RESUMO
The still continuing accelerated development of neurology in Germany is described in this article by a contemporary witness who was active in this field from 1965 to 2005. The personal experiences of the author are obviously only reflected over these 40 years so that the glorious antecedents in the period up to 1933, the era in which our predecessors were the world leaders in neurology, is not sufficiently covered. This dominance was lost by the anti-Semitism during the era of National Socialism and the sequelae of World War II. As a result of the war, German neurologists became effectively isolated and their participation in international congresses was forbidden so that a gradual reestablishment of alignment only became possible after 1960. In this brief description no attempt at completeness has been made and only subjectivity and brevity have been considered. An attempt is made to retrospectively convey what essentially happened. An exact dating of advances over the period was sometimes difficult. The readership will have the opportunity to share the surprise of the author on how meagre the neurological knowledge and diagnostic methods were 50 years ago, how rapidly the subsequent development happened, how rapidly things became obvious which 20 years ago nobody was aware of and despite the progress how pleased we were to find ourselves at the most recent state of error and probably still find ourselves nowadays. In particular, how powerless and untested the therapeutic efforts were at that time. The progress can only be measured by a comparison between then, 50 years ago and the present. A projection of the future based on these experiences is not attempted but it seems to be certain that many conceptions, diagnostic advances and therapy options are still undiscovered and that further exciting times can be expected.
Assuntos
Socialismo Nacional/história , Neurologia/história , II Guerra Mundial , Previsões , Alemanha , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Neurologia/tendênciasRESUMO
When an observer views a wide-angled display rotating around his line of sight, he both feels his body tilted and sees a vertical straight edge tilted opposite to the moving stimulus. Displacement of the perceived vertical increases with stimulus speed to reach a maximum (averaging 15 degrees) at 30 degrees per second.
Assuntos
Percepção de Movimento , Orientação , Humanos , PosturaRESUMO
During the flight of Spacelab 1 the crew performed a number of experiments to explore changes in vestibular function and visual-vestibular interactions on exposure to microgravity. Measurements were made on the threshold for detection of linear oscillation, vestibulo-ocular reflexes elicited by angular and linear movements, oculomotor and posture responses to optokinetic stimulations, and responses to caloric stimulation. Tests were also conducted on the ground, during the 4 months before and on days 1 to 6 after flight. The most significant result was that caloric mystagmus of the same direction as on the earth could also be evoked in the weightless environment.
Assuntos
Aceleração , Testes Calóricos , Voo Espacial , Testes de Função Vestibular , Vestíbulo do Labirinto/fisiologia , Percepção Visual/fisiologia , Eletroculografia , Movimentos Oculares , Cabeça/fisiologia , Humanos , Percepção de Movimento/fisiologia , Movimento , Nistagmo Fisiológico , Ausência de PesoRESUMO
Human malignant gliomas are highly lethal neoplasms. Involved-field radiotherapy is the most important therapeutic measure. Most relapses originate from the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of human malignant glioma cells. This hitherto unknown biological effect of irradiation is p53 independent, involves enhanced alphavbeta3 integrin expression, an altered profile of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9) expression and activity, altered membrane type 1 MMP and tissue inhibitor of metalloproteinases-2 expression, and an altered BCL-2/BAX rheostat favoring resistance to apoptosis. BCL-2 gene transfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner. Sublethal irradiation of rat 9L glioma cells results in the formation of a greater number of tumor satellites in the rat brain in vivo concomitant with enhanced MMP-2 and reduced tissue inhibitor of metalloproteinases-2 expression. Collectively, these data suggest that the current concepts of involved-field radiotherapy for malignant glioma need to be reconsidered and that the pharmacological inhibition of migration and invasion during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.
Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Movimento Celular/efeitos da radiação , Glioblastoma/radioterapia , Glioma/patologia , Células 3T3 , Animais , Neoplasias Encefálicas/metabolismo , Movimento Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Humanos , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Camundongos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Tolerância a Radiação/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Receptores de Vitronectina/antagonistas & inibidores , Esferoides Celulares/patologia , Esferoides Celulares/efeitos da radiação , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
CD95L-induced apoptosis involves caspase activation and is facilitated when RNA and protein synthesis are inhibited. Here, we report that hyperthermia sensitizes malignant glioma cells to CD95L- and APO2L-induced apoptosis in the absence, but not in the presence, of inhibitors of RNA and protein synthesis. Hyperthermia does not alter CD95 expression at the cell surface and does not modulate the morphology of CD95-mediated cell death on electron microscopy. Bcl-2 gene transfer inhibits apoptosis and abrogates the sensitization mediated by hyperthermia. Hyperthermia does not overcome resistance to apoptosis conferred by the viral caspase inhibitor, crm-A, indicating the absolute requirement for the activation of crm-A-sensitive caspases, probably caspase 8, for apoptosis. CD95L-evoked DEVD-amc-cleaving caspase activity is enhanced by hyperthermia, suggesting that hyperthermia operates upstream of caspase processing to promote apoptosis. There is no uniformly enhanced processing of three caspase 3 substrates, poly-ADP ribose polymerase (PARP), protein kinase C (PKC) delta and DNA fragmentation factor (DFF) 45. Yet, hyperthermia promotes CD95L-evoked DNA fragmentation. Interestingly, hyperthermia enhances the CD95L-evoked release of cytochrome c in the absence, but not in the presence, of CHX. In contrast, the reduction of the mitochondrial membrane potential is enhanced by hyperthermia both in the absence and presence of CHX, and enhanced cytochrome c release is not associated with significantly enhanced caspase 9 processing. The potentiation of cytochrome c release at hyperthermic conditions in the absence of CHX is abrogated by Bcl-2. Thus, either hyperthermia or inhibition of protein synthesis by CHX potentiate cytotoxic cytokine-induced apoptosis. These pathways show no synergy, but rather redundance, indicating that CHX may function to promote apoptosis in response to cytotoxic cytokines by inhibiting the synthesis of specific proteins whose synthesis, function or degradation is temperature-sensitive.
Assuntos
Apoptose/fisiologia , Grupo dos Citocromos c/metabolismo , Glioma/metabolismo , Hipertermia Induzida , Glicoproteínas de Membrana/metabolismo , Proteínas Virais , Proteínas Reguladoras de Apoptose , Caspase 8 , Caspase 9 , Inibidores de Caspase , Caspases/metabolismo , Cumarínicos/metabolismo , Cicloeximida/farmacologia , Proteína Ligante Fas , Glioma/patologia , Glioma/terapia , Humanos , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Glicoproteínas de Membrana/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/efeitos dos fármacos , Oligopeptídeos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/metabolismo , Proteína Quinase C-delta , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serpinas/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in vivo and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2 and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas. Oncogene (2000) 19, 4210 - 4220
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Membrana , Proteínas de Neoplasias/fisiologia , Proteínas/fisiologia , Transativadores , Proteínas de Peixe-Zebra , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/genética , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular , Células Clonais/patologia , Meios de Cultura Livres de Soro , Proteínas do Citoesqueleto/metabolismo , Glioblastoma/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Metaloproteinase 2 da Matriz/fisiologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/fisiologia , Transplante Heterólogo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/transplante , Proteínas Wnt , beta CateninaRESUMO
Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
Assuntos
Apoptose , Citocinas/farmacologia , Genes p53/fisiologia , Glioma/metabolismo , Proteínas de Neoplasias/biossíntese , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico/biossíntese , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Cicloeximida/farmacologia , Dexametasona/farmacologia , Genes p53/genética , Glioma/genética , Glioma/patologia , Humanos , Interleucina-1/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Fator de Crescimento Transformador alfa/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Células Tumorais Cultivadas , Receptor fas/fisiologiaRESUMO
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD). Here we show that a peptide caspase inhibitor, N-benzyloxy-carbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.
Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Fatores de Crescimento Neural , Proteínas do Tecido Nervoso/genética , Doença de Parkinson Secundária/terapia , Proteínas/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Apoptose/efeitos dos fármacos , Inibidores de Caspase , Células Cultivadas , Dopamina/metabolismo , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Proteínas/metabolismo , Proteínas/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo XRESUMO
Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K.
Assuntos
Apoptose/fisiologia , Caspases/metabolismo , Células Jurkat/citologia , Proteínas Quinases Ativadas por Mitógeno , Esfingomielina Fosfodiesterase/metabolismo , Proteínas Virais , Receptor fas/metabolismo , Ácidos/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Ceramidas/metabolismo , Inibidores de Cisteína Proteinase/genética , Inibidores de Cisteína Proteinase/farmacologia , Diglicerídeos/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Imipramina/farmacologia , Células Jurkat/enzimologia , Serpinas/genética , Transdução de Sinais/fisiologia , Linfócitos T/citologia , Linfócitos T/enzimologia , Transfecção , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Encéfalo/patologia , Inibidores de Caspase , Corpo Estriado/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Genes bcl-2 , Hipóxia Encefálica/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Clorometilcetonas de Aminoácidos/uso terapêutico , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Caspase 2 , Caspase 3 , Caspases/metabolismo , Corpo Estriado/patologia , Corpo Estriado/fisiologia , Cicloeximida/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Maleato de Dizocilpina/uso terapêutico , Sinergismo Farmacológico , Humanos , Hipóxia Encefálica/induzido quimicamente , Hipóxia Encefálica/patologia , Marcação In Situ das Extremidades Cortadas , Masculino , Malonatos/toxicidade , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Ratos Sprague-DawleyRESUMO
Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.
Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Adolescente , Adulto , Idoso , Análise de Variância , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/patologia , Terapia Combinada , Demografia , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta à Radiação , Tratamento Farmacológico/métodos , Feminino , Humanos , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/epidemiologia , Meduloblastoma/patologia , Pessoa de Meia-Idade , Radioterapia de Alta Energia/métodos , Recidiva , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
A gene encoding the p53 val135 mutant, which assumes mutant conformation at 38.5 degrees C and wild-type conformation at 32.5 degrees C, was introduced into p53-deficient K562 myeloid leukemia cells. Forced expression of wild-type, but not mutant, p53 resulted in growth arrest, accumulation of p21 and Bax proteins, and delayed cell death. Wild-type p53 enhanced the cytotoxic effects of some drugs and attenuated those of others. Compared with wild-type p53, mutant p53 induced much stronger sensitization to drug cytotoxicity. This occurred in the absence of effects on cell cycle progression or activation of several p53 target genes. Although both mutant and wild-type p53 induced changes of immunophenotype, no specific pattern of differentiation was associated with enhanced chemosensitivity. Thus, (1) induction of growth arrest and activation of p53 target genes such as p21 and bax are linked to the wild-type conformation of p53; (2) p53 induces immunophenotypic changes of myeloid leukemia cells suggestive of multidirectional differentiation in a conformation-dependent manner; and (3) (so-called) mutant p53 induces chemosensitization in the absence of effects on cell cycle progression, activation of bax, p21, gadd45 and mdm-2, or a specific pattern of differentiation; and (4) chemosensitization mediated by wild-type p53 may be masked by transcription-dependent induction of growth arrest.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Leucemia Mieloide/patologia , Leucemia Mieloide/fisiopatologia , Camundongos , Microscopia Eletrônica , Mutação , Temperatura , Transfecção , Células Tumorais Cultivadas/ultraestrutura , Proteína Supressora de Tumor p53/genéticaRESUMO
Toxocariasis is a worldwide-occurring parasitic infection leading to tissue damage in various organs due to wandering Toxocara larvae (visceral larva migrans). More than 40 cases of CNS involvement in children and immunocompetent adults have been documented in detail to date. Here, we present evidence of eosinophilic meningomyelitis in an adult without known risk factors and with positive Toxocara antibody response in CSF, but not in blood. Toxocariasis has to remain among the differential diagnosis in patients with eosinophilic CNS infection even if serological tests in blood are negative. Adult cases seem to be more frequent than previously thought (about 60%).
Assuntos
Eosinofilia/parasitologia , Meningite/parasitologia , Mielite/parasitologia , Toxocara canis , Toxocaríase/diagnóstico , Adulto , Animais , Anticorpos Anti-Helmínticos/líquido cefalorraquidiano , Eosinofilia/líquido cefalorraquidiano , Humanos , Meningite/líquido cefalorraquidiano , Mielite/líquido cefalorraquidiano , Toxocara canis/imunologiaRESUMO
CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from nontransformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Glicoproteínas de Membrana/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/metabolismo , Membrana Celular/metabolismo , Sinergismo Farmacológico , Proteína Ligante Fas , Glioma/metabolismo , Humanos , Glicoproteínas de Membrana/efeitos adversos , Glicoproteínas de Membrana/metabolismo , Proteínas Recombinantes , Receptor fas/metabolismoRESUMO
The March COM. A 41-year-old woman presented in 1997 with diffuse abdominal pain, meteorism and intermittent diarrhea. Imaging studies revealed a focal rounded lesion in the liver. Although there was no history of progesterone or estrogen therapy, the radiographic appearance was considered to be suggestive of adenoma. The lesion was monitored by ultrasound until October 2000 when a resection was performed because of the presumed risk of a malignant transformation. H&E stained sections revealed an ectopic ependymoma that was strongly positive for GFAP. The surrounding hepatic tissue was negative for GFAP. An extensive search for a CNS manifestation or any other extraspinal localization was unrevealing. We believe we have encountered the first case of an ectopic ependymoma presenting as a solitary hepatic lesion in the absence of CNS disease. Ependymomas generally arise in the CNS in relation to the ventricular system. Extraneural metastasis from ependymomas may occasionally occur even years after detection and treatment of the primary lesion and have been the subject of several reports. In contrast, there are only anecdotal reports of primary extraneural "ectopic" ependymomas. So far those rare cases have only been found in close vicinity to the neural axis, eg, in the sacrococcygeal region, the posterior mediastinum or the ovaries and are there thought to originate from embryonic remnant cells around the neural tube. Distant metastases of ependymomas invading or arising within the extraneural lumbosacral soft tissue may occur in this situation. Here, we report what appears to be the first case of a primary ectopic ependymoma originating in the liver, with no signs of CNS or other systemic involvement.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Ependimoma/patologia , Fígado/patologia , Dor Abdominal , Adenoma/diagnóstico , Adulto , Neoplasias do Sistema Nervoso Central/metabolismo , Ependimoma/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Fígado/lesões , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
