RESUMEN
Oral malignancy is rare in chimpanzees. A 34-year-old female chimpanzee (Pan troglodytes) at Kumamoto Sanctuary, Japan, had developed it. Treatment is technically difficult for chimpanzees while malignant neoplasm is seemingly rising in captive populations. Widespread expert discussion, guidelines for treatment, especially for great apes in terminal stages is urgently needed.
Asunto(s)
Animales de Zoológico , Enfermedades del Simio Antropoideo/diagnóstico , Neoplasias de la Boca/veterinaria , Pan troglodytes , Sarcoma/veterinaria , Animales , Enfermedades del Simio Antropoideo/patología , Enfermedades del Simio Antropoideo/terapia , Resultado Fatal , Femenino , Hepacivirus/aislamiento & purificación , Japón , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/terapia , Sarcoma/diagnóstico , Sarcoma/terapiaRESUMEN
Chimpanzees are genetically and physiologically similar to humans. Several pharmacokinetic models of propofol are available and target controlled infusion (TCI) of propofol is established in humans, but not in chimpanzees. The purpose of this study was to investigate if human pharmacokinetic models can accurately predict propofol plasma concentration (Cp) in chimpanzees and if it is feasible to perform TCI in chimpanzees. Ten chimpanzees were anaesthetized for regular veterinary examinations. Propofol was used as an induction or maintenance agent. Blood samples were collected from a catheter in a cephalic vein at 3-7 time points between 1 and 100 min following the propofol bolus and/or infusion in five chimpanzees, or TCI in six chimpanzees. Cp was measured using high-performance liquid chromatography. The Marsh, Schnider and Eleveld human pharmacokinetic models were used to predict Cp for each case and we examined the predictive performances of these models using the Varvel criteria Median PE and Median APE. Median PE and Median APE for Marsh, Schnider and Eleveld models were within or close to the acceptable range. A human TCI pump was successfully maintained propofol Cp during general anesthesia in six chimpanzees. Human propofol pharmacokinetic models and TCI pumps can be applied in chimpanzees.
Asunto(s)
Anestésicos Intravenosos/administración & dosificación , Propofol/administración & dosificación , Anestesia General/métodos , Anestesia Intravenosa/métodos , Animales , Femenino , Humanos , Bombas de Infusión , Infusiones Intravenosas/métodos , Masculino , Modelos Biológicos , Pan troglodytesRESUMEN
Fas antigen (Apo-1/CD95) is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor receptor superfamily. Adult T cell leukemia (ATL) cells express Fas antigen and show apoptosis after treatment with an anti-Fas monoclonal antibody. We established the ATL cell line KOB, which showed resistance to Fas-mediated apoptosis, and found that KOB expressed two forms of Fas mRNA, the normal form and a truncated form. The truncated transcript lacked 20 base pairs at exon 9, resulting in a frame shift and the generation of a premature stop codon at amino acid 239. The same mutation was detected in primary ascitic cells and peripheral blood cells. The mutation was not detected in lymph node cells, however, although all of the primary ATL cells were of the same clonal origin. A retroviral-mediated gene transfer of the truncated Fas to Jurkat cells rendered the cells resistant to Fas-mediated apoptosis, suggesting a dominant negative interference mechanism. These results indicate that an ATL subclone acquires a Fas mutation in the lymph nodes, enabling the subclone to escape from apoptosis mediated by the Fas/Fas ligand system and proliferate in the body. Mutation of the Fas gene may be one of the mechanisms underlying the progression of ATL.
