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Research into Schwann cell (SC)-related diseases has been hampered by the difficulty of obtaining human-derived SCs, which have limited proliferative capacity. This has resulted in a delay in progress in drug discovery and cell therapy targeting SCs. To overcome these limitations, we developed a robust method for inducing the differentiation of human induced pluripotent stem cells (hiPSCs) into SCs. We established hiPSC lines and successfully generated high-purity Schwann cell precursors (SCPs) from size-controlled hiPSC aggregates by precisely timed treatment with our proprietary enzyme solution. Such SCPs were successfully expanded and further differentiated into myelin basic protein (MBP) expressing SC populations when treated with an appropriate medium containing dibutyryl-cAMP (db-cAMP). These differentiated cells secreted factors that induced neurite outgrowth in vitro. Our method allows for the efficient and stable production of SCPs and SCs from hiPSCs. This robust induction and maturation method has the potential to be a valuable tool in drug discovery and cell therapy targeting SC-related diseases.
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Diferenciação Celular , Células-Tronco Pluripotentes Induzidas , Células de Schwann , Células de Schwann/citologia , Células de Schwann/metabolismo , Humanos , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteína Básica da Mielina/metabolismo , Proteína Básica da Mielina/genética , Células Cultivadas , Linhagem Celular , Bucladesina/farmacologia , Técnicas de Cultura de Células/métodosRESUMO
We herein report a 37-year-old man who experienced recurrence of metastatic cardiac rhabdomyosarcoma along with intractable ventricular tachycardia (VT) 7 years after resection of rhabdomyosarcoma in his right elbow. At 36 years old, he developed VT unresponsive to radiofrequency catheter ablation (RFCA). Initially, the cardiac tumor was not detected, but it gradually grew in size at the RFCA site. A surgical biopsy confirmed the diagnosis of metastatic cardiac rhabdomyosarcoma. Despite radiation therapy, cardiac tumor progression and VT instability could not be prevented. Ultimately, the patient died 27 months after the initial documentation of VT.
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Dysregulated extracellular pH, the universal feature of tumor, works as an evolutional force to drive dissemination of tumor cells. It is well-established that tumor acidity is associated with tumor growth and metastasis. However, the pH of pre-metastatic niche remains unclear. We hypothesized that primary tumor cells remotely prime acidity in secondary organ to achieve metastatic colonization. Herein, we demonstrated that the pH responsive probe pH Low Insertion Peptide (pHLIP) was notably accumulated in pre-metastatic lungs of 4T1.2 breast tumor-bearing mice. The pHLIP-targeted lungs showed high amounts of lactate and overexpressed glycolysis-related proteins. Pharmacological inhibition of glycolysis suppressed the lung acidification induced by 4T1.2 cancer cell culture supernatant and delayed subsequent metastatic burden of disseminated tumor cells. In the acidic lungs, pHLIP was primarily localized in alveolar type 2 cells which strongly expressed glycolysis-related proteins. 4T1.2-derived extracellular vesicles expressed some of the glycolysis-related proteins, and their administration increased pHLIP accumulation and glycolytic enhancement in lungs. pHLIP-conjugated dexamethasone effectively attenuated lung metastatic burden by disrupting pro-inflammatory response in the acidic lungs. From these results, targeting the metastasis-supporting microenvironment by pHLIP technology creates possibility to identify pre-metastatic organ and prevent metastatic recurrence.
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Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. To generate cardiac-specific Cx43-deficient (cCx43-/-) mice, Cx43flox/flox mice were crossed with α-MHC (Myh6)-cre+/- mice. The resulting offspring, Cx43flox/flox/Myh6-cre+/- mice (cCx43-/- mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from the right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from the ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2',7'-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methyl ester (TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. ROS production within the mitochondria was estimated with MitoSoxRed and mitochondrial Ca2+ with rhod-2 in trabeculae. Diazoxide was used to activate mitochondrial KATP. Most of cCx43-/- mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice but not in cCx43-/- mice. In cCx43-/- mice, the [Ca2+]o,min was lower, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were higher. TMRM fluorescence was more decreased in cCx43-/- mice. Most of these changes were suppressed by diazoxide. In addition, in cCx43-/- mice, antioxidant peptide SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o,min. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to depolarization of mitochondrial membrane potential, an increase in mitochondrial Ca2+, and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.
