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Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare, recurrent oncogenic variant that constitutively activates EGFR in non-small-cell lung cancer. Herein, we report the case of a 70-year-old man with resectable colorectal adenocarcinoma who underwent surgery followed by adjuvant therapy. He relapsed with multiple liver metastases and received standard chemotherapy until his disease became refractory. Comprehensive genomic profiling of his postoperative colorectal cancer tissue revealed EGFR-KDD. He was treated with an EGFR tyrosine kinase inhibitor (TKI), afatinib and achieved a partial response (-â 55%) after 8 weeks; however, he developed massive malignant ascites after 13 weeks. Osimertinib, another EGFR-TKI, controlled his tumors for 9 months. Patient-derived cancer organoids from his malignant ascites confirmed sensitivity to EGFR-TKIs. The findings suggest that EGFR-TKIs can be a potential treatment option for this molecular subgroup.
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Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Trifluridina/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Fosforilación , Histonas , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proteínas Tirosina QuinasasRESUMEN
The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Glucagón , Animales , Arginina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucagón/metabolismo , Células Secretoras de Glucagón/metabolismo , Ratones , Proteína Quinasa C-delta/genética , Proteína Quinasa C-delta/metabolismoRESUMEN
Biobanks are an essential platform for the development of medicine and healthcare. In biobanks, the quality of the biospecimens collected and stored and the quality and quantity of the clinical information associated with them are important. In addition, biobanks handle clinical information, so the management of personal information and the scope of consent are also important. On the other hand, if the collected biological samples are not utilized, they are meaningless. Therefore, it is also required to respond to various needs. In order to address these issues, we have established a hospital-based Clinical Bioresource Center(CBRC)and developed projects to promote the utilization of biospecimens. In this paper, we describe the CBRC at Kyoto University Hospital.
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Bancos de Muestras Biológicas , Investigación Biomédica , Hospitales Universitarios , HumanosRESUMEN
BACKGROUND: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. METHODS: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity. RESULTS: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis. CONCLUSIONS: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Pirrolidinas , Trifluridina , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Humanos , Japón , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Platino/uso terapéutico , Pirrolidinas/uso terapéutico , Taxoides/uso terapéutico , Trifluridina/uso terapéuticoRESUMEN
BACKGROUND: Visceral fat obesity can be defined quantitatively by abdominal computed tomography, however, the usefulness of measuring visceral fat area to assess the etiology of gastrointestinal reflux disease has not been fully elucidated. METHODS: A total of 433 healthy subjects aged 40-69 years (234 men, 199 women) were included in the study. The relationship between obesity-related factors (total fat area, visceral fat area, subcutaneous fat area, waist circumference, and body mass index) and the incidence of reflux erosive esophagitis was investigated. Lifestyle factors and stomach conditions relevant to the onset of erosive esophagitis were also analyzed. RESULTS: The prevalence of reflux erosive esophagitis was 27.2% (118/433; 106 men, 12 women). Visceral fat area was higher in subjects with erosive esophagitis than in those without (116.6 cm2 vs. 64.9 cm2, respectively). The incidence of erosive esophagitis was higher in subjects with visceral fat obesity (visceral fat area ≥ 100 cm2) than in those without (61.2% vs. 12.8%, respectively). Visceral fat obesity had the highest odds ratio (OR) among obesity-related factors. Multivariate analysis showed that visceral fat area was associated with the incidence of erosive esophagitis (OR = 2.18), indicating that it is an independent risk factor for erosive esophagitis. In addition, daily alcohol intake (OR = 1.54), gastric atrophy open type (OR = 0.29), and never-smoking history (OR = 0.49) were also independently associated with the development of erosive esophagitis. CONCLUSIONS: Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in subjects aged 40-69 years.
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Esofagitis Péptica , Grasa Intraabdominal , Adulto , Anciano , Estudios Transversales , Esofagitis Péptica/complicaciones , Esofagitis Péptica/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/epidemiología , Factores de RiesgoRESUMEN
Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.
