RESUMO
Recently we identified a novel gene, gml, whose expression is regulated in a p53-dependent manner and found that gml expression was correlated with the sensitivity of esophageal cancer cells to anticancer drugs. To further investigate the biological mechanism of gml in determining the chemosensitivity of cancer cells to clinically useful agents, we introduced gml cDNA into TE10, an esophageal cancer cell line that lacks endogenous gml expression. In two resulting stable cell lines which expressed gml cDNA in the absence of wildtype p53, cell death occurred within 6 h after treatment with Taxol. TE10 parent cells or TE10 cells transfected with vector alone displayed relative resistance for 36 h. Induction of gml did not by itself affect viability. Morphological analysis confirmed that the increased chemosensitivity to Taxol conferred by gml was due to apoptosis. These data suggest that reduced expression of gml is likely to be associated with poor response rates to chemotherapy, and that an assay for gml expression might serve a clinical purpose as a predictor of chemotherapeutic sensitivity.
Assuntos
Apoptose/genética , Proteínas de Ciclo Celular , Proteínas de Membrana/genética , Proteínas de Neoplasias , Paclitaxel/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Proteínas Ligadas por GPI , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
The genetic alteration of p53 is associated with neovascularization during progression of glioma to its more malignant form, glioblastoma. Hence, one or more of the genes transactivated by p53 is likely to function as an angiogenesis inhibitors. We isolated a novel p53-inducible gene that encodes a 1584-amino-acid product containing five thrombospondin type 1 (TSP-type 1) repeats and is specifically expressed in the brain. A recombinant protein corresponding to the TSP-type 1 repeats of this gene product inhibited in vivo neovascularization induced by bFGF in the rat cornea. The expression of this gene, designated BAI1 (brain-specific angiogenesis inhibitor 1) was absent or significantly reduced in eight of nine glioblastoma cell lines, suggesting BAI1 plays a significant role in angiogenesis inhibition, as a mediator of p53.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Genes p53/fisiologia , Glioblastoma/irrigação sanguínea , Neovascularização Patológica/genética , Trombospondina 1/genética , Sequência de Aminoácidos , Animais , Neoplasias Encefálicas/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Glioblastoma/metabolismo , Humanos , Dados de Sequência Molecular , Neovascularização Patológica/metabolismo , Ratos , Sequências Repetitivas de Ácido Nucleico , Homologia de Sequência de Aminoácidos , Ativação Transcricional , Células Tumorais CultivadasRESUMO
Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.
Assuntos
Translocador 2 do Nucleotídeo Adenina/deficiência , Linfócitos B/citologia , Eritrócitos/citologia , Eritropoese/fisiologia , Linfopoese/fisiologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Translocador 2 do Nucleotídeo Adenina/genética , Translocador 2 do Nucleotídeo Adenina/metabolismo , Trifosfato de Adenosina/metabolismo , Anemia/genética , Anemia/metabolismo , Animais , Linfócitos B/metabolismo , Eritrócitos/metabolismo , Eritropoese/genética , Feminino , Técnicas de Inativação de Genes , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Humanos , Linfopoese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismoRESUMO
BACKGROUND: Depressive (or depression-like) episodes are the most common manifestations of bipolar affective disorder in early teenage years. The present paper analyses the clinical features and their changes over time in these episodes. METHODS: By a prospective study on children who had their first affective or psychotic episodes between the ages of ten and fifteen, those who eventually met the ICD 10 diagnostic criteria for bipolar disorder were selected and followed up. RESULTS: There were three boys and nine girls. Their early depressive episodes were characterised by psychotic features and clinging to the mother in most cases, and in some by brief episodes and/or a good response to sulpiride. However, these characteristics tended to disappear with increasing age. Five children (42%) had an IQ of 61-75. LIMITATIONS: Generalisability of the results is limited because of the small number of patients and the lack of control groups. CONCLUSIONS: Bipolar disorder in early teenage years may show clinical features and a drug response that are different from those in adulthood. Low IQ may expedite the onset of bipolar disorder.
