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BACKGROUND: Missed early gastric cancer (MEGC) is prevalent during esophagogastroduodenoscopy (EGD), which is the first-line recommended strategy for detecting early gastric cancer (EGC). Hence, we explored the risk factors for MEGC and different types of MEGC, based on the endoscopic resected population. METHODS: This retrospective, case-control study was conducted at Nanjing Drum Tower Hospital (NJDTH). We included patients who were diagnosed with EGC during screening EGD, underwent endoscopic resection, and were confirmed by postoperative pathology at the NJDTH from January 2014 to December 2021, and classified them into different types according to the different root causes of misses. Univariable, multivariable, subgroup and propensity score analyses were used to explore the risk factors for MEGC and different types of MEGC. RESULTS: A total of 447 patients, comprising 345 with initially detected early gastric cancer (IDEGC) and 102 with MEGC, were included in this study. Larger size (≥ 1 cm) (OR 0.45, 95% CI 0.27-0.74, P = 0.002) and invasion depth of submucosa (OR 0.26, 95% CI 0.10-0.69, P = 0.007) were negatively associated with MEGC. Use of sedation (OR 0.32, 95% CI 0.20-0.52, P < 0.001) and longer observation time (OR 0.60, 95% CI 0.37-0.96, P = 0.034) exhibited protective effect on MEGC. CONCLUSIONS: Smaller and more superficial EGC lesions are more susceptible to misdiagnosis. The use of sedation and prolonged observation time during EGD could help reduce the occurrence of MEGC.
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Detección Precoz del Cáncer , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Factores de Riesgo , Anciano , Detección Precoz del Cáncer/métodos , Diagnóstico Erróneo/estadística & datos numéricos , Endoscopía del Sistema Digestivo/métodos , Gastroscopía/métodosAsunto(s)
Enfermedades Autoinmunes , Gastritis , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/diagnóstico , Gastritis/patología , Gastritis/complicaciones , Masculino , Persona de Mediana Edad , Femenino , Adenocarcinoma/patologíaRESUMEN
[This corrects the article on p. 546 in vol. 9, PMID: 30949409.].
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BACKGROUND: Ferroptosis is an important iron-dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. METHODS: The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan-Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull-down, immunofluorescence assays, acyl-biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. RESULTS: LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib-induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc-. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull-down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de-palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. CONCLUSIONS: Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , ARN Largo no Codificante/metabolismo , Ferroptosis/genética , Lipoilación , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismoRESUMEN
INTRODUCTION: A modified cap-assisted endoscopic mucosal resection (mEMR-C), introduced in this study, was a novel variation of the standard EMR. We aimed to compare the outcomes of mEMR-C and endoscopic submucosal dissection (ESD) for the treatment of small (≤20 mm) intraluminal gastric gastrointestinal stromal tumors (gGISTs). METHODS: This retrospective study included 43 patients who underwent mEMR-C and 156 patients who received ESD at Nanjing Drum Tower Hospital. Baseline characteristics, adverse events, and clinical outcomes were compared between the 2 groups. Univariate and multivariable analyses were conducted to adjust for confounders. After propensity score matching using sex, year, location, and tumor size, outcomes were compared with 41 patients in each group. RESULTS: A total of 199 patients underwent endoscopic resection and the en bloc resection rate was 100%. The complete resection rate was comparable in both groups ( P = 1.000). Approximately 9.5% of all patients had a positive margin. There was no significant difference in positive margin for patients undergoing mEMR-C or ESD (9.3% vs 9.6%, P = 1.000). No difference in adverse events in both groups ( P = 0.724). The mEMR-C was associated with shorter operation time and lower cost than the ESD. Recurrence was reported in 2 patients at 1 and 5 years after ESD during a median follow-up of 62 months. No metastasis and disease-related death were identified in both groups. Propensity score matching analysis revealed similar results. DISCUSSION: The mEMR-C was found to be the preferable technique for small (≤20 mm) intraluminal gGISTs with shorter operation time and lower cost as compared with ESD.
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Resección Endoscópica de la Mucosa , Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Estudios Retrospectivos , Tumores del Estroma Gastrointestinal/cirugía , Resultado del Tratamiento , Endoscopía , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Márgenes de EscisiónRESUMEN
BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.
