RESUMO
We report on an 11-year-old girl who developed steroid-resistant nephrotic syndrome (NS) at the onset of systemic lupus erythematosus (SLE), and clinical and renal histological findings suggested that her NS would be associated with SLE-related podocytopathy. Although initial treatment with intravenous pulse methylprednisolone was ineffective, following treatment with cyclosporine and an angiotensin receptor blocker was effective for her nephrotic proteinuria. She had developed posterior reversible encephalopathy syndrome (PRES), and mycophenolate mofetil (MMF) was started instead of cyclosporine. At present, 45 months after the onset, she is in remission of both NS and SLE. This case indicates that NS associated with SLE-related podocytopathy should be included in the spectrum of glomerulopathy accompanying SLE, also in the pediatric population.
Assuntos
Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Metilprednisolona/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/etiologia , Criança , Ciclosporina , Resistência a Medicamentos , Feminino , HumanosRESUMO
Sister chromatid cohesion mediated by the cohesin complex is essential for faithful chromosome segregation. Previously we reported that PHB2 (prohibitin2/ASURA), a multifunctional protein, has a role in sister chromatid cohesion. Nevertheless, how ASURA is involved in sister chromatid cohesion still remains unclear. The present co-immunoprecipitation analysis reveals that ASURA interacts with cohesin subunit Scc1 in vivo. We show that ASURA associates with chromatin in a similar manner as Scc1 throughout the cell cycle. Furthermore, our observation using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system indicates that ASURA is important for cohesin maintenance at early mitosis. We have also identified that the conserved PHB domain is responsible for chromatin targeting of ASURA. Our results suggest that the regulation of sister chromatid cohesion is mediated by ASURA binding to chromatin, where ASURA might be involved in cohesin protection through ASURA-Scc1 interactions.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteínas Repressoras/metabolismo , Contagem de Células , Proteínas de Ciclo Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Centrômero/genética , Centrômero/metabolismo , Cromátides/genética , Cromátides/metabolismo , Cromatina/genética , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA , Corantes Fluorescentes/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HeLa , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitose , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proibitinas , Ligação Proteica , Estrutura Terciária de Proteína , Interferência de RNA , Proteínas Repressoras/genética , CoesinasRESUMO
Recent studies in vertebrates and Drosophila melanogaster have revealed that Fringe-mediated activation of the Notch pathway has a role in patterning cell layers during organogenesis. In these processes, a homeobox-containing transcription factor is responsible for spatially regulating fringe (fng) expression and thus directing activation of the Notch pathway along the fng expression border. Here we show that this may be a general mechanism for patterning epithelial cell layers. At three stages in Drosophila oogenesis, mirror (mirr) and fng have complementary expression patterns in the follicle-cell epithelial layer, and at all three stages loss of mirr enlarges, and ectopic expression of mirr restricts, fng expression, with consequences for follicle-cell patterning. These morphological changes are similar to those caused by Notch mutations. Ectopic expression of mirr in the posterior follicle cells induces a stripe of rhomboid (rho) expression and represses pipe (pip), a gene with a role in the establishment of the dorsal-ventral axis, at a distance. Ectopic Notch activation has a similar long-range effect on pip. Our results suggest that Mirror and Notch induce secretion of diffusible morphogens and we have identified TGF-beta (encoded by dpp) as such a molecule in germarium. We also found that mirr expression in dorsal follicle cells is induced by the EGF-receptor (EGFR) pathway and that mirr then represses pip expression in all but the ventral follicle cells, connecting EGFR activation in the dorsal follicle cells to repression of pip in the dorsal and lateral follicle cells. Our results suggest that the differentiation of ventral follicle cells is not a direct consequence of germline signalling, but depends on long-range signals from dorsal follicle cells, and provide a link between early and late events in Drosophila embryonic dorsal-ventral axis formation.
