RESUMEN
BACKGROUND: The endoscopic Hill classification of the gastroesophageal flap valve (GEFV) is of great importance for understanding the functional status of the esophagogastric junction (EGJ). Deep learning (DL) methods have been extensively employed in the area of digestive endoscopy. To improve the efficiency and accuracy of the endoscopist's Hill classification and assist in incorporating it into routine endoscopy reports and GERD assessment examinations, this study first employed DL to establish a four-category model based on the Hill classification. MATERIALS AND METHODS: A dataset consisting of 3256 GEFV endoscopic images has been constructed for training and evaluation. Furthermore, a new attention mechanism module has been provided to improve the performance of the DL model. Combined with the attention mechanism module, numerous experiments were conducted on the GEFV endoscopic image dataset, and 12 mainstream DL models were tested and evaluated. The classification accuracy of the DL model and endoscopists with different experience levels was compared. RESULTS: 12 mainstream backbone networks were trained and tested, and four outstanding feature extraction backbone networks (ResNet-50, VGG-16, VGG-19, and Xception) were selected for further DL model development. The ResNet-50 showed the best Hill classification performance; its area under the curve (AUC) reached 0.989, and the classification accuracy (93.39%) was significantly higher than that of junior (74.83%) and senior (78.00%) endoscopists. CONCLUSIONS: The DL model combined with the attention mechanism module in this paper demonstrated outstanding classification performance based on the Hill grading and has great potential for improving the accuracy of the Hill classification by endoscopists.
A new attention mechanism module has been proposed and integrated into the DL model.According to our knowledge, this is the first study to establish a four-category DL model based on the Hill grading.The DL model demonstrated outstanding classification performance based on the Hill grading and has great potential for improving the accuracy of the Hill classification by endoscopists.
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Aprendizaje Profundo , Reflujo Gastroesofágico , Humanos , Unión Esofagogástrica , Endoscopía GastrointestinalRESUMEN
Cardiac remodeling has no established therapies targeting inflammation. CD4+ T-cell subsets have been reported to play significant roles in healing process after ischemic myocardial injury, but their detailed mechanisms of activation remain unknown. To explore immune reactions during cardiac remodeling, we applied a non-surgical model of coronary heart disease (CHD) induced by a high-fat diet (HFD-CHD) in SR-BI-/-/ApoeR61h/h mice. Flow cytometry analyses throughout the period of progressive cardiac dysfunction revealed that CD4+ T Helper 1 (Th1) cells were predominantly activated in T-cell subsets. Probucol was reported to attenuate cardiac dysfunction after coronary artery ligation model (ligation-MI) in rats. To determine whether probucol suppress cardiac remodeling after HFD-CHD, we treated SR-BI-/-/ApoeR61h/h mice with probucol. We found treatment with probucol in HFD-CHD mice reduced cardiac dysfunction, with attenuated activation of Th1 cells. RNA-seq analyses revealed that probucol suppressed the expression of CXCR3, a Th1-related chemokine receptor, in the heart. XCR1+ cDC1 cells, which highly expresses the CXCR3 ligands CXCL9 and CXCL10, were predominantly activated after HFD-CHD. XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed in bone marrow, with subsequent systemic expansion of XCR1+ cDC1 cells after HFD-CHD. Activation of CXCR3+ Th1 cell and XCR1+ cDC1 cells was also observed in ligation-MI. Notably, post-MI depletion of XCR1+ cDC1 cells suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction. In patient autopsy samples, CXCR3+ Th1 and XCR1+ cDC1 cells infiltrated the infarcted area. In this study, we identified a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling.
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Cardiopatías , Lesiones Cardíacas , Ratones , Ratas , Animales , Células TH1 , Probucol/metabolismo , Remodelación Ventricular , Cardiopatías/metabolismo , Células Dendríticas , Lesiones Cardíacas/metabolismoRESUMEN
OBJECTIVES: Gastroesophageal reflux disease (GERD) is a complex disease with a high worldwide prevalence. The Los Angeles classification (LA-grade) system is meaningful for assessing the endoscopic severity of GERD. Deep learning (DL) methods have been widely used in the field of endoscopy. However, few DL-assisted researches have concentrated on the diagnosis of GERD. This study is the first to develop a five-category classification DL model based on the LA-grade using explainable artificial intelligence (XAI). MATERIALS AND METHODS: A total of 2081 endoscopic images were used for the development of a DL model, and the classification accuracy of the models and endoscopists with different levels of experience was compared. RESULTS: Some mainstream DL models were utilized, of which DenseNet-121 outperformed. The area under the curve (AUC) of the DenseNet-121 was 0.968, and its classification accuracy (86.7%) was significantly higher than that of junior (71.5%) and experienced (77.4%) endoscopists. An XAI evaluation was also performed to explore the perception consistency between the DL model and endoscopists, which showed meaningful results for real-world applications. CONCLUSIONS: The DL model showed a potential in improving the accuracy of endoscopists in LA-grading of GERD, and it has noticeable clinical application prospects and is worthy of further promotion.