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Consumo de Bebidas Alcohólicas/efectos adversos , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Benzamidas/administración & dosificación , Benzodioxoles/administración & dosificación , Carcinogénesis/efectos de los fármacos , Neoplasias Esofágicas/prevención & control , Carcinoma de Células Escamosas de Esófago/prevención & control , Acetaldehído/metabolismo , Acetaldehído/toxicidad , Aldehído Deshidrogenasa Mitocondrial/antagonistas & inhibidores , Aldehído Deshidrogenasa Mitocondrial/genética , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Cianamida/administración & dosificación , Aductos de ADN/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Mucosa Esofágica/efectos de los fármacos , Mucosa Esofágica/patología , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/etiología , Carcinoma de Células Escamosas de Esófago/patología , Etanol/metabolismo , Etanol/toxicidad , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones Transgénicos , Mutación , Neoplasias Experimentales/etiología , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Polimorfismo Genético , Factores de RiesgoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is highly prevalent in Asia. Alcohol and its metabolite, acetaldehyde, are considered definite carcinogens for the esophagus. Polymorphisms in the aldehyde dehydrogenase 2 gene, which encodes an enzyme that eliminates acetaldehyde, have been associated with esophageal carcinogenesis. Studies of the mutagenic and carcinogenic effects of acetaldehyde support this observation. Several recent large-scale comprehensive analyses of the genomic alterations in ESCC have shown a high frequency of mutations in genes such as TP53 and others that regulate the cell cycle or cell differentiation. Moreover, whole genome and whole exome sequencing studies have frequently detected somatic mutations, such as G:CâA:T transitions or G:CâC:G transversions, in ESCC tissues. Genomic instability, caused by abnormalities in the Fanconi anemia DNA repair pathway, is also considered a pathogenic mechanism of ESCC. Advances in diagnostic techniques such as magnifying endoscopy with narrow band imaging or positron emission tomography have increased the accuracy of diagnosis of ESCC. Updated guidelines from the National Comprehensive Cancer Network standardize the practice for the diagnosis and treatment of esophageal cancer. Patients with ESCC are treated endoscopically or with surgery, chemotherapy, or radiotherapy, based on tumor stage. Minimally invasive treatments help improve the quality of life of patients who undergo such treatments. We review recent developments in the diagnosis and treatment of ESCC and advances gained from basic and clinical research.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Terapia Combinada , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/virología , Carcinoma de Células Escamosas de Esófago , Predisposición Genética a la Enfermedad , Humanos , Estilo de Vida , Estadificación de Neoplasias , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Valor Predictivo de las Pruebas , Factores de Riesgo , Transducción de Señal , Fumar/efectos adversos , Fumar/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: The multidiameter balloon catheter is used widely for severe esophageal stricture dilation. However, the relationships between inflation pressure, balloon size, and radial dilation force at the stricture site have not been examined fully. METHODS: We performed an experiment using phantom models to investigate the relationships between inflation pressure, balloon size, and radial dilation force. The balloon dilation procedure was performed for each stricture model using three sizes of balloon: 10-11-12, 12-13.5-15, and 15-16.5-18 mm. RESULTS: A positive association between inflation pressure and dilation force was observed for each balloon size. In balloons inflated by targeting the same diameter, the dilation force was higher for smaller balloons than for larger balloons. An inverse association between stricture size and dilation force was observed in the 12-13.5-15 mm balloon (3 vs 5 mm, P = .002; 5 vs 7 mm, P < .001). CONCLUSIONS: We found relationships between inflation pressure, balloon size, severity of strictures, and dilation force. To perform safe and effective esophageal balloon dilation, the inflation pressure and balloon size should be selected after considering the stricture size and target diameter.
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Cateterismo/instrumentación , Dilatación/métodos , Estenosis Esofágica/terapia , Modelos Biológicos , Dilatación/instrumentación , Diseño de Equipo , Humanos , Fenómenos Mecánicos , PresiónRESUMEN
Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.
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Glucemia/genética , Peso Corporal/genética , Diabetes Mellitus Tipo 2/genética , Metabolismo Energético/genética , Resistencia a la Insulina/genética , Obesidad/genética , Receptor de Insulina/genética , Animales , Diabetes Mellitus Tipo 2/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/metabolismo , Masculino , Ratones , Ratones Transgénicos , Obesidad/metabolismo , Fenotipo , Receptor de Insulina/metabolismoRESUMEN
AIMS/HYPOTHESIS: Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity. METHODS: We targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling. RESULTS: Conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD(+) levels. CONCLUSIONS/INTERPRETATION: ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.
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Hipotálamo/metabolismo , Leptina/farmacología , Sirtuina 1/metabolismo , Aumento de Peso/fisiología , Animales , Calorimetría Indirecta , Genotipo , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Sirtuina 1/genética , Aumento de Peso/genéticaRESUMEN
The pancreas is critical for maintaining glucose homeostasis. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. There are major discrepancies in previous reports on pancreatic ATF3; therefore, its role in the pancreas is unclear. To better elucidate the role of ATF3 in the pancreas, we conducted in vitro studies using pancreatic α and ß cell lines, and also evaluated the use of ATF3 antibodies for immunohistochemistry. We determined ATF3 expression was increased by low glucose and decreased by high glucose in both αTC-1.6 and ßTC3 cells. We also showed that adenovirus-mediated ATF3 overexpression increased glucagon promoter activity and glucagon mRNA levels in αTC-1.6 cells; whereas, it had no effect on insulin promoter activity and insulin mRNA levels in ßTC3 cells. Although immunostaining with the C-19 ATF3 antibody demonstrated predominant expression in α cells rather than ß cells, ATF3 staining was still detected in ATF3 knockout mice as clearly as in control mice. On the other hand, another ATF3 antibody (H-90) detected ATF3 in both α cells and ß cells, and was clearly diminished in ATF3 knockout mice. These results indicate that previous discrepancies in ATF3 expression patterns in the pancreas were caused by the varying specificities of the ATF3 antibodies used, and that ATF3 is actually expressed in both α cells and ß cells.
