Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Proteínas con Dominio LIM/metabolismo , Linfoma de Células B Grandes Difuso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Proteínas Proto-Oncogénicas/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Rituximab/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Addressing the global burden of cancer, understanding its diverse biology, and promoting appropriate prevention and treatment strategies around the world has become a priority for the United Nations and International Atomic Energy Agency (IAEA), the WHO, and International Agency for Research on Cancer (IARC). The IAEA sponsored an international prospective cohort study to better understand biology, treatment response, and outcomes of diffuse large B-cell lymphoma (DLBCL) in low and middle-income countries across five UN-defined geographical regions. We report an analysis of biological variation in DLBCL across seven ethnic and environmentally diverse populations. In this cohort of 136 patients treated to a common protocol, we demonstrate significant biological differences between countries, characterized by a validated prognostic gene expression score (p < .0001), but International Prognostic Index (IPI)-adjusted survivals in all participating countries were similar. We conclude that DLBCL treatment outcomes in these populations can be benchmarked to international standards, despite biological heterogeneity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/epidemiología , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Biomarcadores de Tumor , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Salud Global , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Prednisona/uso terapéutico , Pronóstico , Rituximab , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
As a part of an international study on the molecular analysis of Diffuse Large B-cell Lymphoma (DLBCL), a robust protocol for gene expression analysis from RNA extraction to qRT-PCR using Formalin Fixed Paraffin Embedded tissues was developed. Here a study was conducted to define a strategy to validate the previously reported 6-gene (LMO2, BCL6, FN1, CCND2, SCYA3 and BCL2) model as predictor of prognosis in DLBCL. To avoid variation, all samples were tested in a single centre and single platform. This study comprised 8 countries (Brazil, Chile, Hungary, India, Philippines, S. Korea, Thailand and Turkey). Using the Kaplan-Meier and log rank test on patients (n=162) and two mortality risk groups (with those above and below the mean representing high and low risk groups) confirmed that the 6-gene predictor score correlates significantly with overall survival (OS, p<0.01) but not with event free survival (EFS, p=0.18). Adding the International Prognostic Index (IPI) shows that the 6-gene predictor score correlates significantly with high IPI scores for OS (p<0.05), whereas those with low IPI scores show a trend not reaching significance (p=0.08). This study defined an effective and economical qRT-PCR strategy and validated the 6-gene score as a predictor of OS in an international setting.
Asunto(s)
Biomarcadores de Tumor/genética , Fijadores/química , Formaldehído/química , Perfilación de la Expresión Génica/métodos , Linfoma de Células B Grandes Difuso/genética , Adhesión en Parafina , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fijación del Tejido/métodos , Transcriptoma , Anciano , Asia , Biopsia , Supervivencia sin Enfermedad , Europa (Continente) , Femenino , Perfilación de la Expresión Génica/normas , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , América del Sur , Factores de TiempoRESUMEN
Nectin-1 is a cell adhesion molecule that plays a role in interneuronal synapse formation, in axonal guidance during development and possibly in neuron-glia interactions. To better understand axonal changes in MS, nectin-1 expression was determined by immunohistochemistry in normal adult human cerebral white matter (n = 4) and in six MS plaques (three active and three inactive). The intensity of axonal nectin-1 expression was scored on a scale of 0 to 4+. In normal adult cerebral white matter, axons showed weak nectin-1 expression with a score of 1.25 ± 0.50. Axonal nectin-1 expression was significantly stronger within both active (score = 3.33 ± 0.289, p = 0.001) and inactive (score = 2.16 ± 0.29, p = 0.038) MS plaques than in normal white matter. Axons in white matter adjacent to MS plaques showed nectin-1 expression (score = 1.5 ± 0.50) that was not statistically different from normal controls (p = 0.542). These findings raise the possibility that increased expression of nectin-1 in MS lesions plays a role in the pathogenesis of MS through participation in axonal responses to injury and mediation of altered neuron-glia interactions relevant to myelination.
Asunto(s)
Encéfalo/metabolismo , Moléculas de Adhesión Celular/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Placa Amiloide/patología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Encéfalo/patología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Nectinas , Proteínas de Neurofilamentos/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
AIMS: Follicular lymphoma (FL) is associated with bone marrow (BM) involvement in approximately 40-70% of cases. Previous studies have suggested that the immune-microenvironment of FL plays an important role in the clinical behaviour of the disease. To investigate the role of the microenvironment in BM involvement of FL, we performed immunophenotypical analysis of the reactive cell populations in lymph nodes (LN) and corresponding BM of 35 patients with FL. Microenvironment patterns of BM infiltrates were compared to the corresponding features of the LN in cases with BM manifestation, and the LN microenvironment was compared in FL cases with and without BM involvement. METHODS AND RESULTS: Automated image-segmentation-based quantitation was performed in whole digital slides of tissue microarrays of formalin-fixed paraffin-embedded tissue biopsies. We found significantly more CD8(+) T lymphocytes, forkhead box protein 3 (FoxP3)(+) T lymphocytes and CD68(+) macrophages and fewer PD1(+) T lymphocytes in the BM than in the matching LN samples. Furthermore, we observed significantly fewer CD8(+) T cells and CD68(+) macrophages in cases involving the BM compared to those localized only to the LNs. CONCLUSIONS: Our study showed that different tumour cell growth in the LN and BM may generate different microenvironments, and suggested that the reduced number of cytotoxic T lymphocytes and macrophages in LNs favours BM infiltration of neoplastic cells in FL.