Assuntos
Conexina 43 , Ventrículos do Coração , Camundongos , Animais , Ventrículos do Coração/metabolismo , Conexina 43/metabolismo , Diazóxido/efeitos adversos , Diazóxido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Miócitos Cardíacos/metabolismo , Arritmias Cardíacas/metabolismo , Mitocôndrias , Trifosfato de Adenosina/metabolismoRESUMO
BACKGROUND: Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful. METHODS: We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF>10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated. RESULTS: A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P < 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P < 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P < 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02]. CONCLUSIONS: These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients.
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Antineoplásicos , Neoplasias da Mama , Cardiopatias , Disfunção Ventricular Esquerda , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Volume Sistólico , Função Ventricular Esquerda , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Detecção Precoce de Câncer , Antineoplásicos/uso terapêutico , Fatores de Risco , Espectroscopia de Ressonância Magnética , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Valor Preditivo dos TestesRESUMO
Mechano-electric feedback means that muscle stretching causes depolarization of membrane potential. We investigated whether muscle stretching induces action potential and twitch contraction with a threshold of sarcomere length (SL) and what roles stretch-activated channels (SACs) and stretch-activated NADPH oxidase (X-ROS signaling) play in the induction. Trabeculae were obtained from the right ventricles of rat hearts. Force, SL, and [Ca2+]i were measured. Various degrees of stretching from the SL of 2.0 µm were applied 0.5 s after the last stimulus of the electrical train with 0.4-s intervals for 7.5 s. The SLtwitch was defined as the minimal SL at which twitch contraction was induced by the stretching. Muscle stretching induced twitch contraction with a threshold of SL at 0.4-s stimulus intervals ([Ca2+]o = 0.7 mmol/L). The SLtwitch was not changed by increasing the stimulus intervals and [Ca2+]o and by adding 1 µmol/L isoproterenol. The SLtwitch was not changed by adding 10 µmol/L Gd3+, 100 µmol/L or 200 µmol/L streptomycin, and 5 µmol/L GsMTx4. The SLtwitch was not changed by adding 1 µmol/L ryanodine and 3 µmol/L diphenyleneiodonium chloride. In contrast, the SLtwitch was increased by elevating extracellular K+ from 5 to 10 mmol/L and by adding the stretching during the refractory period of membrane potential. The addition of the stretching-induced twitch contraction more frequently induced arrhythmias. These results suggest that muscle stretching can induce twitch contraction with a threshold of SL and concern the occurrence of arrhythmias and that SACs and X-ROS signaling play no roles in the induction.
Assuntos
Ventrículos do Coração , Contração Miocárdica , Animais , Arritmias Cardíacas , Cálcio , Contração Muscular , Contração Miocárdica/fisiologia , NADPH Oxidase 2 , Ratos , Espécies Reativas de Oxigênio , SarcômerosRESUMO
Background/Aim: Fatigue is the most common symptom in patients with cancer undergoing radiation therapy or cancer chemotherapy. However, cancer-related fatigue remains undertreated and poorly understood. Materials and Methods: Mice were administered a single dose of cisplatin (10 mg/kg, intraperitoneally) or saline (as a control) and then treated with sucrose, fructose, glucose (each at 500 or 5,000 mg/kg, orally), or saline (control) daily for 4 days. cisplatin-induced fatigue-like behavior was investigated by assessment of running activity on a treadmill. The influence of glucose intake on tumor growth was also examined in Lewis lung carcinoma (LLC)-bearing mice. Results: Administration of sucrose and glucose improved cisplatin-induced fatigue-like behavior in mice, whereas administration of fructose showed only slight antifatigue effects. Although glucose-fed mice showed increased tumor growth, this was balanced out by the powerful cytotoxicity of cisplatin. Conclusion: Sucrose, and especially glucose, may improve patient quality of life during treatment with anticancer agents by preventing fatigue without interfering with the antitumor effects of cisplatin.
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AIMS: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. METHODS AND RESULTS: Twelve-week-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy [1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2] or placebo procedure two times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive haemodynamic analysis showed that cardiac diastolic function parameters, such as e', E/e', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, western blot showed that the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. CONCLUSIONS: These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients.