Bag-1 is a heat shock 70 kDa (Hsp70)-binding protein that can collaborate with Bcl-2 in suppressing apoptosis under some conditions. Here, we report that 11 of 12 human glioma cell lines express Bag-1 protein in vitro. Moreover, 15 of 19 human glioblastomas expressed Bag-1 as assessed by immunohistochemistry in primary tumor specimens. To examine the biological effects of Bag-1 in glioma cells, we expressed Bag-1 or Bcl-2 transgenes in 2 human malignant glioma cell lines, LN-18 and LN-229. Bag-1 significantly slowed glioma cell growth and reduced clonogenicity of both cell lines in vitro. Coexpressed Bcl-2 abrogated these effects of Bag-1. Intracranial LN-229 glioma xenografts implanted into nude mice revealed a substantial growth advantage afforded by Bcl-2. Bag-1 had no such effect, either in the absence or presence of Bcl-2. Upon serum starvation in vitro, Bcl-2 prevented cell death whereas Bag-1 did not. Both Bcl-2 and Bag-1 slowed proliferation of serum-starved cells when expressed alone. Importantly, coexpression of Bcl-2 and Bag-1 provided a distinct growth advantage under conditions of serum starvation that is probably the result of (i) the death-preventing activity of Bcl-2 and (ii) the property of Bag-1 to overcome a Bcl-2-mediated enhancement of exit from the cell cycle. In contrast to these Bcl-2/Bag-1 interactions observed under serum starvation conditions, Bag-1 did not further enhance the strong protection from staurosporine-, CD95 (Fas/Apo1) ligand-, Apo2 ligand (TRAIL)- or chemotherapeutic drug-induced apoptosis afforded by Bcl-2. Taken together, these results indicate a role for Bag-1/Bcl-2 interactions in providing a survival advantage to cancer cells in a deprived microenvironment that may be characteristic of ischemic/hypoxic tumors such as human glioblastoma multiforme, and suggest that Bcl-2/Bag-1 interactions also modulate cell proliferation.
Assuntos
Proteínas de Transporte/fisiologia , Glioma/patologia , Glioma/fisiopatologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Divisão Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro , Proteínas de Ligação a DNA , Sinergismo Farmacológico , Glioma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Fatores de Transcrição , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/patologiaRESUMO
CD95 ligand is a cytotoxic cytokine that induces apoptosis. Here we report that CD95-mediated apoptosis of human malignant glioma cells is associated with arachidonic acid (AA) release. Inhibitors of phospholipase A2, phospholipase C or diacylglycerol lipase have minor effects on AA release and fail to modulate apoptosis. Formation of two AA metabolites generated during CD95-dependent apoptosis is attenuated by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA). NDGA also blocks CD95 ligand-induced apoptosis. This effect is independent of antioxidant properties of NDGA. Lipoxygenase may thus play a critical role in CD95 ligand-induced apoptosis of human malignant glioma cells.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/imunologia , Glioma/terapia , Inibidores de Lipoxigenase/farmacologia , Glicoproteínas de Membrana/fisiologia , Receptor fas/metabolismo , Animais , Ácido Araquidônico/metabolismo , Proteína Ligante Fas , Glioma/imunologia , Glioma/metabolismo , Humanos , Ligantes , Masoprocol/farmacologia , Camundongos , Fosfolipases/antagonistas & inibidores , Células Tumorais CultivadasRESUMO
Malignant progression in gliomas is correlated with increased migratory capacity which involves metalloproteolytic activity. Here, we report that ectopic expression of BCL-2 in two malignant glioma sublines markedly promoted glioma cell migration from spheroids and invasion into Matrigel-coated membranes. Invasion of fetal rat-brain aggregates was enhanced by BCL-2. Zymography revealed activation of matrix metalloproteinase-2 (MMP-2) in BCL-2-expressing cells. BCL-2 expressing cells showed an increase in MMP-2/-3/-12 (LN-18), and MMP-9/-12 and cell surface urokinase-type plasminogen activator (u-PA) (LN-229) mRNA and a reduction in tissue inhibitors of metalloproteinases (TIMP)-2 mRNA (LN-229). Taken together, we propose a novel function for BCL-2 in the malignant phenotype of glioma cells, that is, to enhance migration and invasion by altering the expression of a set of metalloproteinases and their inhibitors.