch repair (MMR) gene mutation was found. Right-sided colon carcinomas were more likely to be MSI-positive (14/37 or 38%), followed by left-sided colon carcinomas (7/4 or 17%) (p < 0.05), with 6/14 and 4/7 MMR gene mutations, respectively. The likelihood that a tumor would be MSI-positive was 3.3 times greater for right-sided than for left-sided colon cancer (OR 3.3, p < 0.05). Microsatellite instability was 8.1 times more frequent in colon cancers than in rectal cancers (p < 0.05). The presence of MSI was independently related to fulfillment of the Bethesda criteria (OR 7.0, p = 0.01). In families with multiple cases of colorectal cancer, the rectal cancers are only rarely MSI-positive. This indicates that even in families with multiple colorectal cancers, rectal cancers are most commonly of sporadic origin.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Repeticiones de Microsatélite , Neoplasias del Recto/genética , Adulto , Reparación del ADN , Humanos , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
Uterine cervix represents a convenient model for the study of the gradual transformation of normal squamous epithelium via low- to high-grade squamous intraepithelial lesions (SILs). Because SIL, on the basis of the cytokeratins expressed, are thought to originate from the reserve cells, we analyzed whether SILs also show a reserve cell phenotype with respect to intercellular interactions. The changes in expression and subcellular localization of the components of the adherens junction and desmosomal complexes were investigated in normal, metaplastic, and premalignant cervical epithelium, as well as in cell cultures derived from these tissues. The results suggest that 1) during progression of SILs, E-cadherin is suppressed, with its role in cell-cell connections diminishing; 2) P-cadherin, in contrast, becomes the predominant cadherin in high-grade SILs; 3) the level of cellular alpha-catenin is dramatically decreased in high-grade SILs; 4) the level of beta-catenin is decreased during progression of SILs, with plakoglobin suggestively becoming the predominant catenin mediating connection of cadherins to the cytoskeleton; 5) the assembly of desmosomes is affected during progression of SILs and is accompanied by a dramatically decreased expression for desmogleins and desmoplakins (I, II); and 6) expression of differentiation markers (involucrin, CK13) in high-grade SILs seems to be controlled by P-cadherin as opposed to E-cadherin in the normal tissue counterpart. We conclude that during development of cervical lesions substantial (both quantitative and qualitative) changes occur in cell-cell junctions, making the interactions of cells in lesions dissimilar from those of reserve cells, basal cells, or cells of immature squamous metaplasia, despite existing morphological similarity between all of these cell types and cells of high-grade lesions.
Asunto(s)
Cadherinas/fisiología , Proteínas del Citoesqueleto/fisiología , Transactivadores , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Biomarcadores , Cadherinas/análisis , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/fisiología , Células Cultivadas , Proteínas del Citoesqueleto/análisis , Desmogleínas , Desmoplaquinas , Desmosomas/metabolismo , Progresión de la Enfermedad , Femenino , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Inmunohistoquímica , Proteínas Tirosina Quinasas/análisis , Proteínas Tirosina Quinasas/fisiología , Factores de Tiempo , Neoplasias del Cuello Uterino/diagnóstico , alfa Catenina , beta Catenina , gamma CateninaRESUMEN
BACKGROUND: The stentless xenograft with its favorable hemodynamic performance on the left side of the heart seems an attractive, readily available alternative for the reconstruction of the right ventricular outflow tract in children. METHODS: To assess its function in a preclinical animal investigation, we replaced the pulmonary root with a Freestyle stentless aortic xenograft in 18 piglets of 26.6 +/- 3.2 kg weight. The animals were allowed to grow as much as possible and slaughtered when symptoms of heart failure developed or body weight reached more than 160 kg. All valve explants were analyzed by gross examination and photography and, in 4 representative pigs, by histologic examination. RESULTS: Fourteen animals died prematurely after 2 weeks to 11 months. Twelve xenograft explants showed thick, immobilized, large nodular structures as cuspal remnants causing significant stenosis. At microscopy, large cuspal masses of degenerating collagen and fibrin and various inflammatory cells were frequently found. In the growing pig, most of the xenografts implanted in the pulmonary position showed early degeneration causing severe stenosis. CONCLUSIONS: Use of this valve for right ventricular outflow tract reconstruction in children cannot be recommended.