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Insuficiência Cardíaca Diastólica/terapia , Volume Sistólico , Terapia por Ultrassom , Ondas Ultrassônicas , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Sinalização do Cálcio , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca Diastólica/genética , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Preparação de Coração Isolado , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: Clinical presentations associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) at rest are highly similar. Differentiating between CTEPH and PAH using non-invasive techniques remains challenging. Thus, we examined whether analysis of ventilatory gas in response to postural changes can be useful as a non-invasive screening method for pulmonary hypertension (PH), and help differentiate CTEPH from PAH. METHODS: We prospectively enrolled 90 patients with suspected PH and performed right heart catheterization, ventilation/perfusion scan and ventilatory gas analysis. Various pulmonary function parameters were examined in the supine and sitting postures, and postural changes were calculated (Δ(supine - sitting)). RESULTS: In total, 25 patients with newly diagnosed PAH, 40 patients with newly diagnosed CTEPH and 25 non-PH patients were included. ΔEnd-tidal CO2 pressure (PET CO2 ) was significantly lower in patients with CTEPH and PAH than in non-PH patients (both P < 0.001). ΔPET CO2 < 0 mm Hg could effectively differentiate PH from non-PH (area under the curve (AUC) = 0.969, sensitivity = 89%, specificity = 100%). Postural change from sitting to supine significantly increased the ratio of ventilation to CO2 production (VE/VCO2 ) in the CTEPH group (P < 0.001). By contrast, VE/VCO2 significantly decreased in the PAH group (P = 0.001). Notably, CTEPH presented with higher ΔVE/VCO2 than PAH, although no differences were observed in haemodynamic and echocardiographic parameters between the two groups (P < 0.001). Furthermore, ΔVE/VCO2 > 0.8 could effectively differentiate CTEPH from PAH (AUC = 0.849, sensitivity = 78%, specificity = 88%). CONCLUSION: Postural changes in ventilatory gas analysis are useful as a non-invasive bedside evaluation to screen for the presence of PH and distinguish between CTEPH and PAH.
Assuntos
Testes Respiratórios , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Adulto , Idoso , Área Sob a Curva , Dióxido de Carbono/análise , Doença Crônica , Diagnóstico Diferencial , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Curva ROC , Postura Sentada , Decúbito DorsalRESUMO
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organic thrombotic obstructions in the pulmonary arteries with reduced pulmonary vascular reserve. This study aimed to examine whether postural changes in ventilatory gas analysis parameters are useful for assessing pulmonary hemodynamics in patients with CTEPH. METHODS: A total of 44 patients with newly diagnosed CTEPH (CTEPH group), 33 patients with improved CTEPH (mean pulmonary arterial pressure [mPAP] <25â¯mmâ¯Hg), and 25 controls were enrolled. Patients with improved CTEPH referred to patients without residual PH who were previously diagnosed with CTEPH and already received optimal therapies. Various pulmonary function parameters were examined in supine and sitting positions, and postural changes were calculated (Δ[supine - sitting]). In 32 patients with CTEPH, we examined hemodynamic and ventilatory gas analysis parameters before the first balloon pulmonary angioplasty (BPA) and during follow-up. RESULTS: Patients with CTEPH had significantly lower supine end-tidal carbon dioxide pressure (PETCO2) and ΔPETCO2 than controls (both Pâ¯<â¯0.001), and these parameters were significantly correlated with mPAP (R2â¯=â¯0.507, Pâ¯<â¯0.0001 and R2â¯=â¯0.470, Pâ¯<â¯0.001, respectively). Supine PETCO2 and ΔPETCO2 were significantly lower in patients with improved CTEPH than in controls (both Pâ¯<â¯0.001). Hemodynamic and echocardiographic parameters were comparable in both groups. Furthermore, significant correlation between the change in mPAP and change in supine PETCO2 by BPA was noted (R2â¯=â¯0.478, Pâ¯<â¯0.001). CONCLUSION: These results indicate that postural changes in ventilatory gas analysis parameters are useful and non-invasive method for the evaluation of mPAP, which is one of the hemodynamic parameters of CTEPH severity.
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Hipertensão Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico , Idoso , Testes Respiratórios , Dióxido de Carbono/análise , Doença Crônica , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Oxigênio/análise , Embolia Pulmonar/complicações , Índice de Gravidade de DoençaRESUMO
Congestive heart failure (CHF) is rare during pregnancy. We herein report a 35-year-old woman who developed CHF with severe left ventricular dysfunction at 35 weeks' gestation. She underwent emergency Caesarean section followed by intensive-care treatment for CHF. The diagnosis of Cushing's syndrome (CS) caused by adrenal adenoma was confirmed by endocrinological examinations and histology after adrenalectomy. She was discharged on heart failure medications and glucocorticoid replacement therapy. Both the symptoms and cardiac function had recovered after 12 months of follow-up. This case highlights the importance of considering CS-induced cardiomyopathy as a cause of CHF in pregnant women.