Assuntos
Padronização Corporal/genética , Proteínas de Drosophila , Embrião não Mamífero/embriologia , Fator de Crescimento Epidérmico/metabolismo , Proteínas do Olho/metabolismo , Genes Homeobox/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Membrana/metabolismo , N-Acetilglucosaminiltransferases , Fatores de Transcrição , Animais , Cruzamentos Genéticos , Drosophila melanogaster/embriologia , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Proteínas do Olho/genética , Feminino , Proteínas de Homeodomínio/genética , Hibridização In Situ , Proteínas de Insetos/metabolismo , Masculino , Oogênese/genética , Óvulo/citologia , Óvulo/metabolismo , Receptores Notch , Transdução de Sinais/genéticaRESUMO
We describe a case of FIGO Stage IB2 uterine cervical cancer which showed focal intense bone marrow FDG uptake mimicking bone metastases after the administration of G-CSF This case highlights the importance of avoiding the administration of G-CSF prior to PET imaging.
Assuntos
Neoplasias da Medula Óssea/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Fator Estimulador de Colônias de Granulócitos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias da Medula Óssea/secundário , Neoplasias Ósseas/secundário , Carcinoma de Células Escamosas/secundário , Contraindicações , Reações Falso-Positivas , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Neoplasias do Colo do Útero/patologiaRESUMO
We evaluated the efficacy of a treatment strategy in which infants with acute lymphoblastic leukemia (ALL) were stratified by their MLL gene status and then assigned to different risk-based therapies. A total of 102 patients were registered on two consecutive multicenter trials, designated MLL96 and MLL98, between 1995 and 2001. Those with a rearranged MLL gene (MLL-R, n=80) were assigned to receive intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), while those with germline MLL (MLL-G, n=22) were treated with chemotherapy alone. The 5-year event-free survival (EFS) rate for all 102 infants was 50.9% (95% confidence interval, 41.0-60.8%). The most prominent late effect was growth impairment, observed in 58.9% of all evaluable patients in the MLL-R group. This plan of risk-based therapy appears to have improved the overall prognosis for infants with ALL, compared with previously reported results. However, over half the events in patients with MLL rearrangement occurred before the instigation of HSCT, and that HSCT-related toxic events comprised 36.3% (8/22) of post-transplantation events, suggesting that further stratification within the MLL-R group and the development of more effective early-phase intensification chemotherapy will be needed before the full potential of this strategy is realized.
Assuntos
Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Antineoplásicos/efeitos adversos , Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Indução de Remissão , Risco , Transplante de Células-Tronco/efeitos adversos , Resultado do TratamentoRESUMO
Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.
Assuntos
Cromossomos Humanos Par 17 , Cromossomos Humanos Par 19 , Proteínas de Ligação a DNA/genética , Hipercalcemia/complicações , Hipercalcemia/genética , Proteínas de Fusão Oncogênica/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Translocação Genética , Adolescente , Cálcio/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A 20-year-old female developed a relapse of B-precursor acute lymphoblastic leukemia (ALL) as a mass in her left breast after 6 years of maintained continuous complete remission. No leukemic lesions were identified in other sites such as the bone marrow or cerebrospinal fluid. The relapsed leukemic cells in the breast revealed the same immunophenotypes (CD10(+), CD19(+), CD20(+), HLA-DR(+), CD34(+)) as those of the onset ALL cells in the bone marrow. A literature survey found 10 other cases of ALL relapse in the breast without bone marrow involvement, mostly consisting of adolescent girls. Including the present report, a total of 11 cases were analyzed; the onset ages of ALL were a median of 16.5 (range 5-50) years old and the ages of relapse in the breast a median of 20 (range 12-51) years old. Data suggest that, although rare, the breast could become one of the extramedullary relapse sites of ALL developed in adolescent girls.
