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BACKGROUND: It is unclear whether inactivated influenza vaccination (IIV) or pneumococcal vaccination are associated with the risk of dementia; however, both types of vaccination are recommended for older adults. Studies have shown that the IIV is negatively associated with incident dementia; however, the uptake of pneumococcal vaccinations has not been considered. We investigated the independent associations of IIV and 23-valent pneumococcal polysaccharide vaccine (PPSV23) with incident dementia in older adults. METHODS: Health-related information on older Japanese adults was obtained through a baseline survey conducted in 2013 (baseline survey). The uptake of IIV and PPSV23 was determined in a second survey conducted in 2016 (second wave). Both surveys were conducted among independent Japanese older adults aged ≥ 65 years at the two surveys and who had not been certified as needing long-term care (LTC). In the second wave, 9,865 participants were followed up for 3.5 years (short-term follow-up), and 6,995 participants were followed up for six years and five months (long-term follow-up) until they required LTC due to dementia onset (incident dementia). A competing risk model with stabilized inverse probability weighting (SIPW) was constructed to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of incident dementia. RESULTS: PPSV23 uptake was negatively associated with incident dementia among participants in both the short- and long-term follow-up periods after SIPW (short-term follow-up: HR: 0.77, 95 % CI: 0.63 - 0.95; long-term follow-up: HR: 0.83, 95 % CI: 0.70 - 0.97). Conversely, IIV uptake was not associated with incident dementia among participants in either follow-up group (short-term follow-up: HR: 0.86, 95 % CI: 0.63-1.16; long-term follow-up: HR: 0.99, 95 % CI: 0.76-1.29). The PPSV23 uptake was negatively associated with incident dementia in participants without the IIV uptake (short-term follow-up: HR: 0.44, 95 % CI: 0.24 - 0.81; long-term follow-up: HR: 0.47, 95 % CI: 0.29 - 0.76). Conversely, the IIV uptake was not associated with incident dementia regardless of the PPSV23 status (short-term follow-up: HR: 0.87, 95 % CI: 0.62 - 1.23; long-term follow-up: HR: 1.00, 95 % CI: 0.74 - 1.35). CONCLUSION: Our results suggest that the PPSV23 uptake was independently associated with the incidence of dementia. However, the IIV uptake was not associated with the incidence of dementia.
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Demência , Vacinas contra Influenza , Vacinas Pneumocócicas , Vacinação , Humanos , Demência/epidemiologia , Idoso , Feminino , Masculino , Japão/epidemiologia , Estudos Prospectivos , Vacinas Pneumocócicas/administração & dosagem , Idoso de 80 Anos ou mais , Incidência , Influenza Humana/prevenção & controle , Influenza Humana/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/epidemiologia , População do Leste AsiáticoRESUMO
Nrf2 is an antioxidant transcriptional activator in many types of cells, and its dysfunction plays key roles in a variety of human disorders, including Parkinson's disease (PD). PD is characterized by the selective loss of dopaminergic neurons in PD-affected brain regions. Dopamine treatment of neuronal cells stimulates the production of reactive oxygen species (ROS) and increases ROS-dependent neuronal apoptosis. In this study, we found that the ubiquitin-specific protease 10 (USP10) protein reduces dopamine-induced ROS production of neuronal cells and ROS-dependent apoptosis by stimulating the antioxidant activity of Nrf2. USP10 interacted with the Nrf2 activator p62, increased the phosphorylation of p62, increased the interaction of p62 with the Nrf2 inhibitor Keap1, and stimulated Nrf2 antioxidant transcriptional activity. In addition, USP10 augmented dopamine-induced Nrf2 translation. Taken together, these results indicate that USP10 is a key regulator of Nrf2 antioxidant activity in neuronal cells and suggest that USP10 activators are promising therapeutic agents for oxidative stress-related diseases, including PD.