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Adrenalectomia/métodos , Adenoma Adrenocortical/cirurgia , Cardiomiopatias/complicações , Cesárea/métodos , Síndrome de Cushing/complicações , Insuficiência Cardíaca/cirurgia , Complicações na Gravidez , Doença Aguda , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/diagnóstico , Adulto , Cardiomiopatias/diagnóstico , Síndrome de Cushing/diagnóstico , Ecocardiografia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Recém-Nascido , Laparoscopia , Gravidez , Tomografia Computadorizada por Raios XRESUMO
Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A (α-GAL A). We herein report 10 cases of AFD in 5 families (3 men and 7 women) that were found to have a specific common mutation in R301Q [G-to-A transition in exon 6 (codon 301) resulting in the replacement of a glutamine with an arginine residue]. We evaluated their clinical characteristics, residual enzymatic activity, and plasma concentrations of globotriaosylsphingosine (Lyso-Gb3). Although all 10 cases had cardiac and renal manifestations in common, their clinical manifestations were markedly divergent despite the same genetic abnormality.
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Doença de Fabry/genética , Doença de Fabry/fisiopatologia , Glicolipídeos/genética , Mutação , Esfingolipídeos/genética , alfa-Galactosidase/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
It was reported that hepatitis C virus (HCV) antibody-positivity adversely affects cardiac function. As the screening for HCV began in 1992, we hypothesized that HCV antibody-positive rate would be high in adult congenital heart disease (ACHD) patients who underwent heart surgery before 1992 and adversely affected cardiac function and long-term prognosis. We retrospectively enrolled 243 ACHD patients (mean age 25.9 years) who underwent cardiac surgery before 1992 and visited our hospital from 1995 to 2015. We compared clinical characteristics including cardiac function and long-term prognosis between HCV antibody-positive (nâ¯=â¯48) and antibody-negative (nâ¯=â¯195) patients. The composite end point (CEP) included cardiac death, heart failure hospitalization, lethal ventricular arrhythmias, and cardiac reoperation. The prevalence of reduced systemic ventricular ejection fraction <50% was significantly higher in the HCV antibody-positive group compared with the HCV antibody-negative group (17 vs 5.4%, p = 0.014). During a mean follow-up period of 10.1 years (interquartile range 6 to 14 years), the CEP was noted in 51 patients. Kaplan-Meier analysis showed the HCV antibody-positive group had significantly poor event-free survival than the HCV antibody-negative group (log-rank, p = 0.002). In contrast, HCV ribonucleic acid-positivity was not a significant predictor of the CEP in the HCV antibody-positive group (log-rank, p = 0.442). Furthermore, the HCV antibody-positivity was significantly associated with the CEP in both univariable and multivariable Cox regression models (hazard ratio 2.37, 95% confident interval 1.32 to 4.15, p = 0.005 and 1.96, 1.06 to 3.63, p = 0.032, respectively). In conclusion, these results suggest that more attention should be paid to HCV antibody-positivity in the management of ACHD patients.