Assuntos
Neoplasias da Mama/secundário , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adulto , Feminino , HumanosRESUMO
Senile plaques in the brain of patients with Alzheimer's disease mainly consist of aggregates of amyloid beta peptides (Abeta42, Abeta40). Abeta42 is more neurotoxic than Abeta40. This review describes recent findings from a structural analysis of Abeta42 aggregates and discusses their relevance to neurotoxicity through the formation of radicals.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Radicais Livres/metabolismo , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Animais , Angiopatia Amiloide Cerebral/etiologia , Angiopatia Amiloide Cerebral/metabolismo , Radicais Livres/toxicidade , Humanos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Estrutura Terciária de ProteínaRESUMO
The prognosis of patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) relapse has historically been very poor. Although chemo-radiotherapy has improved outcomes, some patients still have a poor prognosis after CNS relapse. Therefore, allogeneic hematopoietic stem cell transplantation (allo-SCT) has recently become an option for treatment of CNS leukemia; however, information, particularly on the long-term outcome of transplant recipients, is limited. We performed allo-SCT in eight pediatric patients with ALL (n=7) or T-cell type non-Hodgkin's lymphoma (n=1), who had isolated CNS relapse. All patients survived for a median of 70.5 (range, 13-153) months after SCT. Sequelae developed late in some patients: mental retardation (IQ=47) in one patient, severe alopecia in two patients, limited chronic graft-versus-host-disease in three patients, and amenorrhea and/or hypothyroidism in three patients. Except for a pre-school child with post transplant CNS relapse, six out of seven patients show normal school/social performance. Our results clearly indicate a high cure rate of isolated CNS relapse by allo-SCT in pediatric lymphoid malignancies; however, there needs to be further studies to determine which are the appropriate candidates for transplantation and what is the best transplant regimen to achieve high cure rate and maintain good quality of life.
Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Amenorreia/etiologia , Amenorreia/mortalidade , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/secundário , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Hipotireoidismo/etiologia , Hipotireoidismo/mortalidade , Deficiência Intelectual/etiologia , Deficiência Intelectual/mortalidade , Linfoma de Células T/complicações , Linfoma de Células T/mortalidade , Linfoma de Células T/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Qualidade de Vida , Recidiva , Transplante HomólogoRESUMO
BACKGROUND AND PURPOSE: This paper describes the CT findings that characterize the middle and inner ear anomalies in coloboma, heart defects, choanal atresia, mental retardation, genitourinary, and ear anomalies (CHARGE) syndrome. With this information, neuroradiologists will be better prepared to provide clinically relevant information to their referring physicians regarding this rare syndrome. MATERIALS AND METHODS: CT studies from 13 patients were reviewed by 2 neuroradiologists with Certificate of Additional Qualification. Each ear was counted separately for a total of 26 ears. Middle and inner ear anomalies associated with CHARGE syndrome were categorized. Investigational review board approval was obtained. RESULTS: Twenty of 26 (77%) ears demonstrated cochlear aperture atresia. Four of these ears were evaluated with MR imaging and were found to lack a cochlear nerve. Twenty-one of 26 (81%) cochlea had some form of dysplasia. Six of 26 (23%) round windows were aplastic. Three of 26 (12%) round windows were hypoplastic. Twenty-one of 26 (81%) oval windows were atretic or aplastic. Fifteen of 26 (58%) vestibules were hypoplastic or dysplastic. There were 5 of 26 (19%) enlarged vestibular aqueducts. Twelve of 26 (46%) vestibular aqueducts had an anomalous course. All cases demonstrated absent semicircular canals. Twenty-three of 26 (88%) facial nerve canals had an anomalous course. Four of 26 (15%) tympanic segments were prolapsed. Three of 26 (12%) temporal bones had an anomalous emissary vein referred to as a petrosquamosal sinus. Twenty-one of 26 (81%) middle ear cavities were small. Twenty-three of 26 (93%) ossicles were dysplastic with ankylosis. Three of 26 (12%) internal auditory canals were small. CONCLUSION: The CT findings that correlate to the anomalies of CHARGE syndrome affect conductive as well as sensorineural hearing. Stenosis of the aperture for the cochlear nerve aperture on CT is suggestive of hypoplasia or absence of the cochlear nerve, which has been demonstrated in some cases by MR. Absence of the cochlear nerve would be a contraindication to cochlear implantation.
Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Canais Semicirculares/anormalidades , Tomógrafos Computadorizados , Adolescente , Adulto , Criança , Pré-Escolar , Atresia das Cóanas/diagnóstico por imagem , Coloboma/diagnóstico por imagem , Orelha Interna/anormalidades , Orelha Interna/diagnóstico por imagem , Orelha Média/anormalidades , Orelha Média/diagnóstico por imagem , Feminino , Perda Auditiva Condutiva/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Masculino , Radiografia , Estudos Retrospectivos , Canais Semicirculares/diagnóstico por imagem , Sensibilidade e Especificidade , Síndrome , Anormalidades Urogenitais/diagnóstico por imagemRESUMO
Mutated in multiple advanced cancers 1/phosphatase and tensin homologue (MMAC1/PTEN) is a novel tumor suppressor gene candidate located on chromosome 10 that is commonly mutated in human glioblastoma multiforme and several other cancer types. To evaluate the function of this gene as a tumor suppressor, we constructed a replication-defective adenovirus (MMCB) for efficient, transient transduction of MMAC1 into tumor cells. Infection of MMAC1-mutated U87MG glioblastoma cells with MMCB resulted in dose-dependent exogenous MMAC1 protein expression as detected by Western blotting of cell lysates. In vitro proliferation of U87MG cells was inhibited by MMCB in comparison to several control adenoviruses at equal viral doses, implying a specific effect of MMAC1 expression. Anchorage-independent growth in soft agar was also inhibited by MMCB compared to control adenovirus. Tumorigenicity in nude mice of transiently transduced mass cell cultures was then assessed. MMCB-infected U87MG cells were almost completely nontumorigenic compared to untreated and several control adenovirus-treated cells at equal viral doses. These data support an in vivo tumor suppression activity of MMAC1/PTEN and suggest that in vivo gene transfer with this recombinant adenoviral vector has a potential use in cancer gene therapy.
Assuntos
Técnicas de Transferência de Genes , Genes Supressores de Tumor , Terapia Genética , Glioblastoma/terapia , Monoéster Fosfórico Hidrolases , Proteínas Tirosina Fosfatases/genética , Proteínas Supressoras de Tumor , Adenoviridae/genética , Animais , Cromossomos Humanos Par 10 , Citometria de Fluxo , Mutação em Linhagem Germinativa , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , PTEN Fosfo-Hidrolase , Células Tumorais CultivadasRESUMO
PURPOSE: Total extraperitoneal preperitoneal (TEP) repair is widely used for inguinal, femoral, or obturator hernia treatment. However, mesh repair is not often used for strangulated hernia treatment if intestinal resection is required because of the risk of postoperative mesh infection. Complete mesh repair is required for hernia treatment to prevent postoperative recurrence, particularly in patients with femoral or obturator hernia. CASES: We treated four patients with inguinocrural and obturator hernias (a 72-year-old male with a right indirect inguinal hernia; an 83-year-old female with a right obturator hernia; and 86- and 82-year-old females with femoral hernias) via a two-stage laparoscopic surgery. All patients were diagnosed with intestinal obstruction due to strangulated hernia. First, the incarcerated small intestine was released and then laparoscopically resected. Further, 8-24 days after the first surgery, bilateral TEP repairs were performed in all patients; the postoperative course was uneventful in all patients, and they were discharged 5-10 days after TEP repair. At present, no hernia recurrence has been reported in any patient. CONCLUSION: The two-stage laparoscopic treatment is safe for treatment of strangulated inguinal, femoral, and obturator hernias, and complete mesh repair via the TEP method can be performed in elderly patients to minimize the occurrence of mesh infection.