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Dopamina , Neurônios Dopaminérgicos , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Ubiquitina Tiolesterase , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Doença de Parkinson , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
PURPOSE: This study aimed to illustrate the utility of our original system to deliver vascular plugs into aortic side branches during endovascular aneurysm repair (EVAR). TECHNIQUE: Our device, which we named "System-F," consists of a 14 Fr sheath, a 12 Fr long sheath with a side hole, a stiff guidewire as a shaft, and a parallelly-inserted delivery catheter navigated through the side hole into the aneurysm sac. Vertical motion and horizontal rotation of the side hole allow multidimensional movement of the delivery catheter within the aneurysm. This system was applied in 7 cases undergoing EVAR; 4 inferior mesenteric arteries and 14 lumbar arteries were embolized using vascular plugs. Type II endoleak (T2EL) was not observed in the follow-up survey of any case. Conclusion: The applicability of System-F for vascular plug placement in the side branches of abdominal aortic aneurysms has the potential to achieve high delivery capability and be widely applied for the prevention of T2EL. CLINICAL IMPACT: System-F has potential to change the strategies of pre-EVAR embolization.
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BACKGROUND: Radiographic detection of the Adamkiewicz artery (AKA) before aortic surgery helps to avoid spinal cord ischemia (SCI). We applied magnetic resonance angiography (MRA) using gadolinium enhancement (Gd-MRA) by means of the slow-infusion method with sequential k-space filling and compared AKA detectability with that of computed tomography angiography (CTA). METHODS: A total of 63 patients with thoracic or thoracoabdominal aortic disease (30 with aortic dissection [AD] and 33 with aortic aneurysm) who underwent both CTA and Gd-MRA to detect AKA were evaluated. The detectability of the AKA using Gd-MRA and CTA were compared among all patients and subgroups based on anatomical features. RESULTS: The detection rates of the AKAs using Gd-MRA and CTA were higher in all 63 patients (92.1% vs. 71.4%, P = 0.003). In AD cases, the detection rates using Gd-MRA and CTA were higher in all 30 patients (93.3% vs. 66.7%, P = 0.01) as well as in 7 patients whose AKA originated from false lumens (100% vs. 0%). In aneurysm cases, the detection rates using Gd-MRA and CTA were higher in 22 patients whose AKA originated from the nonaneurysmal parts (100% vs. 81.8%, P = 0.03). In clinical, SCI was observed in 1.8% of cases after open or endovascular repair. CONCLUSIONS: Despite the longer examination time and more complicated imaging techniques compared to those of CTA, the high spatial resolution of slow-infusion MRA may be preferable for detecting AKA before performing various thoracic and thoracoabdominal aortic surgeries.
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Aneurisma da Aorta Torácica , Dissecção Aórtica , Isquemia do Cordão Espinal , Humanos , Angiografia por Ressonância Magnética/métodos , Angiografia por Tomografia Computadorizada , Meios de Contraste , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Medula Espinal/irrigação sanguínea , Resultado do Tratamento , Gadolínio , Artérias/patologia , Isquemia do Cordão Espinal/patologia , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgiaRESUMO
A 41-year-old man stuck himself with needle through his pericardium during suicide attempt. Chest radiography revealed several needles in the bilateral lung fields as well. Computed tomography (CT) and echocardiography showed massive pericardial effusion and a needle penetrating the pericardium. The patient was initially treated conservatively, including pericardial drainage, and, seven days later, we removed the needle using syngo Needle Guidance in hybrid operating room. The length of skin incision was only 2 cm, and the postoperative course was uneventful. No previous studies, to the best of our knowledge, have shown the use of syngo Needle Guidance to remove a needle in the pericardial cavity. This surgical procedure is minimally invasive for the patient.