Asunto(s)
Mutación del Sistema de Lectura , Leucemia-Linfoma de Células T del Adulto/genética , Receptor fas/genética , Anciano , Secuencia de Aminoácidos , Anticuerpos Monoclonales/farmacología , Apoptosis , Ascitis/patología , Secuencia de Bases , Progresión de la Enfermedad , Exones/genética , Resultado Fatal , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Inmunoglobulina M/farmacología , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/patología , Ganglios Linfáticos/patología , Masculino , Datos de Secuencia Molecular , Células Neoplásicas Circulantes , ARN Mensajero/genética , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Células Tumorales Cultivadas , Receptor fas/inmunologíaRESUMEN
BACKGROUND: A 24-year-old, male chimpanzee (Pan troglodytes) developed acute tetraparesis. Magnetic resonance imaging showed a diffuse T2-weighted hyperintensive lesion, indicating inflammation at the C1-2 level. All infective, autoimmune, and vascular investigations were unremarkable. RESULTS AND CONCLUSIONS: The chimpanzee's condition most resembled acute transverse myelitis (ATM) in humans. The chimpanzee was in severe incapacitated neurological condition with bedridden status and required 24-hour attention for 2 months followed by special care for over a year. Initially, corticosteroid therapy was performed, and his neurological symptoms improved to some extent; however, the general condition of the chimpanzee deteriorated in the first 6 months after onset. Pressure ulcers had developed at various areas on the animal's body, as the bedridden status was protracted. Supportive therapy was continued, and the general condition, appetite, mobility, and pressure ulcers have slowly but synergistically recovered over the course of 2 years.
Asunto(s)
Enfermedades del Simio Antropoideo/diagnóstico , Mielitis Transversa/veterinaria , Pan troglodytes , Paresia/veterinaria , Traumatismos de la Médula Espinal/veterinaria , Animales , Enfermedades del Simio Antropoideo/terapia , Diagnóstico Diferencial , Cuidados a Largo Plazo , Imagen por Resonancia Magnética , Masculino , Mielitis Transversa/diagnóstico , Estado Nutricional , Paresia/líquido cefalorraquídeo , Paresia/etiología , Úlcera por Presión/etiología , Úlcera por Presión/veterinaria , Traumatismos de la Médula Espinal/líquido cefalorraquídeo , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/terapiaRESUMEN
Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19) or acute (n=22) stages of ATL and subjected them to profiling of gene expression with DNA microarrays containing >44,000 probe sets. Changes in chromosome copy number were also examined for 24 cell specimens with the use of microarrays harboring approximately 50,000 probe sets. Stage-dependent changes in gene expression profile and chromosome copy number were apparent. Furthermore, expression of the gene for MET, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was shown to be specific to the acute stage of ATL, and the plasma concentration of HGF was increased in individuals in either the acute or chronic stage. HGF induced proliferation of a MET-positive ATL cell line, and this effect was blocked by antibodies to HGF. The HGF-MET signaling pathway is thus a potential therapeutic target for ATL.
Asunto(s)
Perfilación de la Expresión Génica , Genoma Humano/genética , Factor de Crecimiento de Hepatocito/genética , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Factores de Crecimiento/genética , Línea Celular Tumoral , Dosificación de Gen , Genómica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-met , Transcripción GenéticaRESUMEN
We have purified and characterized the growth inhibitory factor (GIF) that is abundant in the normal human brain, but greatly reduced in the Alzheimer's disease (AD) brain. GIF inhibited survival and neurite formation of cortical neurons in vitro. Purified GIF is a 68 amino acid small protein, and its amino acid sequence is 70% identical to that of human metallothionein II with a 1 amino acid insert and a unique 6 amino acid insert in the NH2-terminal and the COOH-terminal portions, respectively. The antibodies to the unique sequence of GIF revealed a distinct subset of astrocytes in the gray matter that appears to be closely associated with neuronal perikarya and dendrites. In the AD cortex, the number of GIF-positive astrocytes was drastically reduced, suggesting that GIF is down-regulated in the subset of astrocytes during AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Inhibidores de Crecimiento/metabolismo , Proteínas de la Membrana/metabolismo , Metalotioneína/metabolismo , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Aminoácidos/análisis , Anticuerpos , Astrocitos/metabolismo , Astrocitos/ultraestructura , Encéfalo/ultraestructura , Electroforesis en Gel de Poliacrilamida , Inhibidores de Crecimiento/análisis , Inhibidores de Crecimiento/genética , Humanos , Immunoblotting , Inmunohistoquímica , Proteínas de la Membrana/análisis , Proteínas de la Membrana/genética , Metalotioneína/análisis , Metalotioneína/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Neurofibrillas/metabolismo , Neurofibrillas/ultraestructuraRESUMEN
