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BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
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Antineoplásicos , Neuroblastoma , Adulto , Antineoplásicos/efectos adversos , Niño , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Ftalazinas/efectos adversos , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Poli(ADP-Ribosa) PolimerasasRESUMEN
INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. METHODS: This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS: In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. DISCUSSION/CONCLUSION: Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.
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Anemia/tratamiento farmacológico , Pirazoles/uso terapéutico , Triazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia/etiología , Femenino , Hematínicos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicacionesRESUMEN
INTRODUCTION: Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the "Molidustat Once Daily Improves Renal Anemia by Inducing EPO" (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. METHODS: This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3-5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 µg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and <13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS: In total, 162 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was -0.38 (-0.67, -0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. DISCUSSION/CONCLUSION: In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.
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Anemia/tratamiento farmacológico , Pirazoles/uso terapéutico , Triazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Insuficiencia Renal Crónica/complicaciones , Resultado del Tratamiento , Triazoles/efectos adversosRESUMEN
BACKGROUND: There is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials. METHODS: In this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m2 b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed. DISCUSSION: This study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients. TRIAL REGISTRATION: UMIN-CTR ( UMIN000025521 ); Registered on January 4, 2017.
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Ensayos Clínicos Fase I como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Proyectos de Investigación , Administración Oral , Adolescente , Niño , Preescolar , Ensayos Clínicos Fase I como Asunto/métodos , HumanosRESUMEN
The number of circulating endothelial progenitor cells (EPCs) is considered to be a surrogate marker for coronary artery disease (CAD). Recent studies have identified a novel T-cell subset labeled with CD3(+)/CD31(+), which is necessary for EPC colony formation and constitutes the central cluster. However, the clinical relevance of the CD3(+)/CD31(+) T cells in CAD remains unclear. We sought to clarify whether circulating CD3(+)/CD31(+) T cells are increased in patients with acute coronary syndrome (ACS). Circulating CD3(+)/CD31(+) T cells were determined in 16 ACS patients undergoing emergency percutaneous coronary intervention (PCI) and in 16 control subjects with angiographically normal coronary arteries. Although no differences between the groups were found in baseline patient characteristics, the ratio of circulating CD3(+)/CD31(+) T cells before PCI was higher in ACS patients as compared with that in control subjects (51.8 % ± 7.8 % vs 31.8 % ± 9.6 %, respectively; P < 0.001). The increased ratio of CD3(+)/CD31(+) T cells in ACS patients was not altered 24 h after PCI, but became comparable with that in control subjects within 6 months after PCI. These results suggest that mobilization of CD3(+)/CD31(+) T cells occurs in ACS, but is no longer detectable at 6 months after PCI.
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Síndrome Coronario Agudo/inmunología , Complejo CD3/sangre , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/sangre , Linfocitos T/inmunología , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/terapia , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Angiografía Coronaria , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
BACKGROUND: Statins are frequently administered to reduce low-density lipoprotein cholesterol (LDL-C) and vascular inflammation, because LDL-C and high sensitive C-reactive protein (hs-CRP) are associated with high risk for cardiovascular events. When statins do not reduce LDL-C to desired levels in high-risk patients with coronary artery disease (CAD), ezetimibe can be added or the statin dose can be increased. However, which strategy is more effective for treating patients with CAD has not been established. The present study compares anti-inflammatory effects and lipid profiles in patients with CAD and similar LDL-C levels who were treated by increasing the statin dose or by adding ezetimibe to the original rosuvastatin dose to determine the optimal treatment for such patients. METHODS: 46 patients with high-risk CAD and LDL-C and hs-CRP levels of >70 mg/dL and >1.0 mg/L, respectively, that were not improved by 4 weeks of rosuvastatin (2.5 mg/day) were randomly assigned to receive 10 mg (R10, n = 24) of rosuvastatin or 2.5 mg/day of rosuvastatin combined with 10 mg/day of ezetimibe (R2.5/E10, n = 22) for 12 weeks. The primary endpoint was a change in hs-CRP. RESULTS: Baseline characteristics did not significantly differ between the groups. At 12 weeks, LDL-C and inflammatory markers (hs-CRP, interleukin-6, tumour necrosis factor-alpha and pentraxin 3) also did not significantly differ between the two groups (LDL-C: R10 vs. R2.5/E10: -19.4 ± 14.2 vs. -22.4 ± 14.3 mg/dL). However, high-density lipoprotein cholesterol (HDL-C) was significantly improved in the R10, compared with R2.5/E10 group (4.6 ± 5.9 vs. 0.0 ± 6.7 mg/dL; p < 0.05). CONCLUSION: Both enhanced therapies exerted similar anti-inflammatory effects under an equal LDL-C reduction in patients with high-risk CAD despite 2.5 mg/day of rosuvastatin. However, R10 elevated HDL-C more effectively than R2.5/E10. TRIAL REGISTRATION: UMIN000003746.