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Previsões , Cardiopatias Congênitas/fisiopatologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C Crônica/complicações , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Hepatite C Crônica/virologia , Humanos , Masculino , Prevalência , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. MATERIALS AND METHODS: YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro. RESULTS: Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines. CONCLUSION: A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/metabolismo , Pirimidinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sinergismo Farmacológico , Ácidos Graxos Monoinsaturados/farmacologia , Fluvastatina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfoproteínas/genética , Interferência de RNA , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAPRESUMO
RATIONALE AND OBJECTIVES: Pulmonary involvement in inflammatory bowel disease may reflect the common embryonic origin of the gastrointestinal tract and the bronchial tree. No studies have compared pulmonary high-resolution computed tomography (HRCT) findings between ulcerative colitis (UC) and Crohn disease (CD). This study aimed to assess the relationship between pulmonary HRCT findings and inflammatory bowel disease activity and to compare HRCT findings between UC and CD. MATERIALS AND METHODS: We retrospectively identified 601 consecutive patients (350 with UC and 251 with CD) who had undergone chest HRCT examinations at our institutions between April 2004 and April 2016. Parenchymal abnormalities, enlarged lymph nodes, and pleural effusion were evaluated on HRCT. RESULTS: One hundred sixty-seven patients (94 men, 73 women; aged 12-86 years, mean: 47.2 years) with UC and 93 patients (61 men, 32 women; aged 12-71 years, mean: 37.9 years) with CD had abnormal findings on chest HRCT. The HRCT findings of UC and CD mainly consisted of centrilobular nodules (in 49.1% and 45.2% of cases, respectively) and bronchial wall thickening (in 31.7% and 54.8%, respectively). There was no relationship between HRCT findings and disease activity. Bronchial wall thickening was significantly more frequent in patients with CD than in those with UC (P < .001). CONCLUSION: The main chest HRCT findings in UC and CD are centrilobular nodules and bronchial wall thickening. There are differences in HRCT findings between UC and CD.
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Brônquios/diagnóstico por imagem , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Nódulo Pulmonar Solitário/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brônquios/patologia , Criança , Feminino , Humanos , Linfadenopatia/complicações , Linfadenopatia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Derrame Pleural/complicações , Derrame Pleural/diagnóstico por imagem , Estudos Retrospectivos , Nódulo Pulmonar Solitário/complicações , Adulto JovemRESUMO
AIMS: Although balloon pulmonary angioplasty (BPA) improves haemodynamics and short-term prognosis in patients with inoperable chronic thrombo-embolic pulmonary hypertension (CTEPH), the long-term effects of BPA, and procedure-related complications remain to be fully elucidated. METHODS AND RESULTS: From July 2009 to October 2016, we performed a total of 424 BPA sessions in 84 consecutive patients with inoperable CTEPH. We used 3D reconstructed computed tomography to determine target lesions of pulmonary arteries and optical computed tomography to select balloon size, if needed. In 77 patients (92%) who completed the BPA treatment [65 ± 14 (SD) years-old, male/female 14/63], haemodynamics and exercise capacity were examined at 6 months after last BPA and in the chronic phase [>12 months after first BPA, 31 (20, 41) months]. The BPA treatment significantly improved mean pulmonary arterial pressure (38 ± 10 to 25 ± 6 mmHg), pulmonary vascular resistance (7.3 ± 3.2 to 3.8 ± 1.0 Wood units), and 6-minute walk distance (380 ± 138 to 486 ± 112 m) (all P < 0.01), and the improvements persisted throughout the follow-up period (43 ± 27 months) (N = 53). In the 424 sessions, haemoptysis was noted in 60 sessions (14%), and non-invasive positive pressure ventilation (NPPV) was used to treat haemoptysis and/or hypoxemia in 33 sessions (8%). Furthermore, 5-year survival was 98.4% (only one patient died of colon cancer) with no peri-procedural death. CONCLUSION: These results indicate that BPA improves haemodynamics and exercise capacity in inoperable CTEPH patients with acceptable complication rate and that the beneficial haemodynamic effects of BPA persist for years with resultant good long-term prognosis.