Adult T-cell leukemia/lymphoma (ATLL) is a neoplasia characterized by the massive invasion of various organs by tumor cells. Previously, we found that expression of the gene for c-Met, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was specific to the acute type among 41 patients with ATLL by microarray. First in the present study, we analyzed the survival of the patients in relation to expression of c-Met and HGF in ATLL cells. Expression of the former but not the latter was associated with poor prognosis. Then, we analyzed the growth of ATLL cells caused by HGF and c-Met. c-Met was expressed in 0/7 chronic ATLLs, 12/14 acute ATLLs, 1/1 IL-2-independent ATLL cell line and 1/7 IL-2-dependent ATLL cell lines as assessed by flow cytometry. HGF induced the proliferation of primary cells from most acute cases examined as well as the c-Met-positive KK1 cell line in contrast to c-Met-negative cells. HGF induced autophosphorylation of c-Met in c-Met-positive cells from an acute case and KK1 cells. The plasma level of HGF was elevated in acute as compared to chronic cases. The levels of HGF and/or IL-6 which induces the production of HGF by stromal cells, were elevated in the supernatant of short-term cultured cells from certain patients with acute or chronic disease. Finally, infiltrated ATLL cells and adjacent stromal cells in liver were shown to be positive for c-Met/HGF and HGF, respectively, in acute cases. Autocrine and/or paracrine growth caused by HGF and c-Met was suggested in aggressive ATLL cells secreting HGF and/or IL-6, respectively.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Factor de Crecimiento de Hepatocito/metabolismo , Leucemia-Linfoma de Células T del Adulto/inmunología , Proteínas Proto-Oncogénicas c-met/metabolismo , Apoptosis , Línea Celular Tumoral , Membrana Celular/metabolismo , Proliferación Celular , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Leucemia-Linfoma de Células T del Adulto/metabolismo , Modelos Biológicos , Fosforilación , Factores de TiempoRESUMEN
Primary effusion lymphoma (PEL) was initially designated as a body-cavity-based lymphoma and recognized as a distinct clinical entity without a contiguous tumor mass. PEL was first reported in patients with acquired immunodeficiency syndrome (AIDS) and the distinctive feature of PEL originally reported as a B-cell neoplasm characterized by infection of the tumor cells by human herpes virus 8 (HHV-8). However, there have recently been several reports of PEL in patients without human immunodeficiency virus (HIV) or HHV-8 infection.
Asunto(s)
Antígenos CD4/biosíntesis , Proteínas de Unión al ADN/genética , Reordenamiento Génico , Herpesvirus Humano 8/genética , Linfoma de Efusión Primaria/genética , Linfopenia/terapia , Linfocitos T/metabolismo , Anciano , Antineoplásicos/farmacología , Disnea/diagnóstico , Infecciones por VIH/diagnóstico , Herpesvirus Humano 8/metabolismo , Humanos , Inmunofenotipificación , Linfoma de Efusión Primaria/complicaciones , Linfoma de Efusión Primaria/terapia , Linfopenia/complicaciones , Masculino , Derrame Pericárdico , Proteínas Proto-Oncogénicas c-bcl-6RESUMEN
In the criteria of refractory cytopenia with multilineage dysplasia (RCMD) according to the WHO (World Health Organization) classification, the frequency threshold concerning dysplasia of each lineage was defined as 10%. To predict overall survival (OS) and leukemia-free survival (LFS) for patients with refractory anemia (RA) according to the French-American-British (FAB) classification, we investigated prognostic factors based on the morphological features of 100 Japanese and 87 German FAB-RA patients, excluding 5q-syndrome. In the univariate analysis of all patients, pseudo-Pelger-Huet anomalies >or=10% (Pelger+), micromegakaryocytes >or=10% (mMgk+), dysgranulopoiesis (dys G) >or=10% and dysmegakaryopoiesis (dys Mgk) >or=40% were unfavorable prognostic factors for OS and LFS (OS; P<0.001, LFS; P<0.001). The prognostic effects of the morphological features were similar in both Japanese and German patients. However, dys Mgk >or=10% was not correlated with OS and LFS. In the multivariate analysis, mMgk+ and dys Mgk>or=40% were adverse prognostic factors for OS for all patients, and dys G >or=10% and dys Mgk>or=40% were adverse prognostic factors for LFS for all patients. On the basis of the present analysis, we propose the following modified morphological criteria for RCMD. Modified RCMD should be defined as FAB-RA, excluding 5q-syndrome with dys G >or=10%, dys Mgk>or=40% or mMgk+.