Assuntos
Hérnia Femoral/cirurgia , Hérnia Inguinal/cirurgia , Hérnia do Obturador/cirurgia , Herniorrafia/métodos , Obstrução Intestinal/cirurgia , Laparoscopia/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Hérnia Femoral/diagnóstico por imagem , Hérnia Inguinal/diagnóstico por imagem , Hérnia do Obturador/diagnóstico por imagem , Humanos , Obstrução Intestinal/diagnóstico por imagem , Intestinos/irrigação sanguínea , Intestinos/diagnóstico por imagem , Intestinos/cirurgia , Masculino , Telas Cirúrgicas , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The utility of casual serum triglyceride (TG) as a predictor of type 2 diabetes mellitus (DM) is unclear, especially during the most productive years. METHODS: Participants were 3271 workers (913 men and 2358 women, age 20-57) without DM at baseline. They underwent consecutive annual medical check-ups for 8 years. The association between newly diagnosed DM and casual serum TG level was determined by classifying the participants into 4 groups according to casual serum TG level at baseline: below 50 mg/dL (group A), 50-100 mg/dL (group B), 100-150 mg/dL (group C), and ≥150 mg/dL (group D). The effects of casual serum TG level in combination with sex, obesity, or serum glucose level on newly diagnosed DM were also evaluated. RESULTS: A total of 222 newly diagnosed type 2 DM cases with a mean age of 50 years old were observed during the follow-up period, i.e., 10/406 in group A, 66/1534 in group B, 58/712 in group C, and 88/619 in group D. Compared with group A, the odds ratio (ORs) for newly diagnosed DM (after adjusting for DM-associated factors) was found to increase with casual serum TG level: 1.38 (group B), 1.79 (group C), and 2.36 (group D). Moreover, the OR for newly diagnosed DM was higher in participants with high casual serum TG levels who were also male (OR 2.46), obese (OR 4.18), or had a high serum glucose level (OR 6.96) than in the reference group. CONCLUSIONS: Serum TG level ≥150 mg/dL when fasting or nonfasting is a significant predictor of type 2 diabetes in middle-aged Japanese workers.
RESUMO
PTEN/MMAC1 is a recently characterized tumor suppressor. A pseudogene derived from the human PTEN/MMAC1 phosphatase, psiPTEN, has been reported. Recent analysis of the pseudogene revealed conflicting results about the expression of psiPTEN. In this study, we show that the PTEN/MMAC1 pseudogene is actively transcribed in all cells and tissues examined. In some cases, pseudogene transcripts were found to represent as much as 70% of the total PTEN/MMAC1 RNA. As psiPTEN is transcribed, there is a potential for misinterpretation of PTEN/MMAC1 mutations when RT-PCR techniques are used, as well as potential for a psiPTEN-encoded translation product. Although we were unable to detect a pseudogene protein product in the cell lines examined, a baculovirus produced GST pseudogene fusion protein exhibited phosphatase activity comparable to wild type. The results of this study, taken together, indicate the potential complication of PTEN/MMAC1 molecular analysis caused by the expression of psiPTEN.
