RESUMO
We have reported that an environmental pollutant, cadmium, promotes cell death in the human renal tubular cells (RTCs) through hyperactivation of a serine/threonine kinase Akt. However, the molecular mechanisms downstream of Akt in this process have not been elucidated. Cadmium has a potential to accumulate misfolded proteins, and proteotoxicity is involved in cadmium toxicity. To clear the roles of Akt in cadmium exposure-induced RTCs death, we investigated the possibility that Akt could regulate proteotoxicity through autophagy in cadmium chloride (CdCl2)-exposed HK-2 human renal proximal tubular cells. CdCl2 exposure promoted the accumulation of misfolded or damaged proteins, the formation of aggresomes (pericentriolar cytoplasmic inclusions), and aggrephagy (selective autophagy to degrade aggresome). Pharmacological inhibition of Akt using MK2206 or Akti-1/2 enhanced aggrephagy by promoting dephosphorylation and nuclear translocation of transcription factor EB (TFEB)/transcription factor E3 (TFE3), lysosomal transcription factors. TFEB or TFE3 knockdown by siRNAs attenuated the protective effects of MK2206 against cadmium toxicity. These results suggested that aberrant activation of Akt attenuates aggrephagy via TFEB or TFE3 to facilitate CdCl2-induced cell death. Furthermore, these roles of Akt/TFEB/TFE3 were conserved in CdCl2-exposed primary human RTCs. The present study shows the molecular mechanisms underlying Akt activation that promotes cadmium-induced RTCs death.
Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Cádmio , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular , Cádmio/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Fosforilação/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Compostos Heterocíclicos com 3 Anéis/farmacologia , Túbulos Renais/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/citologia , Túbulos Renais/patologiaRESUMO
Anoikis is a type of apoptosis that occurs in response to the loss of adhesion to the extracellular matrix (ECM). Anoikis resistance is a critical mechanism in cancer and contributes to tumor metastasis. Nitric oxide (NO) is frequently upregulated in the tumor area and is considered an important player in cancer metastasis. The aim of this study was to evaluate the effect of NO on adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cells. Here, we report that anoikis-resistant endothelial cells overexpress endothelial nitric oxide synthase. The inhibition of NO release in anoikis-resistant endothelial cells was able to decrease adhesiveness to fibronectin, laminin, and collagen IV. This was accompanied by an increase in cell invasiveness and migration. Furthermore, anoikis-resistant cell lines displayed a decrease in fibronectin and collagen IV protein expression after L-NAME treatment. These alterations in adhesiveness and invasiveness were the consequence of MMP-2 up-regulation observed after NO release inhibition. The decrease in NO levels was able to down-regulate the activating transcription factor 3 (ATF3) protein expression. ATF3 represses MMP-2 gene expression by antagonizing p53-dependent trans-activation of the MMP-2 promoter. We speculate that the increased release of NO by anoikis-resistant endothelial cells acted as a response to restrict the MMP-2 action, interfering in MMP-2 gene expression via ATF3 regulation. The up-regulation of nitric oxide by anoikis-resistant endothelial cells is an important response to restrict tumorigenic behavior. Without this mechanism, invasiveness and migration potential would be even higher, as shown after L-NAME treatment.
Assuntos
Anoikis , Células Endoteliais , Adesividade , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Humanos , Invasividade Neoplásica , Óxido Nítrico/metabolismo , Regulação para CimaRESUMO
Anoikis is a type of apoptosis that occurs in response to the loss of adhesion to the extracellular matrix (ECM). Anoikis resistance is a critical mechanism in cancer and contributes to tumor metastasis. Nitric oxide (NO) is frequently upregulated in the tumor area and is considered an important player in cancer metastasis. The aim of this study was to evaluate the effect of NO on adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cells. Here, we report that anoikis-resistant endothelial cells overexpress endothelial nitric oxide synthase. The inhibition of NO release in anoikis-resistant endothelial cells was able to decrease adhesiveness to fibronectin, laminin, and collagen IV. This was accompanied by an increase in cell invasiveness and migration. Furthermore, anoikis-resistant cell lines displayed a decrease in fibronectin and collagen IV protein expression after L-NAME treatment. These alterations in adhesiveness and invasiveness were the consequence of MMP-2 up-regulation observed after NO release inhibition. The decrease in NO levels was able to down-regulate the activating transcription factor 3 (ATF3) protein expression. ATF3 represses MMP-2 gene expression by antagonizing p53-dependent trans-activation of the MMP-2 promoter. We speculate that the increased release of NO by anoikis-resistant endothelial cells acted as a response to restrict the MMP-2 action, interfering in MMP-2 gene expression via ATF3 regulation. The up-regulation of nitric oxide by anoikis-resistant endothelial cells is an important response to restrict tumorigenic behavior. Without this mechanism, invasiveness and migration potential would be even higher, as shown after L-NAME treatment.