Asunto(s)
Anemia/epidemiología , Megacariocitos/patología , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/patología , Adulto , Mapeo Cromosómico , Femenino , Alemania , Humanos , Japón , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Análisis de Supervivencia , Sobrevivientes , Organización Mundial de la SaludRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can provide long-term remission for patients with adult T-cell leukemia/lymphoma (ATLL) caused by human retrovirus, human T-lymphocyte virus (HTLV-1). To understand how HTLV-1-positive cells including ATLL cells were suppressed by allo-HSCT, we examined HTLV-1 provirus load and residual ATLL cells in peripheral blood of transplant recipients using PCR-based tests. We found that the copy number of HTLV-1 genome, called provirus, became very small in number after allo-HSCT; however, in most cases, provirus did not disappear even among long-term survivors. Tumor-specific PCR tests demonstrated that most of HTLV-1-positive cells that remained long after transplantation were not primary ATLL cells but donor-derived HTLV-1-positive cells. We also found a case having very low amount of residual disease in peripheral blood even long after transplantation. There was only one recipient in whom we failed to show the presence of HTLV-1 genome and antibody against HTLV-1 even with an extensive search, which strongly suggested the elimination of HTLV-1 after allo-HSCT. These results demonstrated that after allo-HSCT the small amount of residual HTLV-1-positive cells were heterogeneous in origin and that long-term disease control for ATLL could be obtained without the complete elimination of HTLV-1.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia-Linfoma de Células T del Adulto/terapia , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/patología , Reacción en Cadena de la Polimerasa , Inducción de Remisión , Donantes de Tejidos , Trasplante Homólogo , Carga ViralRESUMEN
The significance of concavity in object shape perception by chimpanzees (Pan troglodytes) was investigated in a matching-to-sample procedure. For the task, chimpanzees were required to choose a polygon stimulus that was identical in shape to a sample. The incorrect alternative was defined by the addition or subtraction of a concave or convex apex. Chimpanzees were more sensitive to the concave deformation than to the convex deformation. This tendency conforms to the theories of human visual perception that have treated concave features as important factors in reconstructing three-dimensional structures from two-dimensional images. Our results suggest that shape representation in chimpanzees is similar to that in humans and that chimpanzees visually process two-dimensional images in the same manner as humans.
Asunto(s)
Aprendizaje Discriminativo , Percepción de Forma , Pan troglodytes/psicología , Animales , Femenino , Masculino , Reconocimiento Visual de ModelosRESUMEN
Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral T-cell neoplasm that is highly resistant to chemotherapy. Several groups, including ours, have reported encouraging results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with ATLL. To confirm our previous report and to establish the basis for a phase II clinical study, we analyzed 40 allo-HSCT for acute and lymphoma types of ATLL in seven institutions in Japan between 1997 and 2002. All evaluable cases entered complete remission (CR) after allo-HSCT and the median survival time was 9.6 months for all patients. The estimated 3-year overall and relapse-free survival, and disease relapse were 45.3, 33.8 and 39.3%, respectively. Among 10 cases with ATLL relapse, five cases achieved CR again: three by the reduction or cessation of immunosuppressive agents, which suggested a graft-versus-ATLL (GvATLL) effect. However, univariate or multivariate analysis did not show any benefit of graft-versus-host disease (GVHD) on the prevention of relapse. These results suggested that allo-HSCT was effective for some patients with aggressive ATLL, and that the GvATLL effect could be achieved even without GVHD. A new phase II trial to test the efficacy of allo-HSCT for ATLL is warranted.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma de Células T del Adulto/terapia , Adulto , Análisis de Varianza , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Humanos , Japón/epidemiología , Leucemia-Linfoma de Células T del Adulto/mortalidad , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Trasplante HomólogoRESUMEN
Low-density lipoprotein receptor-related protein (LRP) plays an important role in regulating proteinase activity, which is necessary for cellular invasive processes. In this study, we investigated the presence of both LRP and urokinase-type plasminogen activator receptor (uPAR) in astrocytoma tissues and in glioma cell lines by PCR and immunohistochemical analysis. LRP mRNA was expressed frequently in glioblastomas, as compared with low-grade astrocytomas by PCR analysis and was well correlated with uPAR expression. These results were consistent with the immunohistochemical localization of LRP in glioblastomas. Immunohistochemistry of LRP on sequential frozen sections showed that neoplastic glial cells and endothelial cells of glioblastomas exhibited intense LRP immunoreactivity, whereas LRP was almost undetectable in low-grade astrocytomas and in normal glial cells and endothelial cells of normal brain tissues. In normal brain tissues, LRP immunoreactivity was identified in the pyramidal neurons of the cerebral cortex. In metastatic brain tumors (metastatic lung adenocarcinomas) and primary lung adenocarcinomas, LRP expression was low to undetectable, suggesting that LRP expression is regulated differently in these tumors than in malignant astrocytomas. These results indicate that LRP is overexpressed in malignant astrocytomas, especially in glioblastomas, and the increased expression of LRP appears to correlate with the expression of uPAR and the malignancy of astrocytomas. Our results suggest strongly that LRP may play a role in facilitating glioblastoma invasiveness and neovascularization within tumor tissues by regulating cell surface proteolytic activity.