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Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Fluorobencenos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/farmacología , Azetidinas/farmacología , Proteína C-Reactiva/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad Coronaria/metabolismo , Esquema de Medicación , Combinación de Medicamentos , Ezetimiba , Femenino , Fluorobencenos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirimidinas/farmacología , Rosuvastatina Cálcica , Componente Amiloide P Sérico/metabolismo , Sulfonamidas/farmacología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Free-floating left atrial thrombi are rare. Here we report a case of a 75-year-old woman with atrial fibrillation who was admitted for treatment of acute myocardial infarction. A free-floating left atrial thrombus was found incidentally on echocardiography. Ten days after percutaneous coronary intervention, the patient had mild faintness with transient hypotension, and it was found that the left atrial thrombus had developed intermittent entrapment in the mid-ventricle during diastole, with abrupt rebound back to the left atrial cavity during systole. Urgent removal of the thrombus was performed successfully. Although the free-floating thrombus had appeared to be spherical, like a ball thrombus, on echocardiography, the excised thrombus was pedunculated. A cut section revealed a laminated thrombus with an onion-skin-like appearance.
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Fibrilación Atrial/diagnóstico , Diástole , Cardiopatías/diagnóstico , Hipertrofia Ventricular Izquierda/diagnóstico , Infarto del Miocardio/diagnóstico , Trombosis/diagnóstico , Disfunción Ventricular Izquierda/diagnóstico , Función Ventricular Izquierda , Anciano , Angioplastia Coronaria con Balón , Anticoagulantes/uso terapéutico , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/terapia , Ecocardiografía Transesofágica , Femenino , Cardiopatías/fisiopatología , Cardiopatías/terapia , Humanos , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/terapia , Hallazgos Incidentales , Infarto del Miocardio/terapia , Valor Predictivo de las Pruebas , Trombectomía , Trombosis/fisiopatología , Trombosis/terapia , Resultado del Tratamiento , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/terapiaRESUMEN
This 36-week, open-label, single-arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30-36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.
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Anemia , Eritropoyetina , Hematínicos , Diálisis Peritoneal , Insuficiencia Renal Crónica , Anemia/tratamiento farmacológico , Anemia/etiología , Eritropoyetina/uso terapéutico , Hemoglobinas/análisis , Humanos , Japón , Diálisis Peritoneal/efectos adversos , Pirazoles , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/terapia , Resultado del Tratamiento , TriazolesRESUMEN
BACKGROUND: It is known that HMG-CoA reductase inhibitors (statins) may have a therapeutic benefit in patients with heart failure (HF). However, no studies have yet evaluated the possible interaction of statins and angiotensin-II receptor blockers (ARBs) on left ventricular (LV) function in patients with HF. We hypothesized that statins might alter the effect of ARBs on cardiac function in patients with HF. METHODS AND RESULTS: We prospectively randomized patients with chronic HF who received the ARB, losartan (LOS group), or the statin, simvastatin (SIM), in combination with LOS (SIM+LOS group) at our hospitals and assessed before and after treatment for 6 months. Although no significant improvement of HF symptoms as evaluated by the New York Heart Association (NYHA) classification was observed in the LOS group, HF symptoms in the SIM+LOS group significantly improved. The percent increase of LV ejection fraction after treatment in the SIM+LOS group was significantly larger than in the LOS group. Furthermore, the plasma brain natriuretic peptide level was significantly lower after treatment in the SIM+LOS group than in the LOS group. CONCLUSIONS: Combined statin and ARB therapy significantly improves both symptoms and LV function over time in patients with HF. Thus, the combination of an ARB with a statin may be a useful therapeutic strategy for HF.
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Antagonistas de Receptores de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Losartán/uso terapéutico , Simvastatina/uso terapéutico , Anciano , Antagonistas de Receptores de Angiotensina/farmacología , Enfermedad Crónica , Sinergismo Farmacológico , Quimioterapia Combinada , Electrocardiografía , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Losartán/farmacología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Simvastatina/farmacología , Resultado del Tratamiento , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
INTRODUCTION: Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor for renal anemia treatment, was evaluated in 5 phase 3 studies (MIYABI program). We report the results of the MIYABI hemodialysis-maintenance study. METHODS: This 52-week, randomized, double-blinded, double-dummy study compared the efficacy and safety of molidustat and darbepoetin in Japanese patients receiving hemodialysis and erythropoiesis-stimulating agents. Molidustat (starting dose: 75 mg/day) and darbepoetin were titrated to maintain hemoglobin (Hb) levels in the target range (≥10.0 and <12.0 g/dl). Primary outcomes were mean Hb level during the evaluation period (weeks 33-36) and its change from baseline. Safety outcomes included adverse events. RESULTS: Overall, 229 patients were randomized (molidustat, n = 153; darbepoetin, n = 76). Baseline characteristics were well balanced. Mean baseline Hb level was 10.8 g/dl. Mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period were within the target range in both groups (molidustat: 10.63 [10.42-10.84] g/dl; darbepoetin: 10.77 [10.59-10.95] g/dl). Least-squares mean (95% CI) change in mean Hb level during the evaluation period from baseline was -0.14 (-0.37 to 0.09) g/dl for molidustat and -0.07 (-0.30 to 0.16) g/dl for darbepoetin; molidustat was noninferior to darbepoetin (least-squares mean difference [95% CI] [molidustat-darbepoetin]: -0.13 [-0.46 to 0.19] g/dl), based on a noninferiority margin of 1.0 g/dl. In line with published literature, and as expected in this patient population, most participants had ≥1 treatment-emergent adverse event. CONCLUSION: Molidustat maintained Hb levels throughout the trial in patients receiving dialysis and previously treated with erythropoiesis-stimulating agents, and was noninferior to darbepoetin.
RESUMEN
Molidustat, an orally administered hypoxia-inducible factor prolyl-hydroxylase inhibitor, is under development for the treatment of anemia of CKD. This 24-week, phase 3, single-arm, multicenter study evaluated the efficacy and safety of molidustat in Japanese patients with renal anemia who were undergoing hemodialysis and who were not receiving an erythropoiesis-stimulating agent. Twenty-five patients received molidustat at a starting dose of 75 mg once daily, which was adjusted to maintain a Hb target of ≥10.0 to <12.0 g/dL. The mean rates of Hb increase from baseline and week 0 to the first dose change up to week 8 were -0.030 and 0.080 g/dL/week, respectively. By week 24, 89% of patients had a Hb level within target range. No adverse events of special interest were reported. Treatment with dose-titrated molidustat for 24 weeks was well tolerated in Japanese patients undergoing hemodialysis, and no new safety signal was observed. Clinicaltrials.gov identifier: NCT03351166.
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Anemia/tratamiento farmacológico , Anemia/etiología , Pirazoles/uso terapéutico , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/terapia , Triazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia/fisiopatología , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Diálisis Renal/métodos , Insuficiencia Renal Crónica/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND: The involvement of autophagy in heart disease has been reported. Transgenic mice expressing GFP-LC3 have been a useful tool in detecting autophagosomes systemically. It is difficult to differentiate increased formation of autophagosomes from decreased clearance of autophagosomes in the heart using GFP-LC3 mice. METHODS AND RESULTS: We generated transgenic mice expressing mCherry-LC3 under alphaMyHC promoter and crossed the mice with transgenic mice expressing GFP-LC3. The deference of resistance to acidic conditions between GFP and mCherry overcame the limitation. CONCLUSIONS: This method is an innovative approach to examine the role of autophagy and to analyze autophagosome maturation in cardiomyocytes. (Circ J 2010; 74: 203 - 206).
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Autofagia/fisiología , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Miocardio/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Animales , Apoptosis , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Proteínas Fluorescentes Verdes/genética , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Miocardio/patología , Cadenas Pesadas de Miosina/genéticaRESUMEN
Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
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Factor de Transcripción Activador 3/genética , Lesión Renal Aguda/fisiopatología , Daño por Reperfusión/fisiopatología , Factor de Transcripción Activador 3/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Adenoviridae/genética , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Línea Celular , Creatinina/sangre , Técnicas de Transferencia de Gen , Humanos , Peróxido de Hidrógeno/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
OBJECTIVE: Ischemia/reperfusion in the heart causes myocardial apoptosis and increase nitric oxide (NO) production. We have reported that myocardial apoptosis is related to activation of cell cycle regulatory proteins. However, the role of nitric oxide (NO) in ischemia/reperfusion-induced apoptosis is still unclear. This study was designated to elucidate novel apoptosis mechanisms induced by ischemia/reperfusion, especially the interaction between NO and cell cycle regulators. METHODS AND RESULTS: Neonatal cardiomyocytes from 1- or 2-day-old Wistar rats were subjected to 1-h ischemia and then to reperfusion. The rate of cardiomyocyte apoptosis increased significantly after 24 h of reperfusion as evaluated by TUNEL analysis. NO increased 1.8-fold after 15 min of reperfusion in cardiomyocytes. After 36 h of reperfusion, the apoptosis rate was greatly increased by the NO synthetase inhibitor, Nitro-L-arginine methyl ester (L-NAME), and decreased by the NO donor of S-nitroso-N-acetylpenicillamine (SNAP). Immunoblot analysis showed that the protein levels of cyclin A accumulated in a time-dependent manner in response to ischemia/reperfusion, and L-NAME inhibited this response. Ischemia/reperfusion also increased the activity of cyclin A-associated kinase, and the apoptosis was inhibited by infection of dominant-negative cdk2 adenovirus. To clarify the involvement of p21(cip1/waf1) protein, which is the suppressor of cyclin A-associated kinase, we performed immunoblot analysis and examined its kinase activity. Treatment of cardiomyocytes with L-NAME suppressed the p21(cip1/waf1) protein level and increased the cyclin A-associated kinase activity. The addition of SNAP showed inverse results. CONCLUSION: Our data indicates that NO released from cardiomyocytes under condition of ischemia/reperfusion exerts an antiapoptotic effect by modulating cyclin A-associated kinase activity via p21(cip1/waf1) accumulation.
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Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Óxido Nítrico/metabolismo , Animales , Apoptosis , Proteína Quinasa CDC2/metabolismo , Células Cultivadas , Ciclina A/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Etiquetado Corte-Fin in Situ , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , S-Nitroso-N-Acetilpenicilamina/farmacología , Factores de TiempoRESUMEN
BACKGROUND: Impaired cardiac function and sleep-disordered breathing (SDB) are associated with progression of chronic kidney disease (CKD) in heart failure (HF) patients. Adaptive servo-ventilation (ASV) therapy improves cardiac function in HF patients regardless of the SDB severity through hemodynamic support and prevention of repetitive hypoxic stress. This study was designed to test the hypothesis that ASV therapy improves renal function in HF patients with SDB. METHODS AND RESULTS: Of 59 consecutively enrolled HF patients, 43 with moderate-to-severe SDB underwent ASV therapy. HF patients were divided into the ASV-treated group (n = 27) and the non-ASV-treated group (n = 16). Estimated glomerular filtration rate (eGFR), echocardiographic parameters, and inflammatory biomarkers were measured before and 12 months after ASV initiation. Improvement in the eGFR was found in the ASV-treated group, but not in the non-ASV-treated group. There was a positive correlation between the increases in eGFR and left ventricular ejection fraction (r = 0.488, p = 0.001). The changes in high-sensitivity C-reactive protein were negatively correlated with change in the eGFR (r = -0.416, p = 0.006). CONCLUSIONS: ASV therapy could improve renal dysfunction in HF patients through hemodynamic support. Additionally, prevention of SDB with the use of ASV therapy could exert anti-inflammatory effects, which could contribute to the improvement of renal function in HF patients.