Assuntos
Angioplastia com Balão/métodos , Hipertensão Pulmonar/terapia , Tromboembolia/terapia , Idoso , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/estatística & dados numéricos , Doença Crônica , Teste de Esforço , Tolerância ao Exercício/fisiologia , Feminino , Seguimentos , Hemoptise/etiologia , Hemoptise/terapia , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/mortalidade , Hipóxia/etiologia , Hipóxia/terapia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Respiração com Pressão Positiva , Estudos Retrospectivos , Tromboembolia/diagnóstico por imagem , Tromboembolia/mortalidade , Tomografia Computadorizada por Raios X , Resistência VascularRESUMO
OBJECTIVE: This study aimed to compare CT findings in patients with Epstein-Barr virus positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly with CT findings in patients with Epstein-Barr virus negative (EBV-) DLBCL. METHODS: We retrospectively identified 9 consecutive patients with EBV+ DLBCL (6 males and 3 females; aged 72-83 years, mean: 76.2 years) and 39 consecutive patients with EBV- DLBCL (19 males and 20 females; aged 53-91 years, mean: 71.3 years) who had undergone CT examinations between September 2007 and August 2016. In each type of disease, clinical and CT findings were evaluated. RESULTS: No significant differences in B symptom incidence or serum lactate dehydrogenase levels were found between the two diseases. However, the prognosis of patients with EBV+ DLBCL was significantly poorer than that of those with EBV- DLBCL (p < 0.05). Nodal and extranodal necrosis was found in 6 (66.7%) of 9 patients with EBV+ DLBCL and in 6 (15.4%) of 39 patients with EBV- DLBCL (p < 0.005). CONCLUSION: The CT finding of nodal and extranodal necrosis was significantly more frequent in patients with EBV+ DLBCL than in patients with EBV- DLBCL. Advances in knowledge: This is the first report on the CT findings in patients with EBV+ DLBCL of the elderly. Different CT findings are present in EBV+ DLBCL and EBV- DLBCL.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Infecções por Vírus Epstein-Barr/patologia , Feminino , Avaliação Geriátrica , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: It remains to be elucidated whether cardiac sympathetic nervous activity is impaired in patients with Anderson-Fabry disease (AFD).MethodsâandâResults:We performed 123I-meta-iodobenzylguanidine (MIBG) scintigraphy and gadolinium-enhanced cardiovascular magnetic resonance (CMR) in 5 AFD patients. MIBG uptake in the inferolateral wall, where wall thinning and delayed enhancement were noted on CMR, was significantly lower compared with the anteroseptal wall. The localized reduction in MIBG uptake was also noted in 2 patients with no obvious abnormal findings on CMR. CONCLUSIONS: Cardiac sympathetic nervous activity is impaired in AFD before development of structural myocardial abnormalities. (Circ J 2016; 80: 2550-2551).
Assuntos
3-Iodobenzilguanidina , Doença de Fabry , Miocárdio/metabolismo , 3-Iodobenzilguanidina/administração & dosagem , 3-Iodobenzilguanidina/farmacocinética , Doença de Fabry/diagnóstico por imagem , Doença de Fabry/metabolismo , Feminino , Gadolínio/administração & dosagem , Gadolínio/farmacocinética , Humanos , Imageamento por Ressonância Magnética , Masculino , CintilografiaRESUMO
PURPOSE: To evaluate whether the extent of perfusion defects assessed by examining lung perfused blood volume (PBV) images is a stronger estimator of the clinical severity of chronic thromboembolic pulmonary hypertension (CTEPH) compared with other computed tomography (CT) findings and noninvasive parameters. MATERIALS AND METHODS: We analyzed 46 consecutive patients (10 men, 36 women) with CTEPH who underwent both dual-energy CT and right-heart catheter (RHC) examinations. Lung PBV images were acquired using a second-generation dual-source CT scanner. Two radiologists independently scored the extent of perfusion defects in each lung segment employing the following criteria: 0, no defect, 1, defect in <50% of a segment, 2, defect in ≥50% of a segment. Each lung PBV score was defined as the sum of the scores of 18 segments. In addition, all of the following were recorded: 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, and RHC hemodynamic parameters including pulmonary artery pressure (PAP), right ventricular pressure (RVP), cardiac output (CO), the cardiac index (CI), and pulmonary vascular resistance (PVR). Bootstrapped weighted kappa values with 95% confidence intervals (CIs) were calculated to evaluate the level of interobserver agreement. Correlations between lung PBV scores and other parameters were evaluated by calculating Spearman's rho correlation coefficients. Multivariable linear regression analyses (using a stepwise method) were employed to identify useful estimators of mean PAP and PVR among CT, BNP, and 6MWD parameters. A p value<0.05 was considered to reflect statistical significance. RESULTS: Interobserver agreement in terms of the scoring of perfusion defects was excellent (κ=0.88, 95% CIs: 0.85, 0.91). The lung PBV score was significantly correlated with the PAP (mean, rho=0.48; systolic, rho=0.47; diastolic, rho=0.39), PVR (rho=0.47), and RVP (rho=0.48) (all p values<0.01). Multivariable linear regression analyses showed that only the lung PBV score was significantly associated with both the mean PAP (coefficient, 0.84, p<0.01) and the PVR (coefficient, 28.83, p<0.01). CONCLUSION: The lung PBV score is a useful and noninvasive estimator of clinical CTEPH severity, especially in comparison with the mean PAP and PVR, which currently serve as the gold standards for the management of CTEPH .