Assuntos
Transtorno Bipolar/diagnóstico , Depressão/diagnóstico , Inteligência , Desenvolvimento da Personalidade , Adolescente , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Criança , Depressão/genética , Depressão/psicologia , Feminino , Humanos , Inteligência/genética , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
Resection of bilateral pheochromocytomas of a 33-year-old man with Sipple syndrome was scheduled. Oral prazosin was started twenty days before the operation and increased to a maintenance dose of 6 mg per day. Oral lavetalol 300 mg per day was added for five days before the operation because prazosin alone was insufficient. Intravascular volume was expanded with two units of stored whole blood per day for four days before the operation for preoperative preparation. Anesthesia was induced with thiamylal 250 mg and vecuronium bromide 9 mg, and maintained with enflurane, nitrous oxide and oxygen. Phentolamine, labetalol and nitroglycerin were used for treatment of hypertensive crises during operation and anesthesia. To combat hypotension which follows the resection of the tumor, continuous infusion of norepinephrine was used for four hours after the operation. There were no hypotensive periods and no complications. After removing bilateral pheochromocytomas of the adrenals, treatment of full adrenocortical replacement therapy was performed. Concurrent use of alpha-and beta-adrenergic blocking agents was important for successful anesthetic management for the resection of pheochromocytoma.
Assuntos
Anestesia por Inalação , Labetalol/administração & dosagem , Neoplasia Endócrina Múltipla/cirurgia , Prazosina/administração & dosagem , Administração Oral , Adulto , Humanos , MasculinoRESUMO
Weak opioids have been used as analgesics in cancer patients with moderate to severe chronic pain. Codeine is one of the weak opioids which is assigned as a representative analgesic of the 2nd ladder-drugs for the treatment of cancer pain by WHO cancer pain relief programme. Analgesic effect of codeine is recognized when it is administered with 20 mg p.o. or more. Clinical ceiling effect of codeine is seemed to be 200-300 mg/day, although it is described as 600 mg/day in some textbooks. Side effects of codeine are same as those of morphine, therefore, drugs for the side effects should be given to the patients simultaneously when codeine is administered.
Assuntos
Analgésicos Opioides/administração & dosagem , Codeína/administração & dosagem , Dor/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Doença Crônica , Codeína/efeitos adversos , Constipação Intestinal/induzido quimicamente , Quimioterapia Combinada , Humanos , Neoplasias/complicações , Dor/etiologiaAssuntos
Hemorragia/complicações , Hipotensão/sangue , Nefrectomia , Renina/metabolismo , Animais , Cães , Hipotensão/etiologia , MasculinoRESUMO
A case report of 32-year-old male with renovascular hypertension, suspected to be pheochromocytoma as a result of a tentative diagnosis, is given. The suspicion was based on the observation of high levels of urinary noradrenaline on several occasions with the sign of hyperreninemia. Reduction of the urinary noradrenaline levels by the administration of angiotensin converting enzyme inhibitor (SQ-14225) suggested that the high urinary noradrenaline probably resulted from hyperreninemia which reflected high plasma levels of angiotensin II. Radioisotope renography and intravenous urography strongly suggested a reduction of the right renal blood flow, and the final diagnosis of renovascular hypertension was obtained on the basis of renal arteriography. On the other hand, the possibility of a catecholamine releasing tumor was carefully excluded by angiography before undertaking surgical treatment. The affected kidney was transplanted autogenously into the abdominal cavity. The successful operation led to a decrease in plasma renin activity, blood pressure and urinary noradrenaline excretion. In the present case, we were thus unable to define at first whether the primary genesis of hypertension was related to the hyperactivity of the renin-angiotensin system caused by renovascular stenosis or a noradrenaline releasing tumor.