Asunto(s)
Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Receptores Inmunológicos/metabolismo , Adenocarcinoma/metabolismo , Astrocitoma/patología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Glioblastoma/metabolismo , Humanos , Inmunohistoquímica , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Neoplasias Pulmonares/metabolismo , Invasividad Neoplásica , Activadores Plasminogénicos/metabolismo , ARN Mensajero/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Células Tumorales CultivadasRESUMEN
We investigated the expression and cellular localization of plasminogen activator inhibitor type 1 (PAI-1) in human astrocytoma in vivo. Northern blot and densitometric quantitation of PAI-1 mRNA indicated that PAI-1 transcripts were significantly higher in human malignant astrocytomas and especially in glioblastomas than in low-grade gliomas and normal brain tissues in vivo. Using in situ hybridization with paraffin-embedded surgical specimens of human gliomas and normal brain tissues, PAI-1 mRNA was abundantly expressed in glioblastomas. PAI-1 mRNA was localized mainly in tumor cells and endothelial cells. The distribution of PAI-1 mRNA expression was particularly abundant around areas of vascular proliferation and in remnant tumor cells surrounding necrotic foci. PAI-1 mRNA was also expressed in both the tumor and endothelial cells of anaplastic astrocytomas, whereas it was not expressed or only weakly expressed in low-grade astrocytomas or normal brain tissues. These results suggest that high expression of PAI-1 is associated with the malignant progression of astrocytic tumors and that excessive PAI-1 expression might be associated with intratumoral necrosis in glioblastomas.
Asunto(s)
Astrocitoma/química , Química Encefálica , Neoplasias Encefálicas/química , Glioblastoma/química , Inhibidor 1 de Activador Plasminogénico/análisis , ARN Mensajero/análisis , ARN Neoplásico/análisis , Secuencia de Bases , Northern Blotting , Humanos , Hibridación in Situ , Datos de Secuencia Molecular , Inhibidor 1 de Activador Plasminogénico/genéticaRESUMEN
Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amount of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.