Asunto(s)
Médula Ósea/patología , Linfoma Folicular/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Linfocitos T/patologíaRESUMEN
To better understand the pathogenesis of dementia, it is important to understand histopathologic changes in neurodegenerative diseases because they might highlight key aspects of the degenerative process. In this study, the nuclear diameter of neurons and oligodendrocytes in selected temporal lobe areas were determined in autopsy tissue sections from patients with Alzheimer's disease (AD), Lewy body dementia (LBD) and controls. Our morphometric studies targeted neurons in the CA4 region of the pyramidal cell layer of the hippocampus, neurons in the granular layer of the dentate gyrus and oligodendrocytes in parahippocampal white matter. Mean neuronal nuclear diameters were not different among the studied groups. However, our studies revealed a statistically significant reduction of mean oligodendrocyte nuclear diameter in AD and LBD relative to controls. The reduction of the mean nucleus diameter of oligodendrocytes in LBD was independent of the presence of associated AD pathology in LBD. These findings for the first time identify decreased oligodendrocyte nucleus diameter as a morphologic feature of AD and LBD and may lead to a better understanding of the role of oligodendrocytes in AD and LBD pathogenesis.
Asunto(s)
Enfermedad de Alzheimer/patología , Núcleo Celular/patología , Enfermedad por Cuerpos de Lewy/patología , Oligodendroglía/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , MasculinoRESUMEN
In lymph nodes, chronic lymphocytic leukemia (CLL) cells (prolymphocytes and paraimmunoblasts) form proliferation centers (PCs), which are also known as pseudofollicles. To reveal whether PCs play a role in the accumulation of genetic alterations in CLL, we compared deletion at 11q22.3, 13q14.3, and 17p13.1 loci and trisomy 12 by the fluorescence in situ hybridization (FISH) technique in PCs versus surrounding small lymphocytes (SLs) in 12 formalin-fixed paraffin-embedded (FFPE) lymph nodes. The FFPE sections were stained with methylene blue and PCs were marked by laser beam. Subsequent FISH analysis was performed, relocalizing the previously defined regions. Loss of 11q was detected in five cases, loss of 13q in two cases, loss of 17p in two cases, and trisomy 12 in one case. In seven cases PCs contained a significantly higher ratio of cells with genetic alterations compared with the surrounding SLs. Our results show that CLL cells with genetic alterations tend to accumulate in PCs. The clonal expansion of the cell population carrying genetic alterations within PCs may contribute to CLL progression.
Asunto(s)
Proliferación Celular , Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/genética , Ganglios Linfáticos/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/patología , Linfocitos/metabolismo , Linfocitos/patología , TrisomíaRESUMEN
Numerous epidemiological studies have proposed a link between herpes simplex virus (HSV) infection and several common chronic neuropsychiatric and neurodegenerative diseases. Experimental HSV infection of mice can lead to chronic behavioral and neurological deficits and chronic pain. While neuron injury and loss are well-documented consequences of the acute phase of infection, the pathologic consequences of latent HSV infection are poorly understood. To determine whether latent HSV infection can cause neuronal injury in mice, trigeminal ganglia (TG) derived from adult BALB/c mice 1, 12 and 31 weeks after corneal HSV type 1 (HSV-1) inoculation were analyzed for evidence of productive or latent HSV-1 infection, inflammation and changes in neuron size, density and number. We found that latent HSV-1 infection between 12 and 31 weeks after corneal virus inoculation was associated with inflammation and progressive deficits in mean neuron diameter, neuronal nucleus diameter, neuron density and neuron number in the TG relative to mock-infected controls. The extent of neuronal injury during latent infection correlated with the extent of inflammation. These studies demonstrate that latent HSV infection is associated with progressive neuronal pathology and may lead to a better understanding of the role of HSV infections in chronic neurological diseases.