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Resección Endoscópica de la Mucosa , Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Estudios Retrospectivos , Estudios de Casos y Controles , Cardias/patología , Tumores del Estroma Gastrointestinal/cirugía , Tumores del Estroma Gastrointestinal/patología , Factores de Riesgo , Resultado del Tratamiento , GastroscopíaRESUMEN
BACKGROUND: The clinicopathological features and endoscopic characteristics under magnifying endoscopy with narrow band imaging (ME-NBI) between early-stage gastric-type differentiated adenocarcinoma (GDA) and intestinal-type differentiated adenocarcinoma (IDA) remain controversial. METHODS: Early gastric adenocarcinomas that underwent endoscopic submucosal dissection (ESD) in Nanjing Drum Tower Hospital between August 2017 and August 2021 were included in the present study. GDA cases and IDA cases were selected based on morphology and immunohistochemistry staining of CD10, MUC2, MUC5AC, and MUC6. Clinicopathological data and endoscopic findings in ME-NBI were compared between GDAs and IDAs. RESULTS: The mucin phenotypes of 657 gastric cancers were gastric (n = 307), intestinal (n = 109), mixed (n = 181) and unclassified (n = 60). No significant difference was observed in terms of gender, age, tumor size, gross type, tumor location, background mucosa, lymphatic invasion, and vascular invasion between patients with GDA and IDA. GDA cases were associated with deeper invasion than IDA cases (p = 0.007). In ME-NBI, GDAs were more likely to exhibit an intralobular loop patten, whereas IDAs were more likely to exhibit a fine network pattern. In addition, the proportion of none-curative resection in GDAs was significantly higher than that in IDAs (p = 0.007). CONCLUSION: The mucin phenotype of differentiated early gastric adenocarcinoma has clinical significance. GDA was associated with less endoscopically resectability than IDA.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Neoplasias Gástricas/patología , Endoscopía Gastrointestinal , Adenocarcinoma/patologíaRESUMEN
Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this study, we report and characterize a new intrahepatic CCA cell line, LIV27, derived from a surgically resected tumor in a 67-year-old Caucasian woman with primary sclerosing cholangitis (PSC). LIV27 cells grow well in collagen-coated flasks or plates with a doubling time of 57.8 h at passage 14. LIV27 cells have high tumorigenicity in nude mice and stain positive for CK7 and CK19, markers that differentiate CCA from hepatocellular carcinoma. Karyotype analysis showed that LIV27 is aneuploid. We established a single-locus short tandem repeat profile for the LIV27 cell line. This newly established cell line will be a useful model for studying the molecular pathogenesis of, and developing novel therapies for, cholangiocarcinoma.
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Carcinoma Adenoide Quístico , Resección Endoscópica de la Mucosa , Neoplasias Esofágicas , Humanos , Carcinoma Adenoide Quístico/cirugía , Carcinoma Adenoide Quístico/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Esofagoscopía , Resultado del TratamientoRESUMEN
BACKGROUND: Diagnosis of early gastric cancer (EGC) under narrow band imaging endoscopy (NBI) is dependent on expertise and skills. We aimed to elucidate whether artificial intelligence (AI) could diagnose EGC under NBI and evaluate the diagnostic assistance of the AI system. METHODS: In this retrospective diagnostic study, 21,785 NBI images and 20 videos from five centers were divided into a training dataset (13,151 images, 810 patients), an internal validation dataset (7057 images, 283 patients), four external validation datasets (1577 images, 147 patients), and a video validation dataset (20 videos, 20 patients). All the images were labeled manually and used to train an AI system using You look only once v3 (YOLOv3). Next, the diagnostic performance of the AI system and endoscopists were compared and the diagnostic assistance of the AI system was assessed. The accuracy, sensitivity, specificity, and AUC were primary outcomes. RESULTS: The AI system diagnosed EGCs on validation datasets with AUCs of 0.888-0.951 and diagnosed all the EGCs (100.0%) in video dataset. The AI system achieved better diagnostic performance (accuracy, 93.2%, 95% CI, 90.0-94.9%) than senior (85.9%, 95% CI, 84.2-87.4%) and junior (79.5%, 95% CI, 77.8-81.0%) endoscopists. The AI system significantly enhanced the performance of endoscopists in senior (89.4%, 95% CI, 87.9-90.7%) and junior (84.9%, 95% CI, 83.4-86.3%) endoscopists. CONCLUSION: The NBI AI system outperformed the endoscopists and exerted potential assistant impact in EGC identification. Prospective validations are needed to evaluate the clinical reinforce of the system in real clinical practice.