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Factor de Transcripción Activador 3/genética , Expresión Génica/efectos de los fármacos , Glucagón/genética , Glucosa/administración & dosificación , Insulina/genética , Islotes Pancreáticos/metabolismo , Factor de Transcripción Activador 3/análisis , Animales , Línea Celular , Células Secretoras de Glucagón/química , Células Secretoras de Glucagón/metabolismo , Células Secretoras de Insulina/química , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , ARN Mensajero/análisisRESUMEN
AIMS/INTRODUCTION: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic ß-cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α-cells. MATERIALS AND METHODS: Experiments were carried out in high-fat, high-sucrose diet-fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme-linked immunosorbent assay; the latter eliminates cross-reactivities with other proglucagon-derived peptides. RESULTS: Plasma glucagon, insulin and glucagon-like peptide-1 levels were increased by imeglimin administration in high-fat, high-sucrose diet-fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long-term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long-term administration of imeglimin did not alter α-cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein-1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. CONCLUSIONS: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.
RESUMEN
Endoscopy is essential for the diagnosis and treatment of cancers derived from the gastrointestinal tract. However, a conventional white-light image has technical limitations in detecting small or superficial lesions. Narrow-band imaging, especially with magnification, allows visualization of microstructure patterns and microvascular patterns on the mucosal surface. These technical breakthroughs enable endoscopists to easily detect small pre-neoplastic and neoplastic lesions and to make a differential diagnosis of these lesions. Appropriate diagnosis with narrow-band imaging contributes to minimally invasive endoscopic resection.
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Endoscopía Gastrointestinal , Neoplasias Gastrointestinales/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Imagen de Banda Estrecha , Tracto Gastrointestinal Superior/patología , Adenocarcinoma/diagnóstico , Esófago de Barrett/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Neoplasias Duodenales/diagnóstico , Detección Precoz del Cáncer , Endoscopía Gastrointestinal/instrumentación , Endoscopía Gastrointestinal/métodos , Neoplasias Esofágicas/diagnóstico , Reflujo Gastroesofágico/diagnóstico , Neoplasias Gastrointestinales/patología , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Gástricas/diagnósticoRESUMEN
Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.
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1-Desoxinojirimicina/análogos & derivados , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiología , Fármacos Antiobesidad/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Obesidad/prevención & control , 1-Desoxinojirimicina/farmacología , Acarbosa/farmacología , Adipocitos Marrones/metabolismo , Animales , Línea Celular , Dieta Alta en Grasa , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Digestión/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Inhibidores de Glicósido Hidrolasas , Masculino , Ratones , Ratones Endogámicos C57BL , Consumo de Oxígeno/efectos de los fármacos , Receptores Adrenérgicos beta/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-ß superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1ß release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
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Receptores de Activinas Tipo I , Adiposidad , Enfermedades Metabólicas , Animales , Ratones , Receptores de Activinas/metabolismo , Receptores de Activinas Tipo I/inmunología , Receptores de Activinas Tipo I/metabolismo , Anticuerpos Neutralizantes , Ácidos Grasos , Enfermedades Metabólicas/metabolismo , Obesidad/metabolismo , Modelos Animales de EnfermedadRESUMEN
Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.
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Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Mutación , Línea Celular TumoralRESUMEN
Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort (n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4+ T cells including CXCR3+ circulating follicular helper T cells and the TH1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific TH1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8+ T cell responses. Thus, an inefficient CD4+ T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4+ T cell response following the first dose is key to improving vaccine efficacy in older adults.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Anciano , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Vacunación/efectos adversos , Inmunidad Celular , Linfocitos T CD4-PositivosRESUMEN
Diabetes is characterized by an absolute or relative deficiency of pancreatic ß-cells. New strategies to accelerate ß-cell neogenesis or maintain existing ß-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits ß-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against ß-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (ß-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not ß-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased ß-cell mass due to increased islet number rather than islet size, indicating accelerated ß-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not ß-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or ß-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits ß-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress.
Asunto(s)
Complicaciones de la Diabetes/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/fisiología , Células Secretoras de Insulina/metabolismo , Obesidad/metabolismo , Páncreas/metabolismo , Animales , Recuento de Células , Diferenciación Celular , Cruzamientos Genéticos , Complicaciones de la Diabetes/patología , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/prevención & control , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/ultraestructura , Ratones , Ratones Noqueados , Ratones Mutantes , Obesidad/complicaciones , Obesidad/patología , Páncreas/patología , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , ARN Mensajero/metabolismo , RatasRESUMEN
Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin ß-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In ß-glucuronidase (GUSB)-proficient mice, both curcumin ß-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin ß-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation.