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1.
Gan To Kagaku Ryoho ; 50(13): 1887-1888, 2023 Dec.
Artículo en Japonés | MEDLINE | ID: mdl-38303241

RESUMEN

A 78-year-old man was diagnosed as HER2-positive unresectable advanced gastric cancer(cT4aN3M1[LYM], Stage Ⅳ). After 2 courses of first-line chemotherapy(S-1 plus oxaliplatin plus trastuzumab), PR was achieved. The treatment could not be continued due to adverse events after 5 courses, thus second-line chemotherapy was conducted. Corresponding to the physical condition. The third-line chemotherapy was also introduced. However, we clinically judged PD because of amount of ascites and chemotherapy was terminated. After that, he has survived for more than 2 years without chemotherapy, and endoscopy and CT showed the disappearance of the tumor, metastatic lymph nodes, and ascites at 41 months after diagnosis. Looking back on the changes in tumor markers, it was possible that he had already achieved CR at the first-line chemotherapy.


Asunto(s)
Neoplasias Gástricas , Anciano , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ascitis , Gastrectomía , Receptor ErbB-2 , Neoplasias Gástricas/tratamiento farmacológico , Trastuzumab
2.
Gan To Kagaku Ryoho ; 50(13): 1546-1547, 2023 Dec.
Artículo en Japonés | MEDLINE | ID: mdl-38303336

RESUMEN

A 78-year-old man was diagnosed with lymph node metastasis 2 months after surgery for gastric neuroendocrine carcinoma. He received chemotherapy(CDDP plus CPT-11)and showed partial response(PR)after 3 courses of the regimen. Serum CEA increased 5 months after surgery, thus nab-paclitaxel plus ramucirumab was administered. Although the lymph node kept shrinked after 2 courses of the regimen, the lymph node was detected 12 cm of the size in CT after 5 courses of the regimen. He started to receive nivolumab. The lymph nodes showed PR after 4 courses, and complete response after 6 courses of the regimen for 1 year and 4 months until now.


Asunto(s)
Carcinoma Neuroendocrino , Neoplasias Gástricas , Masculino , Humanos , Anciano , Nivolumab/uso terapéutico , Metástasis Linfática , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gastrectomía , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Cisplatino/uso terapéutico , Irinotecán , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/cirugía , Ganglios Linfáticos
3.
Int J Surg Case Rep ; 96: 107372, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35809478

RESUMEN

INTRODUCTION AND IMPORTANCE: Giant megacolon requiring emergency surgery is rare. Eventration of the diaphragm associated with giant megacolon is also uncommon. CASE PRESENTATION: We report a 66-year-old male who presented with abdominal distention and progressive dyspnea. After resuscitation following cardiopulmonary arrest, the patient underwent emergent subtotal abdominal colectomy. Eventration of the diaphragm was found postoperatively and his respiratory condition was insufficient to allow liberation. Plication of both diaphragms was performed through left and right thoracotomy via the 8th intercostal space. Postoperatively the patient made a full recovery. CLINICAL DISCUSSIONS: Chronic constipation is a common health condition. A life-threatening condition secondary to chronic constipation is a rarely documented complication. Diaphragmatic eventration that was caused due to chronic megacolon in symptomatic patients requires surgical treatment. CONCLUSIONS: We describe a patient with giant megacolon and diaphragmatic eventration secondary to idiopathic megacolon. The patient underwent subtotal colectomy and diaphragmatic plication and recovered fully.

4.
PLoS One ; 6(2): e16734, 2011 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-21364991

RESUMEN

Induced pluripotent stem cells (iPSCs) are novel stem cells derived from adult mouse and human tissues by reprogramming. Elucidation of mechanisms and exploration of efficient methods for their differentiation to functional cardiomyocytes are essential for developing cardiac cell models and future regenerative therapies. We previously established a novel mouse embryonic stem cell (ESC) and iPSC differentiation system in which cardiovascular cells can be systematically induced from Flk1(+) common progenitor cells, and identified highly cardiogenic progenitors as Flk1(+)/CXCR4(+)/VE-cadherin(-) (FCV) cells. We have also reported that cyclosporin-A (CSA) drastically increases FCV progenitor and cardiomyocyte induction from mouse ESCs. Here, we combined these technologies and extended them to mouse and human iPSCs. Co-culture of purified mouse iPSC-derived Flk1(+) cells with OP9 stroma cells induced cardiomyocyte differentiation whilst addition of CSA to Flk1(+) cells dramatically increased both cardiomyocyte and FCV progenitor cell differentiation. Spontaneously beating colonies were obtained from human iPSCs by co-culture with END-2 visceral endoderm-like cells. Appearance of beating colonies from human iPSCs was increased approximately 4.3 times by addition of CSA at mesoderm stage. CSA-expanded human iPSC-derived cardiomyocytes showed various cardiac marker expressions, synchronized calcium transients, cardiomyocyte-like action potentials, pharmacological reactions, and ultra-structural features as cardiomyocytes. These results provide a technological basis to obtain functional cardiomyocytes from iPSCs.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ciclosporina/farmacología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Adulto , Animales , Diferenciación Celular/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Fenómenos Electrofisiológicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Ratones , Miocitos Cardíacos/fisiología , Especificidad de la Especie , Regulación hacia Arriba/efectos de los fármacos
5.
J Mol Cell Cardiol ; 50(6): 972-81, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21284946

RESUMEN

Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Proteínas Represoras/metabolismo , Remodelación Ventricular/genética , Adulto , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , Femenino , Orden Génico , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Unión Proteica , ARN Mensajero/genética , Ratas , Proteínas Represoras/genética
6.
Mol Cell Biol ; 30(17): 4134-48, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20606005

RESUMEN

Subjecting cardiomyocytes to mechanical stress or neurohumoral stimulation causes cardiac hypertrophy characterized in part by reactivation of the fetal cardiac gene program. Here we demonstrate a new common mechanism by which these stimuli are transduced to a signal activating the hypertrophic gene program. Mechanically stretching cardiomyocytes induced nuclear accumulation of myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), in a Rho- and actin dynamics-dependent manner. Expression of brain natriuretic peptide (BNP) and other SRF-dependent fetal cardiac genes in response to acute mechanical stress was blunted in mice lacking MRTF-A. Hypertrophic responses to chronic pressure overload were also significantly attenuated in mice lacking MRTF-A. Mutation of a newly identified, conserved and functional SRF-binding site within the BNP promoter, or knockdown of MRTF-A, reduced the responsiveness of the BNP promoter to mechanical stretch. Nuclear translocation of MRTF-A was also involved in endothelin-1- and angiotensin-II-induced activation of the BNP promoter. Moreover, mice lacking MRTF-A showed significantly weaker hypertrophic responses to chronic angiotensin II infusion than wild-type mice. Collectively, these findings point to nuclear translocation of MRTF-A as a novel signaling mechanism mediating both mechanical stretch- and neurohumoral stimulation-induced BNP gene expression and hypertrophic responses in cardiac myocytes.


Asunto(s)
Regulación de la Expresión Génica , Péptido Natriurético Encefálico/genética , Estrés Mecánico , Transactivadores/metabolismo , Angiotensina II/metabolismo , Animales , Células Cultivadas , Endotelina-1/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Proteínas Nucleares , Regiones Promotoras Genéticas , Transporte de Proteínas , Ratas , Factor de Respuesta Sérica/metabolismo , Transactivadores/genética
7.
Circ Res ; 106(12): 1849-60, 2010 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-20448219

RESUMEN

RATIONALE: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. OBJECTIVE: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca(2+) channel known to positively regulate prohypertrophic calcineurin-nuclear factor of activated T cells (NFAT) signaling. METHODS AND RESULTS: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca(2+) influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II-induced cardiac hypertrophy in mice. CONCLUSIONS: Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.