RESUMO
PURPOSE: The objectives of this study were to clarify whether resection of primary tumor in the extremities for patients with metastatic soft-tissue sarcoma (STS) improves survival, and to clarify patient groups for whom primary tumor resection should be considered. METHODS/PATIENTS: Using the surveillance, epidemiology, and end results database, we identified 1453 patients with metastatic STS of the extremities at initial presentation between 1983 and 2016. Of these 1453 patients, 898 patients underwent primary tumor resection (Surgery group), and 555 patients did not (No-surgery group). RESULTS: After adjusting for patient background by propensity score matching, a total of 804 patients were included for analysis. Patients in the Surgery group showed improved survival (cancer-specific survival (CSS) hazard ratio (HR) = 0.59, 95% confidence interval (CI) 0.50-0.71 overall survival rate (OS) HR = 0.60, 95% CI 0.51-0.70). In subclass analysis, patients with high-grade STS, undifferentiated pleomorphic sarcoma, leiomyosarcoma, or synovial sarcoma showed improved survival in the Surgery group (high grade-CSS HR = 0.57, 95% CI 0.45-0.72, OS HR = 0.58, 95% CI 0.48-0.71; undifferentiated pleomorphic sarcoma-CSS HR = 0.60, 95% CI 0.42-0.84, OS HR = 0.61, 95% CI 0.46-0.82; leiomyosarcoma-CSS HR = 0.50, 95% CI 0.33-0.75, OS HR = 0.50, 95% CI 0.35-0.72; synovial sarcoma-CSS HR = 0.46, 95% CI 0.31-0.68, OS HR = 0.43, 95% CI 0.30-0.62). CONCLUSIONS: Our results indicated that primary tumor resection in metastatic STS exerts positive impacts on survival. Further clinical research is needed to confirm these results.
Assuntos
Extremidades/cirurgia , Programa de SEER/estatística & dados numéricos , Sarcoma/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sarcoma/secundário , Sarcoma/cirurgia , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. DESIGN: We generated knockout (KO) mice by targeting the ß1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. RESULTS: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. CONCLUSION: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.
Assuntos
Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Gangliosídeos/fisiologia , Osteoartrite/metabolismo , Envelhecimento/fisiologia , Animais , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Progressão da Doença , Gangliosídeos/deficiência , Gangliosídeos/farmacologia , Deleção de Genes , Crescimento/genética , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Metaloproteinase 13 da Matriz/biossíntese , Camundongos Knockout , N-Acetilgalactosaminiltransferases/deficiência , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/fisiologia , Óxido Nítrico/metabolismo , Osteoartrite/patologia , Sialiltransferases/deficiência , Sialiltransferases/genética , Sialiltransferases/fisiologia , Técnicas de Cultura de Tecidos , Regulação para Cima/fisiologia , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
OBJECTIVES: Antimicrobial resistance (AMR) is a priority for surveillance in bacterial infections. For leprosy, AMR has not been assessed because Mycobacterium leprae does not grow in vitro. We aim to obtain AMR data using molecular detection of resistance genes and to conduct a prospective open survey of resistance to antileprosy drugs in countries where leprosy is endemic through a WHO surveillance network. METHODS: From 2009 to 2015, multi-bacillary leprosy cases at sentinel sites of 19 countries were studied for resistance to rifampicin, dapsone and ofloxacin by PCR sequencing of the drug-resistance-determining regions of the genes rpoB, folP1 and gyrA. RESULTS: Among 1932 (1143 relapse and 789 new) cases studied, 154 (8.0%) M. leprae strains were found with mutations conferring resistance showing 182 resistance traits (74 for rifampicin, 87 for dapsone and 21 for ofloxacin). Twenty cases showed rifampicin and dapsone resistance, four showed ofloxacin and dapsone resistance, but no cases were resistant to rifampicin and ofloxacin. Rifampicin resistance was observed among relapse (58/1143, 5.1%) and new (16/789, 2.0%) cases in 12 countries. India, Brazil and Colombia reported more than five rifampicin-resistant cases. CONCLUSIONS: This is the first study reporting global data on AMR in leprosy. Rifampicin resistance emerged, stressing the need for expansion of surveillance. This is also a call for vigilance on the global use of antimicrobial agents, because ofloxacin resistance probably developed in relation to the general intake of antibiotics for other infections as it is not part of the multidrug combination used to treat leprosy.
Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , Hanseníase/epidemiologia , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/genética , Antibacterianos/efeitos adversos , Proteínas de Bactérias/genética , Biópsia por Agulha , Brasil/epidemiologia , Colômbia/epidemiologia , DNA Girase/genética , Dapsona/uso terapêutico , Doenças Endêmicas/estatística & dados numéricos , Monitoramento Epidemiológico , Saúde Global , Humanos , Índia/epidemiologia , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Testes de Sensibilidade Microbiana , Mutação , Ofloxacino/uso terapêutico , Reação em Cadeia da Polimerase , Estudos Prospectivos , Recidiva , Rifampina/uso terapêutico , Vigilância de Evento Sentinela , Pele/microbiologia , Pele/patologia , Inquéritos e Questionários , Organização Mundial da SaúdeRESUMO
We previously reported that PU.1 is downregulated in the majority of myeloma cell lines and primary myeloma cells of certain myeloma patients, and conditional expression of PU.1 in such myeloma cell lines induced cell cycle arrest and apoptosis. We found downregulation of IRF4 protein in the U266 myeloma cell line following induction of PU.1. Previous studies reported that knockdown of IRF4 in myeloma cell lines induces apoptosis, prompting us to further investigate the role of IRF4 downregulation in PU.1-induced cell cycle arrest and apoptosis in myeloma cells. PU.1 induced downregulation of IRF4 at the protein level, cell cycle arrest and apoptosis in six myeloma cell lines. Chromatin immunoprecipitation (ChIP) revealed that PU.1 directly binds to the IRF4 promoter, whereas a reporter assay showed that PU.1 may suppress IRF4 promoter activity. Stable expression of IRF4 in myeloma cells expressing PU.1 partially rescued the cells from apoptosis induced by PU.1. As it was reported that IRF4 directly binds to the IRF7 promoter and downregulates its expression in activated B cell-like subtype of diffuse large B cell lymphoma cells, we performed ChIP assays and found that IRF4 directly binds the IRF7 promoter in myeloma cells. It is known that IRF7 positively upregulates interferon-ß (IFNß) and induces apoptosis in many cell types. Binding of IRF4 to the IRF7 promoter decreased following PU.1 induction, accompanied by downregulation of IRF4 protein expression. Knockdown of IRF7 protected PU.1-expressing myeloma cells from apoptosis. Furthermore, IFNß, which is a downstream target of IRF7, was upregulated in myeloma cells along with IRF7 after PU.1 induction. Finally, we evaluated the mRNA expression levels of PU.1, IRF4 and IRF7 in primary myeloma cells from patients and found that PU.1 and IRF7 were strongly downregulated in contrast to the high expression levels of IRF4. These data strongly suggest that PU.1-induced apoptosis in myeloma cells is associated with IRF4 downregulation and subsequent IRF7 upregulation.