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Bioprótesis , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Válvula Pulmonar/cirugía , Animales , Válvula Aórtica/trasplante , Peso Corporal , Calcinosis/patología , Gasto Cardíaco Bajo/etiología , Causas de Muerte , Colágeno/ultraestructura , Constricción Patológica/patología , Modelos Animales de Enfermedad , Endocarditis/patología , Fibrina/ultraestructura , Crecimiento , Diseño de Prótesis , Falla de Prótesis , Propiedades de Superficie , PorcinosRESUMEN
BACKGROUND: Changes in several (onco)genes and their protein expression play a role in the development of Head and Neck Squamous Cell Carcinoma (HNSCC). If protein expression is to be used for clinical purposes, their expression should preferably be evaluated during the initial diagnostic work-up when only biopsy material will be available. To investigate the correlation between assessment of expression in biopsy and resection material, protein expression in both was evaluated and compared. MATERIALS AND METHODS: In this study we compared the expression of P53, Rb protein, E-Cadherin, Ep-CAM, Desmoplakin1 and cortactin by immunohistochemistry. Expression of the proteins was studied in biopsy and resection material of 26 laryngeal carcinomas. RESULTS: A variable rate of mismatches between the scoring on biopsy and resection material was found for the different proteins. CONCLUSION: If protein expression is to be used in clinical practice and decision making it should be realized that a discrepancy exists between the expression in biopsy material and the complete resection material.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patología , Oncogenes , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/genética , Biopsia , Cadherinas/análisis , Cadherinas/genética , Carcinoma de Células Escamosas/cirugía , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/genética , Cortactina , Proteínas del Citoesqueleto/análisis , Proteínas del Citoesqueleto/genética , Desmoplaquinas , Molécula de Adhesión Celular Epitelial , Femenino , Humanos , Inmunohistoquímica/métodos , Neoplasias Laríngeas/cirugía , Masculino , Proteínas de Microfilamentos/análisis , Proteínas de Microfilamentos/genética , Estadificación de Neoplasias , Proteína de Retinoblastoma/análisis , Proteína de Retinoblastoma/genética , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Ep-CAM, an epithelial adhesion molecule, is absent in normal squamous epithelia but can be detected in some squamous carcinomas. Using a panel of monoclonal antibodies to keratinocyte differentiation and proliferation markers, we investigated the association of EP-CAM expression with differentiation-related and/or neoplastic changes in cervical epithelium. Normal endocervical glandular epithelium (Both columnar and reserve cells) appeared strongly positive for EP-CAM, whereas ectocervical squamous epithelial cells did not express this molecule. Expression of Ep-CAM (in basal cells) was sometimes observed in morphologically normal ectocervical tissue but only in areas bordering cervical intraepithelial neoplasia (CIN) lesions. At the early stages of neoplasia the expression of Ep-CAM was regularly present in squamous epithelium, in general consistent with the areas of atypical, undifferentiated cells. Thus, in CIN grades I and II, the basal/suprabasal layers of the epithelia were positive, whereas in CIN grade III lesions, up to 100% of the cells over the whole thickness of the epithelium sometimes excluding the very upper layers, expressed Ep-CAM. A clear increase, not only in number of positive cells but also in levels of Ep-CAM expression (intensity) was observed during progression from CIN I to CIN III. Expression of Ep-CAM in ectocervical lesions did not coincide with a reappearance of the simple epithelium cytokeratins (CK8 and CK18). On the other hand, expression of Ep-CAM in atypical cells of CIN lesions correlated with the disappearance of CK13, which normally marks cells undergoing squamous differentiation. As was shown with Ki-67, a marker for proliferating cell populations, the areas of Ep-CAM expression were also the areas of enhanced proliferation. Cells expressing Ep-CAM did not express involucrin, a marker for cells committed to terminal differentiation. In the majority of both squamous and adenocarcinomas of the cervix a strong expression of Ep-CAM was observed, although some decrease in the expression (both the intensity and the number of positive cells), as compared with CIN III lesions, was observed in the areas of squamous differentiation. This study demonstrates that the expression of Ep-CAM in cervical squamous epithelium is associated with abnormal proliferation of cell populations that are not committed to terminal differentiation.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismo , Cuello del Útero/citología , Cuello del Útero/metabolismo , Biomarcadores , Biomarcadores de Tumor , Diferenciación Celular , División Celular , Cuello del Útero/patología , Molécula de Adhesión Celular Epitelial , Epitelio/metabolismo , Femenino , Humanos , Queratinas/metabolismo , Metaplasia , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/metabolismoRESUMEN
We investigated 49 acquired immunodeficiency syndrome-related lymphomas (ARLs) for Epstein-Barr virus (EBV) by Southern blotting and in situ hybridization and, in positive cases, used cryostat immunohistology to compare EBV-latent gene expression (EBV encoded small RNA-1 [EBER-1], EBV nuclear antigen-2 [EBNA-2], latent membrane protein-1 [LMP-1] and host cell immunophenotype (CD11a, CD18, CD54, CD58, CD21, CD23, CD30, CD39, CDw70, immunoglobulin) patterns with those reported in other EBV infections. EBV+ immunoblast-rich/large cell ARLs (n = 22) showed three patterns of latency: broad (EBER+EBNA-2+/LMP-1+; n = 9), reminiscent of a lymphoblastoid cell line phenotype; restricted (EBER+/EBNA-2-/LMP-1-; n = 6), similar to endemic Burkitt's lymphoma; and intermediate (EBER+/EBNA-2-/LMP-1+; n = 7), a pattern rarely described in vitro but seen in certain EBV-related malignancies. EBNA-2 expression was associated with extranodal lymphomas. EBV+ Burkitt-type ARLs (n = 11) usually showed the restricted latency pattern (n = 8), but some expressed the intermediate form (n = 3). Adhesion (CD54, CD58) and activation (CD30, CD39, CDw70) molecule expression varied with morphology (immunoblast-rich/large cell versus Burkitt-type), but was not independently correlated with EBV-positivity. CD30 and LMP-1 expression were associated. ARLs show heterogeneity regarding both the presence of EBV and latency pattern. Comparison of these phenotypically distinct lymphoma groups with known forms of EBV infection provides clues to their possible pathogenesis.