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Derrame Pericárdico , Adulto , Humanos , Masculino , Agulhas , Paracentese , Derrame Pericárdico/terapia , Pericárdio/cirurgia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: There is no concrete evidence to support the association between the amount of subcutaneous fat area (SFA) in the central venous port-insertion site (precordium) and port-related complications. We aimed to investigate the relationship between SFA in the midclavicular line and postoperative infectious complications in patients undergoing port-insertion surgery. METHODS: This was a single-institute and historical cohort study of 174 patients who underwent first central venous port implantation surgery for chemotherapy between January 2014 and December 2018. SFA in the midclavicular line was measured using preoperative computed tomography scans. The patients were divided into three groups according to SFA amount tertiles, and we investigated the association of SFA with infectious and all-cause complication events within 1 year. RESULTS: Within a median follow-up of 306 days, the patients with intermediate SFA had significantly higher infection-free survival than those with low and high SFA (low vs. intermediate vs. high: 80.4% vs. 97.7% vs. 83.4%, respectively, p=0.034). In contrast, there was no significant difference in the overall complication-free survival among the groups (low vs. intermediate vs. high: 80.4% vs. 88.9% vs. 81.8%, respectively, p=0.29). Low SFA was independently associated with high risk of infectious complications (hazard ratio, 9.45; 95% confidence interval, 1.07-83.22, p=0.043). CONCLUSION: Low SFA in the midclavicular line was an independent risk factor for infectious complications in the chemotherapy setting. This practical indicator can be useful for optimizing patients' nutritional status and when considering other types of vascular access to support administration of intravenous chemotherapy.
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Cateterismo Venoso Central , Neoplasias , Infecções Relacionadas à Prótese , Idoso , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Infecções Relacionadas à Prótese/etiologia , Estudos Retrospectivos , Fatores de Risco , Gordura Subcutânea/diagnóstico por imagemRESUMO
Aquaporin-2 is found in the apical cell membranes of the principal cells of the collecting duct of the kidney. Plasma arginine vasopressin has been reported to be markedly elevated during cardiac surgery. However fluctuations in urine aquaporin-2 levels have never been reported. We aimed to determine the responses of urine aquaporin-2 and evaluated the relationship between urine aquaporin-2 and plasma arginine vasopressin levels during perioperative periods in cardiac surgical patients. Eight patients undergoing elective isolated aortic valve replacement in normothermia were enrolled prospectively. Blood and urine samples were collected preoperatively and on postoperative days 1, 4, and 7. Patients received furosemide and spironolactone, as needed, during the clinical course; tolvaptan was not needed. Median plasma arginine vasopressin levels [with interquartile range] significantly increased to 1.5 [1.3-2.0], 15.3 [11.4-22.2]*, 2.2 [2.1-2.3], 1.7 [1.5-1.9] pg/mL preoperatively, on postoperative days 1, 4, and 7, respectively (*: p = 0.0001). Similarly, levels of urine aquaporin-2 markedly increased in 3.4 [1.9-5.6], 25.8 [18.4-33.5]**, 9.3 [5.9-14.0], 5.4 [5.3-6.1] (ng/mL), respectively (**p = 0.0004). A significant correlation between plasma arginine vasopressin and urine aquaporin-2 was observed during the entire investigation (R2 = 0.616, p < 0.0001). Plasma arginine vasopressin and urine aquaporin-2 levels were significantly elevated on postoperative day 1 in patients who underwent aortic valve replacement with cardiopulmonary bypass. A significant correlation between plasma arginine vasopressin and urine aquaporin-2 was observed. Urine aquaporin-2 should be further investigated as a potential biomarker for postoperative cardiac dysfunction.
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Valva Aórtica/cirurgia , Aquaporina 2/urina , Implante de Prótese de Valva Cardíaca , Neurofisinas/sangue , Precursores de Proteínas/sangue , Eliminação Renal , Vasopressinas/sangue , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Masculino , Período Perioperatório , Estudos Prospectivos , Fatores de Tempo , Regulação para CimaRESUMO
We present a case of an 85-year-old woman with bilateral limb-threatening ischemia caused by acute-on-chronic occlusion of the infrarenal aorta. The patient once underwent endovascular recanalization using nitinol and stainless-steel bare-metal stent implantation; however, the stainless-steel stent collapsed 3 months later. In the second endovascular therapy, "Squid-Capture" modified in situ stent-graft fenestration technique followed by stent-in-stent implantation with stent graft and bare-metal stent was successfully applied, and it can be regarded as a promising treatment option for the repair of abdominal aortic occlusive disease in some limited anatomical conditions.