Asunto(s)
Infecciones por VIH/patología , Herpesvirus Humano 1/patogenicidad , Neuronas/patología , Ganglio del Trigémino/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Edad , Análisis de Varianza , Animales , Recuento de Células/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Viral de la Expresión Génica , Inflamación/etiología , Inflamación/virología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Neuronas/virología , Fosfoproteínas/metabolismo , Factores de Tiempo , Ganglio del Trigémino/virología , Proteínas Virales/metabolismoRESUMEN
BACKGROUND: Follicular lymphoma is characterized by the t(14;18) translocation resulting in constitutive expression of BCL-2 protein; however approximately 10-15% of follicular lymphomas do not express BCL-2 protein, and a small fraction of these cases does not exhibit translocation of the BCL-2 gene either. It is highly debated whether cases of follicular lymphoma without BCL-2 gene rearrangement and expression represent a separate lymphoma entity with distinct biological characteristics, different from the BCL-2-positive cases. DESIGN AND METHODS: To further characterize follicular lymphomas without BCL-2 gene rearrangement and expression, we analyzed and compared the mutational status of IGVH genes as well as other genes (C-MYC, PAX-5 and RHOH) frequently involved in the specific type of genomic instability called aberrant somatic hypermutation in 11 cases of BCL-2-negative and 7 cases of BCL-2-positive follicular lymphomas. We also determined the levels of expression of activation-induced cytidine deaminase in these cases. RESULTS: The analyzed cases were grade 2 and grade 3A follicular lymphomas. Our findings demonstrate that follicular lymphomas without BCL-2 gene rearrangement and expression are associated with ongoing somatic hypermutation of the IGVH genes, low activity of aberrant somatic hypermutation and elevated activation-induced cytidine deaminase expression. These results were in concordance with the results found in the cases of BCL-2-positive follicular lymphoma. CONCLUSIONS: Although, BCL-2 protein overexpression is considered to be a critical pathogenic event in the development of follicular lymphoma, our findings suggest that follicular lymphomas with the same morphology, immunophenotype, mutational pattern and activation-induced cytidine deaminase expression may develop without the involvement of BCL-2 gene. The present data support the hypothesis that BCL-2-positive and BCL-2-negative follicular lymphomas (grades 1-3A) represent a homogenous group with different initial but several common additional molecular pathways.
Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfoma Folicular/genética , Hipermutación Somática de Inmunoglobulina , Adulto , Anciano , Ciclina D1/análisis , Ciclina D1/genética , Femenino , Genes de Inmunoglobulinas , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Chronic lymphocytic leukaemia (CLL) with increased prolymphocytes (CLL/PL) has been defined by the World Health Organization (WHO) classification and considered as a progressive and clinically aggressive variant of CLL. To further characterize the biological features of this disease, we performed IgVH gene mutational status, FISH and high-resolution comparative genomic hybridization (HR-CGH) analysis in 17 cases of CLL/PL. All CLL/PL utilized members of VH1, VH3 and VH4 families, with the highest prevalence of the VH1-69 gene. In all but one cases analyzed, the VH genes were unmutated. The FISH and HR-CGH analyses showed frequent occurrence of trisomy 12, del(11)(q23), del(17)(p13) and genetic imbalances, but recurrent genetic lesion characteristic for CLL/PL was not found. The follow-up HR-CGH analysis of two cases showed that increase of prolymphocytes in the course of CLL or CLL/PL are associated with clonal evolution and selection of the tumour clone. In conclusion, this study suggests that CLL/PL is a relatively homogeneous disease regarding VH gene mutation, but heterogeneous regarding genetic lesions. The heterogeneity and high number of genomic imbalances found in CLL/PL suggest that a genome-wide instability of the neoplastic cells may play a role in the development of the disease.
Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Hibridación de Ácido NucleicoRESUMEN
The FMS-like tyrosine kinase-3 (FLT3), which belongs to the class III receptor tyrosine kinase family, expressed by immature hematopoietic cells, plays an important role in the proliferation, differentiation and survival of stem cells. The activating mutations of FLT3 gene have been reported to be of prognostic significance. The most common somatic alteration of the FLT3 gene is the Internal Tandem Duplication (FLT3/ITD), which is caused by the elongation of the juxtamembrane (JM) domain of FLT3. The duplicated fragment size varies from 3 to more than 400 base pair, always occurs in multiples of three while the reading frame is preserved. The elongated segment of DNA can be amplified by polymerase chain reaction (PCR), and the products are separated by gel electrophoresis. The FLT3/ITD is found in 20-40% of adult AML patients and is the most frequent mutation in leukemia. Using native peripheral blood and bone marrow from AML and non-AML patients (total of 19 samples), and samples from the RNA bank (total of eight samples), the authors purpose was to work out a method for FLT3/ITD detection, which can be used in routine diagnostics. All samples produced detectable PCR products, which proofs that this procedure can be used for the detection of FLT3/ITD mutations in daily clinical practice.