Assuntos
Genes Supressores de Tumor , Monoéster Fosfórico Hidrolases/genética , Pseudogenes , Transcrição Gênica , Proteínas Supressoras de Tumor , Sequência de Aminoácidos , Sequência de Bases , DNA Complementar , Expressão Gênica , Humanos , Dados de Sequência Molecular , PTEN Fosfo-Hidrolase , Monoéster Fosfórico Hidrolases/metabolismo , Células Tumorais CultivadasRESUMO
Loss of the tumor suppressor MMAC1 has been shown to be involved in breast, prostate and brain cancer. Consistent with its identification as a tumor suppressor, expression of MMAC1 has been demonstrated to reduce cell proliferation, tumorigenicity, and motility as well as affect cell-cell and cell-matrix interactions of malignant human glioma cells. Subsequently, MMAC1 was shown to have lipid phosphatase activity towards PIP3 and protein phosphatase activity against focal adhesion kinase (FAK). The lipid phosphatase activity of MMAC1 results in decreased activation of the PIP3-dependent, anti-apoptotic kinase, AKT. It is thought that this inhibition of AKT culminates with reduced glioma cell proliferation. In contrast, MMAC1's effects on cell motility, cell - cell and cell - matrix interactions are thought to be due to its protein phosphatase activity towards FAK. However, recent studies suggest that the lipid phosphatase activity of MMAC1 correlates with its ability to be a tumor suppressor. The high rate of mutation of MMAC1 in late stage metastatic tumors suggests that effects of MMAC1 on motility, cell - cell and cell - matrix interactions are due to its tumor suppressor activity. Therefore the lipid phosphatase activity of MMAC1 may affect PIP3 dependent signaling pathways and result in reduced motility and altered cell - cell and cell - matrix interactions. We demonstrate here that expression of MMAC1 in human glioma cells reduced intracellular levels of inositol trisphosphate and inhibited extracellular Ca2+ influx, suggesting that MMAC1 affects the phospholipase C signaling pathway. In addition, we show that MMAC1 expression inhibits integrin-linked kinase activity. Furthermore, we show that these effects require the catalytic activity of MMAC1. Our data thus provide a link of MMAC1 to PIP3 dependent signaling pathways that regulate cell - matrix and cell - cell interactions as well as motility. Lastly, we demonstrate that AKT3, an isoform of AKT highly expressed in the brain, is also a target for MMAC1 repression. These data suggest an important role for AKT3 in glioblastoma multiforme. We therefore propose that repression of multiple PIP3 dependent signaling pathways may be required for MMAC1 to act as a tumor suppressor.
Assuntos
Genes Supressores de Tumor/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fosfolipases Tipo C/antagonistas & inibidores , Animais , Encéfalo/enzimologia , Sinalização do Cálcio/fisiologia , Ativação Enzimática , Glioblastoma/enzimologia , Glioma/enzimologia , Humanos , Isoenzimas/biossíntese , Isoenzimas/fisiologia , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt , Células Tumorais Cultivadas , Fosfolipases Tipo C/metabolismoRESUMO
MMAC1, also known as PTEN or TEP-1, was recently identified as a gene commonly mutated in a variety of human neoplasias. Sequence analysis revealed that MMAC1 harbored sequences similar to those found in several protein phosphatases. Subsequent studies demonstrated that MMAC1 possessed in vitro enzymatic activity similar to that exhibited by dual specificity phosphatases. To characterize the potential cellular functions of MMAC1, we expressed wild-type and several mutant variants of MMAC1 in the human glioma cell line, U373, that lacks endogenous expression. While expression of wild-type MMAC1 in these cells significantly reduced their growth rate and saturation density, expression of enzymatically inactive MMAC1 significantly enhanced growth in soft agar. Our observations indicate that while wild-type MMAC1 exhibits activities compatible with its proposed role as a tumor suppressor, cellular expression of MMAC1 containing mutations in the catalytic domain may yield protein products that enhance transformation characteristics.