Asunto(s)
Factor Natriurético Atrial/metabolismo , Miocardio/patología , Péptido Natriurético Encefálico/metabolismo , Receptores del Factor Natriurético Atrial/metabolismo , Transducción de Señal/fisiología , Canales Catiónicos TRPC/antagonistas & inhibidores , Anilidas/farmacología , Animales , Canales de Calcio/metabolismo , Células Cultivadas , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Humanos , Hipertrofia/metabolismo , Hipertrofia/patología , Hipertrofia/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factores de Transcripción NFATC/metabolismo , Técnicas de Placa-Clamp , Ratas , Receptores del Factor Natriurético Atrial/genética , Canales Catiónicos TRPC/metabolismo , Canal Catiónico TRPC6 , Tiadiazoles/farmacología
8.
Circ Res ; 105(8): 746-54, 2009 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-19729597

RESUMEN

RATIONALE: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized. OBJECTIVE: We have now investigated the physiological function of p300 in adult hearts. METHODS AND RESULTS: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300DeltaC/H3 transgenic [TG] mice). p300DeltaC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300DeltaC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300DeltaC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300DeltaC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300DeltaC/H3-TG mice, and p300DeltaC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1alpha promoter activity and disrupted the transcriptional activity of PGC-1alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300DeltaC/H3-TG hearts. CONCLUSIONS: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.


Asunto(s)
Potencial de la Membrana Mitocondrial , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Adenosina Trifosfato/genética , Adenosina Trifosfato/metabolismo , Animales , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Supervivencia Celular/genética , Células Cultivadas , Corazón/embriología , Corazón/crecimiento & desarrollo , Ratones , Ratones Transgénicos , Mitocondrias Cardíacas/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Estructura Terciaria de Proteína/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ratas , Elementos de Respuesta/genética , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/genética , Factores de Transcripción p300-CBP/genética
9.
Circulation ; 120(9): 743-52, 2009 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-19687356

RESUMEN

BACKGROUND: Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. METHODS AND RESULTS: We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction. CONCLUSIONS: T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Cardiomiopatía Dilatada/tratamiento farmacológico , Muerte Súbita Cardíaca/prevención & control , Dihidropiridinas/farmacología , Nitrofenoles/farmacología , Animales , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/prevención & control , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiología , Presión Sanguínea , Peso Corporal , Canales de Calcio Tipo L/metabolismo , Cardiomiopatía Dilatada/mortalidad , Modelos Animales de Enfermedad , Femenino , Mibefradil/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Miocitos Cardíacos/fisiología , Nitrendipino/farmacología , Compuestos Organofosforados/farmacología , Técnicas de Placa-Clamp
10.
Am J Physiol Heart Circ Physiol ; 296(6): H1804-10, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19346456

RESUMEN

Ventricular myocytes are known to show increased expression of the cardiac hormones atrial and brain natriuretic peptide (ANP and BNP, respectively) in response to pathological stress on the heart, but their function during the progression of nonischemic dilated cardiomyopathy remains unclear. In this study, we crossed a mouse model of dilated cardiomyopathy and sudden death, which we generated by cardioselectively overexpressing a dominant-negative form of the transcriptional repressor neuron-restrictive silencer factor (dnNRSF Tg mice), with mice lacking guanylyl cyclase-A (GC-A), a common receptor for ANP and BNP, to assess the effects of endogenously expressed natriuretic peptides during progression of the cardiomyopathy seen in dnNRSF Tg mice. We found that dnNRSF Tg;GC-A(-/-) mice were born normally, but then most died within 4 wk. The survival rates among dnNRSF Tg;GC-A(+/-) and dnNRSF Tg mice were comparable, but dnNRSF Tg;GC-A(+/-) mice showed greater systolic dysfunction and a more severe cardiomyopathic phenotype than dnNRSF Tg mice. Collectively, our findings suggest that endogenous ANP/BNP protects the heart against the death and progression of pathological remodeling in a mouse model of dilated cardiomyopathy and sudden death.


Asunto(s)
Factor Natriurético Atrial/metabolismo , Cardiomiopatía Dilatada/mortalidad , Cardiomiopatía Dilatada/fisiopatología , Muerte Súbita Cardíaca/prevención & control , Péptido Natriurético Encefálico/metabolismo , Animales , Factor Natriurético Atrial/genética , Cardiomiopatía Dilatada/patología , Modelos Animales de Enfermedad , Femenino , Expresión Génica/fisiología , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Péptido Natriurético Encefálico/genética , Fenotipo , ARN Mensajero/metabolismo , Receptores del Factor Natriurético Atrial/genética , Proteínas Represoras/genética , Sístole , Remodelación Ventricular/fisiología
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