Assuntos
Fatores Reguladores de Interferon/fisiologia , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Apoptose , Humanos , Fator Regulador 7 de Interferon/genética , Fatores Reguladores de Interferon/genética , Interferon beta/biossíntese , Mieloma Múltiplo/patologia , Regiões Promotoras Genéticas , Transcrição Gênica , Células U937RESUMO
TiO2-encapsulated H-ZSM photocatalysts were prepared by physical mixing of TiO2 and zeolites. Pt was immobilized on the surface of the TiO2-encapsulated zeolite (H-ZSM) catalysts by a simple photochemical reduction method. Different weight ratios of both TiO2 and Pt were hybridized with H-ZSM and the catalytic performance of the prepared catalysts was investigated for 2-propanol oxidation in liquid phase and acetaldehyde in gas phase reaction. Around 5-10 wt% TiO2-encapsulated H-ZSM catalysts was found to be optimal amount for the effective oxidation of the organics. Prior to light irradiation, Pt-TiO2-H-ZSM showed considerable amount of catalytic degradation of 2-propanol in the dark, forming acetone as an intermediate. In this study, Pt has played a major and important role on the total oxidation of 2-propanol as well as acetaldehyde. As a result, no residual organics were present in the pores of the zeolites. The catalysts could be reused more than three times without losing their catalytic activity in both phases. The Pt-TiO2-H-ZSM photocatalysts could overcome the problem of strong adsorption of organics in the zeolite pores (after the reaction). Thus, Pt-TiO2-H-ZSM can be used as a potential catalyst for both liquid and gas phase oxidation of organic pollutants.
Assuntos
2-Propanol/química , Acetaldeído/química , Recuperação e Remediação Ambiental/métodos , Titânio/química , Poluentes Químicos da Água/química , Zeolitas/química , Adsorção , Catálise , Oxirredução , Platina/químicaRESUMO
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that induces a fatal T-cell malignancy, adult T-cell leukemia (ATL). Among several regulatory/accessory genes in HTLV-1, HTLV-1 bZIP factor (HBZ) is the only viral gene constitutively expressed in infected cells. Our previous study showed that HBZ functions in two different molecular forms, HBZ protein and HBZ RNA. In this study, we show that HBZ protein targets retinoblastoma protein (Rb), which is a critical tumor suppressor in many types of cancers. HBZ protein interacts with the Rb/E2F-1 complex and activates the transcription of E2F-target genes associated with cell cycle progression and apoptosis. Mouse primary CD4(+) T cells transduced with HBZ show accelerated G1/S transition and apoptosis, and importantly, T cells from HBZ transgenic (HBZ-Tg) mice also demonstrate enhanced cell proliferation and apoptosis. To evaluate the functions of HBZ protein alone in vivo, we generated a new transgenic mouse strain that expresses HBZ mRNA altered by silent mutations but encoding intact protein. In these mice, the numbers of effector/memory and Foxp3(+) T cells were increased, and genes associated with proliferation and apoptosis were upregulated. This study shows that HBZ protein promotes cell proliferation and apoptosis in primary CD4(+) T cells through activation of the Rb/E2F pathway, and that HBZ protein also confers onto CD4(+) T-cell immunophenotype similar to those of ATL cells, suggesting that HBZ protein has important roles in dysregulation of CD4(+) T cells infected with HTLV-1.
Assuntos
Apoptose , Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Linfócitos T CD4-Positivos/patologia , Proteína do Retinoblastoma/fisiologia , Proteínas dos Retroviridae/fisiologia , Transdução de Sinais/fisiologia , Animais , Linfócitos T CD4-Positivos/virologia , Ciclo Celular , Proliferação de Células , Células Cultivadas , Fator de Transcrição E2F1/fisiologia , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína Supressora de Tumor p53/fisiologiaAssuntos
Regulação da Expressão Gênica , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , NF-kappa B/metabolismo , RNA Antissenso/metabolismo , RNA Viral/metabolismo , eIF-2 Quinase/metabolismo , Adulto , Sequência de Bases , Western Blotting , Citometria de Fluxo , Genoma Viral , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Dados de Sequência Molecular , NF-kappa B/genética , RNA Antissenso/genética , RNA Mensageiro/genética , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , eIF-2 Quinase/genéticaRESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases that overlap clinically, genetically, and pathologically. Dysregulation of fused in sarcoma (FUS) has been hypothesized to cause ALS and FTLD in gain-of-function and/or loss-of-function manners. However, the link between the pathogenesis of ALS/FTLD and dysfunction of FUS has not been clearly determined. In this study, we found that overexpression of FUS, but not knocking-down of endogenous FUS expression, induces death in motor neuronal NSC34 cells and primary cortical neurons via the mitochondrial apoptotic pathway, possibly independently of transactive response DNA-binding protein-43. Furthermore, we found that nuclear FUS, but not cytoplasmic FUS, is responsible for FUS-induced neuronal cell death. These observations suggest that the gain-of-function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases.