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Aprendizaje Profundo , Reflujo Gastroesofágico , Humanos , Inteligencia Artificial , Los Angeles , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/epidemiología , Endoscopía GastrointestinalRESUMEN
Primary hyperchylomicronemia is characterized by marked hypertriglyceridemia exceeding 1,000 mg/dL. It is caused by dysfunctional mutations in specific genes, namely those for lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), apolipoprotein C2 (ApoC-II), lipase maturation factor 1 (LMF1), or apolipoprotein A5 (ApoA-V). Importantly, antibodies against LPL or GPIHBP1 have also been reported to induce autoimmune hyperchylomicronemia. The patient was a 46-year-old man diagnosed with immune thrombocytopenia (ITP) at 41 years. At the time, he was administered prednisolone (PSL) and eltrombopag, a thrombopoietin receptor agonist. At 44 years, he suffered from acute myocardial infarction, and PSL was discontinued to avoid enhancing atherogenic risks. He was maintained on eltrombopag monotherapy. After discontinuing PSL, marked hypertriglyceridemia (ï¼3,000 mg/dL) was observed, which did not improve even after a few years of pemafibrate therapy. Upon referral to our clinic, the triglyceride (TG) level was 2,251 mg/dL, ApoC-II was 19.8 mg/dL, LPL was 11.1 ng/mL (0.02-1.5 ng/mL), GPIHBP1 was 47.7 pg/mL (740.0-1,014.0 pg/mL), and anti-GPIHBP1 antibody was detected. The patient was diagnosed to have anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia. He was administered PSL 15 mg/day, and TG levels were controlled at approximately 200 mg/dL. Recent studies have reported that patients with anti-GPIHBP1 antibody-induced autoimmune hyperchylomicronemia had concomitant rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's disease, and Graves' disease. We report a rare case of anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia with concomitant ITP, which became apparent when PSL was discontinued due to the onset of steroid-induced acute myocardial infarction.
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Hipertrigliceridemia , Púrpura Trombocitopénica Idiopática , Receptores de Lipoproteína , Masculino , Humanos , Persona de Mediana Edad , Receptores de Lipoproteína/química , Receptores de Lipoproteína/genética , Receptores de Lipoproteína/metabolismo , Lipoproteína Lipasa/metabolismo , Apolipoproteína C-II/genética , Apolipoproteína C-II/metabolismo , Hipertrigliceridemia/genéticaRESUMEN
Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.
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Dermatitis , Enfermedad del Hígado Graso no Alcohólico , Oxiesteroles , Psoriasis , Ratones , Animales , Imiquimod/efectos adversos , Ratones Endogámicos C57BL , Psoriasis/inducido químicamente , Cetocolesteroles , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Dieta Alta en Grasa , Modelos Animales de EnfermedadRESUMEN
Although patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported. We established a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy and evaluated the effect of pemafibrate. C57Bl/6 male mice were fed a (1) chow diet (C), (2) high-fat, high-cholesterol, high-sucrose, bile acid diet (NASH diet; N), or (3) N with pemafibrate 0.1 mg/kg (NP) for 8 weeks. In the liver, macrophage infiltration and fibrosis in the liver was observed in the N group compared to the C group, suggesting steatohepatitis. Free cholesterol accumulated, and cholesterol crystals were observed. In the heart, free cholesterol similarly accumulated and concentric hypertrophy was observed. Ultrahigh magnetic field magnetic resonance imaging revealed that the left ventricular (LV) ejection fraction (EF) was attenuated and LV strain was focally impaired. RNA sequencing demonstrated that the NOD-like receptor and PI3 kinase-Akt pathways were enhanced. mRNA and protein expression of inflammasome-related genes, such as Caspase-1, NLRP3, and IL-1ß, were upregulated in both the liver and heart. In the NP compared to the N group, steatohepatitis, hepatic steatosis, and cardiac dysfunction were suppressed. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction.
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Benzoxazoles/farmacología , Butiratos/farmacología , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Inflamasomas/metabolismo , Hígado/metabolismo , Miocardio/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Benzoxazoles/administración & dosificación , Butiratos/administración & dosificación , Cardiomiopatías/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Inflamasomas/genética , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológicoRESUMEN
AIMS: Age-related cardiac hypertrophy and subsequent heart failure are predicted to become increasingly serious problems in aging populations. Progranulin (PGRN) deficiency is known to be associated with accelerated aging in the brain. We aimed to evaluate the effects of PGRN deficiency on cardiac aging, including left ventricular hypertrophy. METHODS AND RESULTS: Echocardiography was performed on wild-type (WT) and PGRN-knockout (KO) mice every 3 months from 3 to 18 months of age. Compared to that of WT mice, PGRN KO mice exhibited age-dependent cardiac hypertrophy and cardiac dysfunction at 18 months. Morphological analyses showed that the heart weight to tibia length ratio and cross-sectional area of cardiomyocytes at 18 months were significantly increased in PGRN KO mice relative to those in WT mice. Furthermore, accumulation of lipofuscin and increases in senescence markers were observed in the hearts of PGRN KO mice, suggesting that PGRN deficiency led to enhanced aging of the heart. Enhanced complement C1q (C1q) and activated ß-catenin protein expression levels were also observed in the hearts of aged PGRN KO mice. Treatment of PGRN-deficient cardiomyocytes with C1q caused ß-catenin activation and cardiac hypertrophy. Blocking C1q-induced ß-catenin activation in PGRN-depleted cardiomyocytes attenuated hypertrophic changes. Finally, we showed that C1 inhibitor treatment reduced cardiac hypertrophy and dysfunction in old KO mice, possibly by reducing ß-catenin activation. These results suggest that C1q is a crucial regulator of cardiac hypertrophy induced by PGRN ablation. CONCLUSION: The present study demonstrates that PGRN deficiency enhances age-related cardiac hypertrophy via C1q-induced ß-catenin activation. PGRN is a potential therapeutic target to prevent cardiac hypertrophy and dysfunction.