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Proteína C-Reactiva/metabolismo , Insuficiencia Cardíaca/fisiopatología , Enfermedades Renales/fisiopatología , Respiración Artificial/métodos , Síndromes de la Apnea del Sueño/fisiopatología , Anciano , Biomarcadores/sangre , Ecocardiografía , Femenino , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/terapia , Hemodinámica , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/terapia , Masculino , Índice de Severidad de la Enfermedad , Síndromes de la Apnea del Sueño/sangre , Síndromes de la Apnea del Sueño/terapia , Resultado del TratamientoRESUMEN
PURPOSE: Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in angiogenesis and tumor growth. However, the clinical relevance of EPCs in non-small-cell lung cancer (NSCLC) remains unclear. Recently, some reports suggested that EPCs correlate with clinical behavior of cancer patients. We assessed the hypothesis that EPCs correlate with efficient of therapy, prognosis, and clinicopathological factors, and EPCs may offer a possible biomarker for treatment outcome in NSCLC. METHODS: EPCs labeled with CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2) antibodies were counted by flow cytometry in the peripheral blood of 31 NSCLC patients. We categorized two groups of NSCLC patients according to circulating EPC numbers. We examined age, pathological stage, histological type, Fluoro-D: -glucose Positron emission tomography (FDG-PET), response to therapy, progression-free survival, and tumor size of NSCLC patients and investigated whether these factors correlate with EPC counts. RESULTS: Circulating EPC numbers before antitumor therapy were increased in NSCLC patients compared with healthy controls (P < 0.05). In NSCLC patients, therapy was significantly effective in low circulating EPC group compared with that of high (P < 0.05). Furthermore, the low EPC group showed significantly longer progression-free survival times than that of high (P < 0.05). However, no significant associations with age, gender, histological type, pathological stage, or FDG-PET were detected. CONCLUSION: Peripheral blood levels of bone marrow-derived EPCs are significantly increased in patients with NSCLC and correlate with response to chemotherapy. EPCs may offer a possible biomarker for efficient of treatment and prognosis.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Células Endoteliales/citología , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre/fisiología , Antígeno AC133 , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Femenino , Glicoproteínas/análisis , Humanos , Interleucina-8/sangre , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Péptidos/análisis , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
We investigated the functional role of STIM1, a Ca(2+) sensor in the endoplasmic reticulum (ER) that regulates store-operated Ca(2+) entry (SOCE), in vascular smooth muscle cells (VSMCs). STIM1 was mainly localized at the ER and plasma membrane. The knockdown of STIM1 expression by small interfering (si) RNA drastically decreased SOCE. In contrast, an EF-hand mutant of STIM1, STIM1(E87A), produced a marked increase in SOCE, which was abolished by co-transfection with siRNA to transient receptor potential canonical 1 (TRPC1). In addition, transfection with siRNA against STIM1 suppressed phosphorylation of cAMP-responsive element binding protein (CREB) and cell growth. These results suggest that STIM1 is an essential component of SOCE and that it is involved in VSMC proliferation.
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Calcio/metabolismo , Proteínas de la Membrana/fisiología , Músculo Liso Vascular/metabolismo , Proteínas de Neoplasias/fisiología , Transporte Biológico , Proliferación Celular , Células Cultivadas , Vasos Coronarios/citología , Humanos , Proteínas de la Membrana/análisis , Proteínas de la Membrana/metabolismo , Músculo Liso Vascular/citología , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/metabolismo , Molécula de Interacción Estromal 1 , Canales Catiónicos TRPC/fisiologíaRESUMEN
Store-operated Ca(2+) entry (SOCE) is a physiologically important process that is triggered by intracellular Ca(2+) depletion. Recently, human Orai1 (the channel-forming subunit) and STIM1 (the calcium sensor) were identified as essential molecules for SOCE. Here, we report the cloning and functional analysis of three murine orthologs of Orai1, termed Orai1, 2, and 3. Among the genes identified, Orai1 contains a distinctive proline- and arginine-rich N-terminal cytoplasmic sequence. Co-expression of STIM1 with Orai1 produced a marked effect on SOCE, while co-expression with Orai2 or Orai3 had little effect. Expression of Orai1 without its N-terminal tail had a marginal effect on SOCE, while chimeric Orai2 containing the Orai1 N-terminus produced a marked increase in SOCE. In addition, a truncated version of Orai1 containing the N-terminus without the pore-forming transmembrane domain had a dominant negative effect on SOCE. These results reveal the essential role of Orai1 and its N-terminal sequence in SOCE.