Assuntos
Apoptose , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Mitocôndrias/metabolismo , Proteína FUS de Ligação a RNA/genética , Regulação para CimaRESUMO
We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl2), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl2-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-α or inhibition of PI3K with LY294002 suppressed CdCl2-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl2. However, knockdown of Notch1 did not affect CdCl2-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl2-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl2. Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl2-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell-cell adhesion.
Assuntos
Cloreto de Cádmio/toxicidade , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Cromonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1 , Proteína Jagged-2 , Túbulos Renais Proximais/citologia , Maleimidas/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Quinazolinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Proteínas Serrate-Jagged , Fatores de Transcrição da Família Snail , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Tirfostinas/farmacologiaRESUMO
Pancreaticoduodenectomy is the standard care for invasive ampullary adenocarcinomas. However, endoscopic snare papillectomy (ESP) might play a curative role in very selected patients. We studied a series of 15 patients with T1 ampullary adenocarcinoma who were treated by ESP alone and followed up for a mean of 29.6 ± 21.9 months (range 8 - 81 months). ESP was curative for eight patients (57.1 %). No tumor-related death was observed in patients with a cancer infiltration depth of ≤ 4 mm. According to this preliminary experience, we suggest that this measurable variable threshold should be considered as a possible basis for future large-scale studies.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Ampola Hepatopancreática , Neoplasias do Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/cirurgia , Recidiva Local de Neoplasia/cirurgia , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Duodenoscopia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos RetrospectivosRESUMO
A strong association between inactive aldehyde dehydrogenase-2 (ALDH2) and risk of esophageal cancer has been demonstrated in East Asian drinkers. An alcohol flushing questionnaire asking about past and current tendency for facial flushing to occur after drinking a glass (≈180 mL) of beer predicts the presence of inactive ALDH2 among Japanese aged 40 years or older with a sensitivity and specificity of approximately 90%. We invented a health-risk appraisal (HRA) model that makes it possible to identify Japanese men who are at high risk for esophageal cancer based on their past and current alcohol flushing tendency, drinking, smoking, and intake of vegetables and fruits. Between 2008 and 2009, 2221 Japanese men aged 50 years or older filled out the HRA questionnaire before undergoing a screening examination by upper gastrointestinal endoscopy at five medical facilities. The endoscopic examination resulted in a diagnosis of esophageal cancer in 19 subjects, and 117 (5.27%) subjects had an HRA score ≥ 11. The proportion of subjects with an HRA score ≥ 11 was higher in the 50-69 age group (6.11-6.88%) than in 70-89 age group (2.84-2.86%). The esophageal cancer detection rate was 4.27% among the subjects with an HRA score ≥ 11 and only 0.67% among the other subjects. Based on a receiver operating characteristic curve analysis, when an HRA score of ≥ 9 was used for subjects aged 50-69 years and of ≥ 8 for those aged 70-89 years as the cutoff value to select individuals with a high risk for esophageal cancer, its sensitivity and false-positive rate was 52.6% and 15.2%, respectively, and the cancer detection rate was 2.91% in the high-risk group, as opposed to 0.48% in the other group. In conclusion, the high detection rates for esophageal cancer in the high-risk groups encouraged screening based on our HRA model in larger Japanese populations.