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Angioplastia com Balão/instrumentação , Aorta Abdominal/cirurgia , Doenças da Aorta/terapia , Arteriopatias Oclusivas/cirurgia , Implante de Prótese Vascular , Stents , Idoso de 80 Anos ou mais , Angioplastia com Balão/efeitos adversos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/fisiopatologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/fisiopatologia , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/fisiopatologia , Prótese Vascular , Implante de Prótese Vascular/instrumentação , Feminino , Humanos , Desenho de Prótese , Falha de Prótese , Recidiva , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
PURPOSES: To retrospectively evaluate the effect of negative-pressure sternal wound closure (NPSWC) with a subcutaneous closed drain tube on the sternal surgical site infection (SSI) incidence. METHODS: After propensity score matching of 231 patients undergoing coronary artery bypass grafting (CABG), we compared 104 pairs in the NPSWC and historical control groups. In the molecular analysis, the interleukin-6 (IL-6), basic fibroblast growth factor (b-FGF), and transforming growth factor ß1 (TGF-ß1) levels in the wound fluid were measured using two different reservoir types at postoperative days 2 and 7. RESULTS: NPSWC significantly reduced the SSI incidence from 10.6 to 2.9%. No mediastinitis occurred in the NPSWC group. A multivariate logistic regression analysis identified female sex (p = 0.0040) and no NPSWC (p = 0.0084) as significant risk factors for sternal SSI development. The Negative-pressure value was 49.4 ± 4.1 and 115.5 ± 15.2 mmHg in the standard-type (SSR) and bulb-type suction reservoirs (BSR), respectively. Given that growth factors were affected by the difference in negative pressure, the IL-6, b-FGF, and TGF-ß1 levels were significantly higher in the BSR than in the SSR. CONCLUSIONS: NPSWC using a subcutaneous closed drain tube was effective in preventing sternal SSI after CABG and may accelerate wound healing even when both internal thoracic arteries are harvested. CLINICAL REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trials Registry, registration number: UMIN000037060.
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Ponte de Artéria Coronária , Drenagem/métodos , Tratamento de Ferimentos com Pressão Negativa/métodos , Complicações Pós-Operatórias/prevenção & controle , Esternotomia , Infecção da Ferida Cirúrgica/prevenção & controle , Técnicas de Sutura , Humanos , Estudos Retrospectivos , CicatrizaçãoRESUMO
BACKGROUND: To investigate the association between preoperative pulmonary function evaluations and surgical outcomes of patients with chronic lung disease following cardiac surgery. METHODS: This retrospective observational study evaluated 148 patients using preoperative pulmonary function tests before undergoing cardiac surgery. Patients were divided into 4 groups (normal, obstructive, restrictive, and combined disorder), based on the result of the pulmonary function tests. Additionally, we evaluated the percent predicted forced expiratory volume in 1 second. Finally, we investigated the mechanical ventilation duration, length of postoperative hospital stay, and the 30-day mortality rate between the groups in each study. RESULTS: The mechanical ventilation duration and length of postoperative hospital stay in the combined group was significantly longer than that in the other groups (P < .0001, P < .0001, respectively). Patients in the restrictive group had a significantly longer postoperative ventilation or hospitalization than those in the normal group (P = .0479, P = .0164, respectively). However, there were no significant differences in the 30-day mortality rates between the groups. There also was a significant negative correlation between the percent predicted forced expiratory volume in 1 second and mechanical ventilation (R2 = 0.052, P = .0054) and postoperative hospitalization (R2 = 0.042, P = .0122). CONCLUSION: Risk stratification by preoperative pulmonary function tests may be used to accurately identify the postoperative outcomes in chronic lung disease patients following cardiac surgery.