Assuntos
Genes Supressores de Tumor , Glioma/genética , Monoéster Fosfórico Hidrolases/biossíntese , Proteínas Supressoras de Tumor , Domínio Catalítico/genética , Adesão Celular , Divisão Celular , Transformação Celular Neoplásica , Glioma/enzimologia , Humanos , Mutação , PTEN Fosfo-Hidrolase , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Proteínas Recombinantes/biossíntese , Células Tumorais CultivadasRESUMO
A young female patient in a second remission of acute lymphoblastic leukemia underwent bone marrow transplantation after total body irradiation and high-dose cytarabine from her HLA-matched brother. Following successful engraftment, mixed chimerism was seen 75 days post transplant. The karyotype contained numerous abnormalities in residual recipient cells. Chromosomes 1, 7, 13, and X were significantly more affected than other chromosomes. The high-frequency breakpoints identified were 1p22.2, 5q31.2, and 13q14.2. Some karyotypes specific for leukemia, such as t(9;22)(q34.1;q11.2) and t(8;21)(q22.2;q22.2), not seen with the original disease, were also present. As the frequency of aberrant chromosomes increased markedly with time, donor leukocytes were infused 14 months after BMT, which effectively eradicated the abnormal karyotypes.
Assuntos
Células da Medula Óssea/patologia , Transplante de Medula Óssea/efeitos adversos , Aberrações Cromossômicas , Pré-Escolar , Células Clonais/patologia , Terapia Combinada , Feminino , Humanos , Cariotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante HomólogoRESUMO
Infant acute lymphoblastic leukemia (ALL) is characterized by the presence of the proB phenotype (CD10(-)/CD19(+)), poor prognosis and frequent rearrangement of the mixed lineage leukemia (MLL) gene. The most frequent rearrangement is t(4;11)(q21;q23), the role of whose product, the MLL-AF4 fusion transcript, has been extensively studied in leukemogenesis. In a cell line of infant leukemia with MLL rearrangement denoted KP-L-RY, panhandle PCR amplification of cDNA revealed the presence of a fusion transcript, MLL-AF5q31, indicating that AF5q31 is also a partner gene of MLL. In this fusion transcript the MLL exon 6 is fused in frame to the 5' side of the putative transactivation domain of AF5q31. The AF5q31 protein is a member of the AF4/LAF4/FMR2-related family of proteins, which have been suggested to play a role in hematopoietic cell growth and differentiation. The MLL-AF5q31 fusion transcript, although probably rare, appears to be associated with the pathogenesis of infant ALL like MLL-AF4. Co-expression of HoxA9 and Meis1 genes in the KP-L-RY cell line indicated possible functional similarity between MLL-AF4 and MLL-AF5q31. Further understanding of the function of AF5q31 as well as the specific leukemogenic mechanism of MLL-AF5q31 awaits future studies.
Assuntos
Biomarcadores Tumorais/genética , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Doença Aguda , Fusão Gênica Artificial , Southern Blotting , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Primers do DNA/química , DNA de Neoplasias/análise , Éxons , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Proteína Meis1 , Proteína de Leucina Linfoide-Mieloide , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase , Translocação GenéticaRESUMO
BACKGROUND: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. OBJECTIVE: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients METHODS: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. RESULTS: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. CONCLUSIONS: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.
Assuntos
Histiocitose de Células não Langerhans/genética , Mutação/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Idade de Início , Análise Mutacional de DNA , Éxons/genética , Feminino , Histiocitose de Células não Langerhans/imunologia , Histiocitose de Células não Langerhans/fisiopatologia , Humanos , Lactente , Íntrons/genética , Japão , Masculino , Dados de Sequência Molecular , LinhagemRESUMO
Intravitreally administered lampalizumab is an investigational complement inhibitor directed against complement factor D (CFD) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. We sought to develop an integrated ocular and systemic pharmacokinetic/pharmacodynamic model for lampalizumab in patients with GA using the data from the clinical phase I and II studies. The kinetics of lampalizumab and CFD disposition were well described by the combined ocular/serum target-mediated drug disposition model using a quasi-steady-state approximation. This model takes into account the drug, target, and drug-target complex clearance, their transfer rates between ocular and serum compartments, and turnover kinetics of CFD. The constructed model provided a prediction of target occupancy in ocular tissues and supported that the two dosing regimens (10 mg q4w and 10 mg q6w) selected for the phase III studies are expected to be efficacious and able to achieve near-complete target engagement in the vitreous humor.