Assuntos
Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Neoplasias Esofágicas/diagnóstico , Esofagoscopia , Programas de Rastreamento/métodos , Idoso , Idoso de 80 Anos ou mais , Aldeído Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/genética , Reações Falso-Positivas , Marcadores Genéticos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Curva ROC , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Inquéritos e QuestionáriosRESUMO
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). HTLV-1 bZIP factor (HBZ), the viral gene transcribed from the antisense strand, is consistently expressed in ATL cells and promotes their proliferation. In this study, we found that a Wnt pathway-related protein, disheveled-associating protein with a high frequency of leucine residues (DAPLE), interacts with both HTLV-1 Tax and HBZ. In the presence of DAPLE, Tax activated canonical Wnt signaling. Conversely, HBZ markedly suppressed canonical Wnt activation induced by either Tax/DAPLE or ß-catenin. As a mechanism of HBZ-mediated Wnt suppression, we found that HBZ targets lymphoid enhancer-binding factor 1, one of the key transcription factors of the pathway, and impairs its DNA-binding ability. We also observed that the canonical Wnt pathway was not activated in HTLV-1-infected cells, whereas the representative of noncanonical Wnt ligand, Wnt5a, which antagonizes canonical Wnt signaling, was overexpressed. HBZ was able to induce Wnt5a transcription by enhancing its promoter activity through the TGF-ß pathway. Importantly, knocking down of Wnt5a in ATL cells repressed cellular proliferation and migration. Our results implicate novel roles of HBZ in ATL leukemogenesis through dysregulation of both the canonical and noncanonical Wnt pathways.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Leucemia-Linfoma de Células T do Adulto/metabolismo , Proteínas Virais/metabolismo , Via de Sinalização Wnt , Adulto , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem Celular , Movimento Celular/genética , Proliferação de Células , Expressão Gênica , Técnicas de Silenciamento de Genes , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas dos Retroviridae , Proteínas Virais/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5aRESUMO
Experimental models of lung fibrosis have been disappointing in predicting therapeutic responses to a wide variety of interventions in clinical fibrosing lung diseases. There are multiple potential reasons, but this fundamentally calls into question the validity of the models and their fidelity to clinical syndromes. We propose that the clinical diseases associated with pulmonary fibrosis, although manifesting a broad array of widely different clinical presentations and features, result in essentially two distinct phenotypes of fibrosis that we will describe. The most common and problematic of these are not effectively modeled experimentally. In this review, we present several clinical entities as examples of the phenotypic distinctions. The first two represent the extremes: postinflammatory fibrosis observed in hypersensitivity pneumonitis (HP) and dysregulated matrix deposition as observed in idiopathic pulmonary fibrosis (IPF). We also present a third clinical entity, that of lung disease associated with rheumatoid arthritis (rheumatoid lung), representing a condition that can manifest as either phenotype, and offering a potential opportunity to explore the mechanisms underlying the pathogenesis of the two distinct fibrotic phenotypes.
Assuntos
Alveolite Alérgica Extrínseca/patologia , Artrite Reumatoide/patologia , Fibrose Pulmonar Idiopática/patologia , Pneumonia/patologia , Animais , Autoimunidade , Fibrose , Humanos , Modelos Animais , Fenótipo , SíndromeRESUMO
BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo.
Assuntos
Neurônios Motores/citologia , Neurônios Motores/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Caenorhabditis elegans , Morte Celular/fisiologia , Inativação Gênica , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
The aim of this study was to measure the heat generated when using a self-drilling miniscrew at speeds of 50, 100, 150, and 250 rpm. Specimens were classified into two groups: in the thin group the cortical bone thickness was 1.2 ± 0.02 mm on average and in the thick group it was 2.0 ± 0.03 mm on average. The thin group was used to model maxillary bone and the thick group to model mandibular bone in humans. The temperature in the 1.2-mm and 2.0-mm cortical bone specimens was measured according to revolution speed. As the revolution speed increased, the temperature significantly increased in both bone thicknesses. The temperature increased significantly more in the thicker cortical bone. The temperature increase in the 2.0-mm thick bone at 250 rpm exceeded 10°C, regarded as the threshold for bone damage in this study; other temperature increases were below this threshold. Installing self-drilling screws at high speeds with an implanter is not recommended; low speeds of less than 150 rpm should be used.
Assuntos
Parafusos Ósseos , Queimaduras/etiologia , Implantação Dentária Endóssea/métodos , Procedimentos de Ancoragem Ortodôntica/instrumentação , Animais , Osso e Ossos/lesões , Equipamentos Odontológicos/efeitos adversos , Implantação Dentária Endóssea/efeitos adversos , Desenho de Equipamento , Fricção , Temperatura Alta , Miniaturização , SuínosRESUMO
The human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus discovered to be causative of a human cancer, adult T-cell leukemia. The transforming entity of HTLV-1 has been attributed to the virally-encoded oncoprotein, Tax. Unlike the v-onc proteins encoded by other oncogenic animal retroviruses that transform cells, Tax does not originate from a c-onc counterpart. In this article, we review progress in our understanding of HTLV-1 infectivity, cellular transformation, anti-sense transcription and therapy, 30 years after the original discovery of this virus.