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Envejecimiento/metabolismo , Cardiomegalia/metabolismo , Complemento C1q/metabolismo , Progranulinas/deficiencia , beta Catenina/metabolismo , Animales , Aorta/patología , Biomarcadores/metabolismo , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Constricción Patológica , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Miocardio/ultraestructura , Miocitos Cardíacos/metabolismo , Fenotipo , Presión , Progranulinas/metabolismo , Ratas , Transducción de SeñalRESUMEN
Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.
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Colesterol en la Dieta/administración & dosificación , Cetocolesteroles/administración & dosificación , Hígado/metabolismo , Macrófagos/metabolismo , Obesidad/metabolismo , Oxiesteroles/administración & dosificación , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Colesterol en la Dieta/efectos adversos , Mediadores de Inflamación/metabolismo , Cetocolesteroles/efectos adversos , Hígado/efectos de los fármacos , Hígado/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Obesos , Obesidad/patología , Oxiesteroles/efectos adversosRESUMEN
AIM: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling. METHODS: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61h/h mice (Hypo E mice) that developed MI by high-fat diet loading. RESULTS: Hypo E mice were fed rivaroxaban-containing (n=49) or control chow diets (n=126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p=0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes. In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts. CONCLUSIONS: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway.
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Cardiomiopatías/prevención & control , Dieta/efectos adversos , Modelos Animales de Enfermedad , Inhibidores del Factor Xa/farmacología , Infarto del Miocardio/complicaciones , Isquemia Miocárdica/prevención & control , Rivaroxabán/farmacología , Animales , Cardiomiopatías/etiología , Cardiomiopatías/patología , Progresión de la Enfermedad , Masculino , Ratones , Ratones Noqueados , Ratones Noqueados para ApoE , Infarto del Miocardio/patología , Isquemia Miocárdica/etiología , Isquemia Miocárdica/patología , Receptores Depuradores de Clase B/fisiologíaRESUMEN
The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.
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Carcinogénesis/patología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , MicroARNs/metabolismo , Transporte Activo de Núcleo Celular , Animales , Apoptosis , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Ciclo Celular , Núcleo Celular/metabolismo , Proliferación Celular , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Invasividad Neoplásica , Polimorfismo Genético , Transducción de SeñalRESUMEN
Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Morfinanos/farmacología , Células CACO-2 , Celecoxib , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Humanos , FN-kappa B/metabolismo , Pirazoles/farmacología , Transducción de Señal , Sulfonamidas/farmacologíaRESUMEN
Octreotide (OCT) can inhibit tumor growth with few sideeffects. In this study, we hypothesized that an OCT- and poloxamer 407 (P407)-based temperaturesensitive gel may compensate for the short halflife of OCT, which may thus lead to the development of a novel therapy for patients with endstage liver cancer by intratumoral injection. The proliferation and apoptosis of mouse HcaF hepatocellular carcinoma cells were determined by MTT assay and Annexin VPI staining. A mouse model of hepatocellular carcinoma was established by the subcutaneous transplantion of HcaF cells and OCTP407 or OCT solution were injected into the tumors, followed by the detection of OCT levels by high performance liquid chromatography (HPLC) over a specific time period. OCTP407, ethanol, OCT, P407 or normal saline (NS) were injected into the tumors and the tumor size, weight and inhibition rate were measured 8 days later. Additionally, the expression of somatostatin receptor2 (SSTR2), vascular endothelial growth factor (VEGF) and caspase3 was detected by immunohistochemistry and RTPCR. Compared with the OCT group, the tumor inhibition rate and the apoptotic rate in the OCTP407 group were higher and the effects were longer. The tumor size and weight in the OCTP407 group were lower and the tumor inhibition rate higher compared with the OCT, P407 and NS groups, with the exception of the ethanol group. The protein and mRNA expression of SSTR2 and caspase3 in the OCTP407 group was higher, and that of VEFG was lower compared with the other groups, with the exception of the ethanol group. In the present study, we demonstrate that the intratumoral injection of OCTP407 maintains OCT local effective concentration and prolongs its action time, with a greater therapeutic effect than that of OCT on its own. Although ethanol is more effective in certain aspects, its tumor inhibitory effects are similar to OCTP407 and as such, OCTP407 may be a suitable alternative.