Assuntos
Hipertensão Renal/urina , Hipertensão Renovascular/urina , Norepinefrina/urina , Adulto , Angiotensinas/fisiologia , Captopril/uso terapêutico , Catecolaminas/biossíntese , Humanos , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/etiologia , Masculino , Renina/sangueRESUMO
NK4 composed of the N-terminal hairpin and subsequent four-kringle domains of hepatocyte growth factor (HGF) is bifunctional, acting as a competitive antagonist for HGF and an angiogenesis inhibitor. In this study, we determined whether or not four-kringle domains of HGF (K1-4) have anti-angiogenic activity. For this purpose, we prepared recombinant K1-4 and NK4, using the baculovirus expression system. Although NK4 antagonized HGF-induced DNA synthesis of rat hepatocytes, cell scattering of MDCK cells and the c-Met/HGF receptor tyrosine phosphorylation in endothelial cells, K1-4 failed to antagonize HGF-induced DNA synthesis, cell scattering and the c-Met/HGF receptor tyrosine phosphorylation in endothelial cells, thus, indicating that K1-4 lacks HGF-antagonist activity. However, endothelial proliferation and migration induced by HGF was inhibited by K1-4, similar to the case seen with NK4. Furthermore, K1-4 inhibited the proliferation and migration of human dermal microvascular endothelial cells induced by vascular endothelial growth factor or by basic fibroblast growth factor. We propose that kringle 1-4 of HGF inhibits angiogenic responses in endothelial cells, independently of HGF-c-Met signaling pathways.
Assuntos
Inibidores da Angiogênese , Movimento Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Kringles , Animais , Células CHO , Divisão Celular/efeitos dos fármacos , Cricetinae , Fatores de Crescimento Endotelial/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Fator 2 de Crescimento de Fibroblastos/fisiologia , Fator de Crescimento de Hepatócito/química , Humanos , Linfocinas/fisiologia , Neovascularização Fisiológica , Fosforilação , Conformação Proteica , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Supramaximal paired stimuli were applied to the ulnar nerve, and the amplitude of the muscle action potential evoked in the abductor digiti minimi by the second member of the stimulus pair (test response) was compared with that evoked by the first component (conditioning response). The interval between the two components of the stimulus pair (the pair interval) was increased stepwise from 7 to 100 msec and a curve (recovery curve) was obtained by relating the changes in pair interval to the difference in amplitude of the test and conditioning responses. Alterations of the recovery curve (RC) during partial paralysis by muscle relaxants were investigated in healthy adult patients under the lightest plane of general anaesthesia. The control curve obtained in 32 subjects before the administration of a muscle relaxant drug was characterized by slight depressions at very short intervals of paired stimuli, followed by a slight potentiation at 20-100 msec. With non-depolarizing relaxants, RC altered to the characteristic pattern of potentiation at very short intervals of stimuli, followed by a notable depression at longer intervals. In depolarizing blocks with small doses of suxamethonium, the depression of RC at short intervals in the control was enhanced and the pattern of RC was different from that of non-depolarizing agents. When desensitization blocks were instigated by the i.v. administration of suxamethonium, the RC patterns were similar to those of competitive agents.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Relaxantes Musculares Centrais/farmacologia , Adulto , Alcurônio/administração & dosagem , Alcurônio/farmacologia , Estimulação Elétrica , Eletromiografia , Potenciais Evocados/efeitos dos fármacos , Feminino , Trietiodeto de Galamina/administração & dosagem , Trietiodeto de Galamina/farmacologia , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Pancurônio/administração & dosagem , Pancurônio/farmacologia , Succinilcolina/administração & dosagem , Succinilcolina/farmacologia , Fatores de Tempo , Tubocurarina/administração & dosagem , Tubocurarina/farmacologia , Nervo Ulnar/efeitos dos fármacosRESUMO
Plasma renin activity (PRA) was measured in 14 control subjects and 27 patients with essential hypertension (EH) (low renin group: 9, normal renin group: 11, and high renin group: 7) before and after the following stimulation tests. Test procedures: 1) Circadian rhythm (0600, 1600 and 2400h). 2) Adrenal stimulation test (ACTH: 12.5 I.U.). 3) Adrenal suppression test (Dexamethasone: 1.0 mg). 4) Metopirone test (1.5 g). 5) Angiotensin II infusion test (8 ng/kg/min). 6) Saline infusion test (1000 ml/hr). Patients with low PRA showed significantly lower levels of PRA than those of other two groups in circadian rhythm, after 2 hours of ACTH infusion and after angiotensin II infusion. Furthermore, these patients showed significantly higher responses of PRA than other two groups after furosemide test under dexamethasone and after metopirone test. In case of saline infusion test, patients with low and normal PRA did not show significantly decreased levels of PRA after the infusion, though all patients with high PRA and all control subjects showed significantly decreased levels of PRA. From the present studies, it might be concluded that patients with low PRA has an unknown mineralocorticoid excess which is ACTH dependent and 11 hydroxylated and some of hypertensive patients have an abnormality in their renin-angiotensin-aldosterone volume feed back loop as a factor for hypertension.