Asunto(s)
Antígenos Virales/metabolismo , Proteínas de Unión al ADN/metabolismo , Expresión Génica , Linfoma Relacionado con SIDA/metabolismo , Linfoma no Hodgkin/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Ribosómicas , Proteínas de la Matriz Viral/metabolismo , Latencia del Virus , Adulto , Anciano , Preescolar , ADN Viral/análisis , Antígenos Nucleares del Virus de Epstein-Barr , Herpesvirus Humano 4/inmunología , Humanos , Inmunofenotipificación , Linfoma Relacionado con SIDA/clasificación , Linfoma Relacionado con SIDA/genética , Linfoma no Hodgkin/clasificación , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Proteínas Oncogénicas Virales/metabolismo , ARN Viral/análisisAsunto(s)
Proteínas Proto-Oncogénicas/metabolismo , Secuencia de Aminoácidos , Proteínas Fúngicas/genética , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfocitos/metabolismo , Linfocitos/ultraestructura , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-bcl-2 , Homología de Secuencia de Aminoácido , Fracciones Subcelulares/metabolismoRESUMEN
Myelodysplasia (MDS) and leukaemia following acquired aplastic anaemia has been reported as a rare event occurring in about 5% of patients. Improved results in survival of patients with severe aplastic anaemia (SAA) and subsequent prolonged follow-up created the possibility of evaluating the occurrence of MDS and leukaemia in 38 adult patients with acquired SAA surviving two or more years without bone marrow transplantation. Five patients, age 22, 35, 47, 56, 72 years, two females, three males, all with idiopathic SAA and normal cytogenetic analysis developed a refractory anaemia (RA) 7, 30, 48, 56, 142 months after diagnosis of SAA. In 3/5 RA evolved into an acute myeloid leukaemia (AML) either via a chronic myelomonocytic leukaemia (CMML) (2/3) or via RA with excess of blasts (RAEB) (1/3). Three patients revealed a monosomy 7 during MDS and/or leukaemic phase. One patient died during RA phase without cytogenetic abnormalities. A pattern of evolution could be identified in these patients revealing well-documented SAA - improvement of bone marrow haematopoiesis - dyshaematopoietic features of one or more cell lines with predominance of dyserythropoiesis - RA - RAEB or CMML - AML. These five patients represent more than 10% of all patients surviving at least 2 years. This implies that the risk of developing MDS and leukaemia in SAA patients surviving with autologous marrow, might increase with longer follow-up.
Asunto(s)
Anemia Aplásica/complicaciones , Anemia Refractaria/etiología , Leucemia Mieloide/etiología , Adulto , Anciano , Anemia Aplásica/patología , Anemia Refractaria/patología , Médula Ósea/patología , Femenino , Humanos , Cariotipificación , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Masculino , Persona de Mediana EdadRESUMEN
Some formulas are given for the relationship between the sizes of wheals and flares of skin reactions to three allergen extracts and to histamine and compound 48/80. Only compound 48/80 shows a somewhat different wheal/flare relationship.
Asunto(s)
Histamina/farmacología , Hipersensibilidad Inmediata/diagnóstico , Ácaros , Extractos Vegetales/inmunología , Poaceae , Polen , p-Metoxi-N-metilfenetilamina/farmacología , Humanos , Pruebas CutáneasRESUMEN
It is demonstrated that the sum of the length and width of the flare is linearly correlated with the logarithm of the sum of the length and width of the wheal; on this basis a valuable "skin-reaction index" is proposed. Furthermore, the log-dose response curve of the skin reaction, at least in the medium-sized reactions, proved to be a straight line. These methods permit a bio-assay of allergens extracts giving a maximal dispersion of 100% above and below the exact value. Coefficient of variation: 62%.