Asunto(s)
Astrocitoma/enzimología , Activador de Plasminógeno de Tipo Uroquinasa/análisis , Secuencia de Bases , Humanos , Inmunohistoquímica , Hibridación in Situ , Datos de Secuencia Molecular , Peso Molecular , ARN Mensajero/análisis , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
Human T-lymphotropic virus type 1 (HTLV-1) is etiologically associated with adult T-cell leukemia/lymphoma (ATL). Nevertheless, most individuals infected with HTLV-1 do not develop ATL. To attempt to identify genetic factors promoting the progression to ATL, we investigated in HTLV-1 carriers the relationship between susceptibility to ATL and several polymorphisms: the three "decreased-detoxifying" polymorphisms in GSTM1, GSTT1, and CYP1A1, the "proapoptotic" polymorphism in BCL2, and the five "high-production" polymorphisms in tumor necrosis factor alpha (TNF-alpha) using PCR-based genotyping assays. ATL patients (n = 71) were younger than HTLV-1 carriers (n = 80; 57 +/- 12 versus 63 +/- 10 years; P = 0.0017). MALE:female ratio in ATL patients was higher than in carriers (52:19 versus 19:61, respectively; P < 0.0001), probably reflecting a higher incidence of HTLV-1 infection in females and a higher incidence of development of ATL in males. We found that the frequency of the TNF-alpha-857T allele, reported to be associated with high transcriptional activity of the promoter/enhancer region of the TNF-alpha gene, was enriched in individuals with ATL compared with healthy carriers (18.3% versus 8.8%, respectively; odds ratio, 2.34; 95% confidence interval, 1.2-4.7). None of the other four TNF-alpha polymorphisms was a significant indicator of risk of development of ATL, although odds ratios (ATL versus carrier) of all of the TNF-alpha polymorphisms were higher than 1.0. Furthermore, analysis of polymorphisms for GSTM1, GSTT1, CYP1A1, and BCL2 showed no significant difference between ATL patients and healthy carriers. Genetic polymorphism leading to increased TNF-alpha production may enhance susceptibility to ATL among HTLV-1 carriers. Alternatively, but less likely, the HLA loci might be an important factor because the TNF-alpha gene lies within the class III region of the MHC; however, the 857T allele is not in linkage disequilibrium with HLA alleles associated with ATL development.
Asunto(s)
Portador Sano/virología , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Citocromo P-450 CYP1A1/genética , Progresión de la Enfermedad , Femenino , Genes bcl-2/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/virología , Masculino , Persona de Mediana Edad , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Infection by human T-cell leukemia virus type (HTLV) I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis. Leukocytes are attracted to sites of inflammation by chemokines. One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines. We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia. The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-kappaB sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-kappaB binding to both MCP-1 kappaB sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappaB. Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases.
Asunto(s)
Quimiocina CCL2/genética , Productos del Gen tax/fisiología , FN-kappa B/fisiología , Activación Transcripcional/fisiología , Sitios de Unión , Quimiocina CCL2/biosíntesis , Elementos de Facilitación Genéticos/fisiología , Regulación Viral de la Expresión Génica , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Infecciones por HTLV-I/genética , Infecciones por HTLV-I/metabolismo , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/virología , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Oncogénicas v-rel/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal/fisiología , Linfocitos T/metabolismo , Linfocitos T/fisiología , Linfocitos T/virologíaRESUMEN
Aneuploidy is a characteristic of the majority of human cancers, and recent studies suggest that defects of mitotic checkpoints play a role in carcinogenesis. MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability. Rare mutations of this gene have been reported in colon and lung cancers. We examined a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast and glioblastoma) for alterations of MAD1L1 by RT-PCR-SSCP and nucleotide sequencing. Eight mutations consisting of missense, nonsense and frameshift mutations were found, together with a number of nucleotide polymorphisms. All the alterations in cell lines were heterozygous. Frequency of mutations was relatively high in prostate cancer (2/7 cell lines and 2/33 tumor specimens). We placed a mutant truncated MAD1L1, found in a lymphoma sample, into HOS, Ht161 and SJSA cell lines and found that it was less inhibitory than wild type MAD1L1 at decreasing cell proliferation. Co-expression experiments showed that the mutant form had a dominant-negative effect. Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in HOS cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent, nocodazole. Our results suggest a pathogenic role of MAD1L1 mutations in various types of human cancer.
Asunto(s)
Transformación Celular Neoplásica/genética , Mitosis/genética , Mutación , Proteínas de Neoplasias/genética , Neoplasias de la Mama/genética , Codón sin Sentido , Femenino , Mutación del Sistema de Lectura , Neoplasias Hematológicas/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Mutación Missense , Osteosarcoma/genética , Neoplasias de la Próstata/genéticaRESUMEN
PURPOSE: To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome. MATERIALS AND METHODS: Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined. RESULTS: Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase. CONCLUSION: The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Eliminación de Gen , Genes Supresores de Tumor , Leucemia Prolinfocítica de Células T/genética , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas Supresoras de Tumor , Adulto , Recuento de Células , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patología , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
PURPOSE: To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS: In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS: The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION: M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.