Assuntos
Hipertensão/enzimologia , Renina/sangue , Hormônio Adrenocorticotrópico , Adulto , Angiotensina II , Ritmo Circadiano , Dexametasona , Humanos , Hipertensão/etiologia , Masculino , Metirapona , Pessoa de Meia-IdadeRESUMO
We have identified two novel human genes homologous to BAI1 (brain-specific angiogenesis inhibitor 1), an angiogenesis inhibitor that is a candidate for involvement in development of glioblastoma. Like BAI1, these two genes, designated BAI2 and BAI3, were specifically expressed in brain, and are likely to be expressed in the same type of cells. However, in spite of similar tissue specificity among the three BAI genes, only BAI1 is transcriptionally regulated by p53. BAI3 expression was absent in two of nine glioblastoma cell lines examined and was significantly reduced in three of the remaining seven. These data suggest that members of this novel gene family may play important roles in suppression of glioblastoma. BAI1, BAI2 and BAI3 were mapped to 8q24, 1p35 and 6q12, respectively.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 6 , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Proteínas do Tecido Nervoso/genética , Astrócitos/citologia , Clonagem Molecular , DNA Complementar/isolamento & purificação , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Dados de Sequência Molecular , Família Multigênica/genética , Neovascularização Patológica/genética , RNA Mensageiro/análise , Homologia de Sequência de Aminoácidos , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
Brain-specific angiogenesis inhibitor 1 (BAI1), which is a p53-target gene specifically expressed in brain, encodes a seven-span transmembrane protein. Using a two-hybrid system, we isolated a cDNA that encodes a protein, named BAP1 (BAI1-associated protein), which interacts with the cytoplasmic region of BAI1. BAP1 is a novel member of the MAGUK (membrane-associated guanylate kinase homologue) family; it possesses a guanylate kinase domain, WW domains, and multiple PDZ domains. Interaction between BAI1 and BAP1 was mediated by a QTEV motif in the carboxy-terminal region of BAI1 and PDZ domains of BAP1. By immunocytochemical analysis of COS-7 cells transfected with BAI1 and BAP1, both products were co-localized at the cytoplasmic membrane, especially at cell-cell junctions. Cells transfected with BAI1 formed filopodia-like cytoplasmic extensions. These results suggest that BAI1 and BAP1 might be involved in cell adhesion and signal transduction in brain.
Assuntos
Encéfalo/fisiologia , Moléculas de Adesão Celular Neuronais/química , Proteínas de Drosophila , Neovascularização Fisiológica/fisiologia , Proteínas do Tecido Nervoso/química , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Células COS , Adesão Celular/fisiologia , Moléculas de Adesão Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Clonagem Molecular , Guanilato Quinases , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteínas de Insetos/química , Dados de Sequência Molecular , Núcleosídeo-Fosfato Quinase/química , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Homologia de Sequência de Aminoácidos , Transdução de Sinais/fisiologia , Transfecção/genéticaRESUMO
BAI1 (brain-specific angiogenesis inhibitor 1), a p53-target gene specifically expressed in brain, encodes a seven-span transmembrane protein considered to be a member of the secretin receptor family. Using a two-hybrid system, we isolated a cDNA encoding a product that interacts with the cytoplasmic region of BAI1 and designated it BAP3 (BAI1-associated protein 3). The BAP3 product is a novel C2 domain-containing molecule with homology to Munc13 and synaptotagmin. As with Munc13, BAP3 is expressed predominantly in brain. Deletion-mutant analysis revealed that the interaction between BAI1 and BAP3 was not mediated by the C2 domains. Its predominant expression in brain and homology to Munc13 indicate that BAP3, by interacting with BAI1, might be involved in some neuronal function such as regulating release of neurotransmitters.