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Procedimentos Cirúrgicos Cardíacos/métodos , Volume Expiratório Forçado/fisiologia , Pneumopatias/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Cuidados Pré-Operatórios/métodos , Idoso , Feminino , Seguimentos , Humanos , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Prognóstico , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de RiscoRESUMO
Background This study aimed to analyze age-related changes in shear wave speed (SWS) of the normal uterine cervix. Methods We studied 362 women with a normal singleton pregnancy at 12-35 weeks' gestation. The SWS of the cervix was measured using transvaginal ultrasonography at the internal os region of the anterior cervix (IOA), posterior cervix (IOP) and cervical canal (IOC), and at the external os region of the anterior cervix (EOA), posterior cervix (EOP) and cervical canal (EOC). The following parameters were analyzed: (1) time trend of SWS of the individual sampling points, (2) comparison of SWS in the internal cervical region and SWS in the external cervical region, and (3) comparison of SWS between the internal and external cervical regions. Statistical analyses were performed using mixed-effects models. Results The SWS of IOP decreased in bilinear regression, with a critical change in the rate at 22 weeks, whereas the SWS of the remaining points decreased linearly. The estimated values of SWS of IOP at 84, 154 and 251 days were higher than those of IOA and IOC (P<0.001). The estimated values of SWS of IOP at 84 and 154 days were higher than those of EOP (P<0.001). Significant differences between IOP and EOP were shown until 244 days (P<0.05). The estimated value of SWS of IOC at 84 days was higher than that of EOC (P<0.001). Significant differences between IOC and EOC were shown until 210 days (P<0.05). Conclusion The SWS of the uterine cervix in pregnancy decreases with advancing gestation. The SWS of IOP had the highest value among the sampling points with unique characteristics.
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Colo do Útero/diagnóstico por imagem , Adulto , Feminino , Humanos , Gravidez , Trimestres da Gravidez , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
BACKGROUND: Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional difference in the subgroup-specific viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein-protein interaction. RESULTS: (1) Transcriptional changes in Jurkat Tet-On human T-cells that express each subgroup of Tax or HBZ protein under the control of an inducible promoter revealed different target gene profiles; (2) the number of differentially regulated genes induced by HBZ was 2-3 times higher than that induced by Tax; (3) Tax and HBZ induced the expression of different classes of non-coding RNAs (ncRNAs); (4) the chemokine CXCL10, which has been proposed as a prognostic biomarker for HAM/TSP, was more efficiently induced by subgroup-A Tax (Tax-A) than subgroup-B Tax (Tax-B), in vitro as well as in unmanipulated (ex vivo) PBMCs obtained from HAM/TSP patients; (5) reporter gene assays indicated that although transient Tax expression in an HTLV-1-negative human T-cell line activated the CXCL10 gene promoter through the NF-κB pathway, there was no difference in the ability of each subgroup of Tax to activate the CXCL10 promoter; however, (6) chromatin immunoprecipitation assays showed that the ternary complex containing Tax-A is more efficiently recruited onto the promoter region of CXCL10, which contains two NF-κB binding sites, than that containing Tax-B. CONCLUSIONS: Our results indicate that different HTLV-1 subgroups are characterized by different patterns of host gene expression. Differential expression of pathogenesis-related genes by subgroup-specific Tax or HBZ may be associated with the onset of HAM/TSP.
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Produtos do Gene tax/genética , Infecções por HTLV-I/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Paraparesia Espástica Tropical/genética , Transativadores/genética , Adulto , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem Celular , Feminino , Vírus Linfotrópico T Tipo 1 Humano/classificação , Humanos , Células Jurkat , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/virologia , RNA não Traduzido/genética , Proteínas dos Retroviridae/genética , Fatores de Risco , Transcriptoma , Proteínas Virais/genéticaRESUMO
Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.
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Inibidor de Quinase Dependente de Ciclina p21/genética , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXB1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Prognóstico , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXB1/metabolismo , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
In normal human T cells, telomerase activity is strictly regulated. T cells are thought to express telomerase to avoid replicative senescence, unlike most normal somatic cells with definite replicative lifespan. T cells in blood and tissues are usually in a state of quiescence without expression of the limiting catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). In contrast to activation, repression of hTERT transcription has not been studied well. Our previous studies have found an hTERT promoter element with repressive function. Here we identified KLF2, which represses hTERT transcription by binding to the putative promoter element. KLF2 and hTERT exhibited reciprocal mRNA expression patterns in primary human T cells. In activated T cells, KLF2 binding to the hTERT promoter was eliminated, relieving the repression of hTERT transcription found in resting T cells. Our results suggest that KLF2 is involved in strict repression of hTERT expression through binding to the promoter in primary human T cells.
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Fatores de Transcrição Kruppel-Like/fisiologia , Linfócitos T/enzimologia , Telomerase/metabolismo , Transcrição Gênica/fisiologia , Sequência de Bases , Western Blotting , Domínio Catalítico , Células Cultivadas , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Reação em Cadeia da Polimerase , RNA Interferente Pequeno/genética , Telomerase/química , Telomerase/genéticaRESUMO
Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with α-GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon-γ from NKT cells. RASAL3-deficient NKT cells treated with α-GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases.
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Células T Matadoras Naturais/imunologia , Proteínas Ativadoras de ras GTPase/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Galactosilceramidas/administração & dosagem , Galactosilceramidas/imunologia , Técnicas de Silenciamento de Genes , Humanos , Interferon gama/biossíntese , Interleucina-4/biossíntese , Células Jurkat , Fígado/imunologia , Fígado/lesões , Fígado/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/metabolismo , Receptores CXCR6 , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro. To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5α expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5α variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5α by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5α is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development. IMPORTANCE: HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5α is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5α is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5α-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5α-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5α serves as a potential molecular target to treat HTLV-1-related leukemia.
Assuntos
Transformação Celular Viral/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Proteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Linhagem Celular Transformada , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/genética , Transformação Celular Neoplásica/genética , Humanos , Interleucina-2/metabolismo , Janus Quinases/metabolismo , Leucemia-Linfoma de Células T do Adulto/virologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , NADPH Oxidase 5 , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , Oniocompostos/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-κB2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-κB2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-κB2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2.
Assuntos
Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Vírus Linfotrópico T Tipo 2 Humano/fisiologia , Subunidade p52 de NF-kappa B/metabolismo , Ligante OX40/biossíntese , Células HEK293 , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 2 Humano/imunologia , Humanos , Células Jurkat , Linfócitos T/imunologia , Linfócitos T/virologiaRESUMO
BACKGROUND: Laparoscopic Kasai portoenterostomy has been performed in infants with biliary atresia at several institutions, but laparoscopic anastomosis requiring multi-directional suturing on a vertical plane of the liver remains a challenge. To assist multi-directional suturing, we developed a multi-degree-of-freedom (DOF) needle driver whose tip length was 15 mm and shaft diameter was 3.5 mm. The tip of the multi-DOF needle driver has three DOFs for grasp, flection and rotation. The aim of this study was to evaluate the performance of the multi-DOF needle driver in two kinds of in vivo experiments. METHODS: Surgeons were asked to perform four-directional laparoscopic suturing on a vertical plane of the liver in six rabbits using the multi-DOF needle driver or a conventional needle driver. The needle grasping time, the needle handling time, the number of needle insertions, the number of liver lacerations, the suturing width and depth, and the area of necrotic tissues were analyzed and compared. Additionally, one surgeon was asked to perform laparoscopic hepato-jejunostomy in four rabbits to assess the feasibility of Kasai portoenterostomy using the multi-DOF needle driver. RESULTS: The suturing depth using the multi-DOF needle driver was significantly larger than that using the conventional needle driver in both the right and downward suturing directions. No statistically significant differences were found in other metrics. Liver lacerations were observed only when suturing was performed using the conventional needle driver. The experimental laparoscopic hepato-jejunostomy using the multi-DOF needle driver was successful. CONCLUSIONS: Using the multi-DOF needle driver, uniform multi-directional suturing on a vertical plane of the liver could be performed. The short distal tip of the multi-DOF needle driver demonstrated its advantages in multi-directional suturing in a small body cavity. The multi-DOF needle driver may be able to be used to perform complex tasks in laparoscopic Kasai portoenterostomy.