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Aprendizaje Profundo , Neoplasias Gástricas , Inteligencia Artificial , Endoscopía Gastrointestinal , Humanos , Imagen de Banda Estrecha/métodos , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico por imagenRESUMEN
Cholangiocarcinoma (CCA) is a malignant hepatic tumor with a poor prognosis, which needs early diagnosis urgently. The gut microbiota has been shown to play a crucial role in the progression of liver cancer. Here, we explored a gut microbiota model covering genera Burkholderia-Caballeronia-Paraburkholderia, Faecalibacterium, and Ruminococcus_1 (B-F-R) for CCA early diagnosis. A case-control study was conducted to enroll 53 CCA patients, 47 cholelithiasis patients, and 40 healthy controls. The feces samples and clinical information of participants were collected in the same period. The gut microbiota and its diversity of individuals were accessed with 16S rDNA sequencing, and the gut microbiota profile was evaluated according to microbiota diversity. Finally, four enriched genera in the CCA group (genera Bacteroides, Muribaculaceae_unclassified, Muribaculum, and Alistipes) and eight enriched genera in the cholelithiasis group (genera Bifidobacterium, Streptococcus, Agathobacter, Ruminococcus_gnavus_group, Faecalibacterium, Subdoligranulum, Collinsella, Escherichia-Shigella) constitute an overall different microbial community composition (P = 0.001). The B-F-R genera model with better diagnostic value than carbohydrate antigen 19-9 (CA19-9) was identified by random forest and Statistical Analysis of Metagenomic Profiles (STAMP) to distinguish CCA patients from healthy controls [area under the curve (AUC) = 0.973, 95% CI = 0.932-1.0]. Moreover, the correlative analysis found that genera Burkholderia-Caballeronia-Paraburkholderia were positively correlated with body mass index (BMI). The significantly different microbiomes between cholelithiasis and CCA were found via principal coordinates analysis (PCoA) and linear discriminant analysis effect size (LEfSe), and Venn diagram and LEfSe were utilized to identify four genera by comparing microbial compositions among patients with malignant obstructive jaundice (MOJ-Y) or not (MOJ-N). In brief, our findings suggest that gut microbiota vary from benign and malignant hepatobiliary diseases to healthy people and provide evidence supporting gut microbiota to be a non-invasive biomarker for the early diagnosis of CCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Microbioma Gastrointestinal , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Intrahepáticos , Estudios de Casos y Controles , Colangiocarcinoma/diagnóstico , Detección Precoz del Cáncer , Heces , Humanos , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.
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Carcinoma Hepatocelular/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Células Madre Neoplásicas/metabolismo , Factor de Transcripción AP-2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Animales , Carcinoma Hepatocelular/patología , Proliferación Celular/fisiología , Modelos Animales de Enfermedad , Retroalimentación Fisiológica , Xenoinjertos , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Células Madre Neoplásicas/patologíaRESUMEN
Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.
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Colangiocarcinoma/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Neovascularización Patológica/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/efectos de los fármacos , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Colangiocarcinoma/patología , Cisplatino/farmacología , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Citoesqueleto/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Gemcitabina , Neoplasias PancreáticasRESUMEN
BACKGROUND AND AIMS: Prediction of intramucosal gastric cancer (GC) is a big challenge. It is not clear whether artificial intelligence could assist endoscopists in the diagnosis. METHODS: A deep convolutional neural networks (DCNN) model was developed via retrospectively collected 3407 endoscopic images from 666 gastric cancer patients from two Endoscopy Centers (training dataset). The DCNN model's performance was tested with 228 images from 62 independent patients (testing dataset). The endoscopists evaluated the image and video testing dataset with or without the DCNN model's assistance, respectively. Endoscopists' diagnostic performance was compared with or without the DCNN model's assistance and investigated the effects of assistance using correlations and linear regression analyses. RESULTS: The DCNN model discriminated intramucosal GC from advanced GC with an AUC of 0.942 (95% CI, 0.915-0.970), a sensitivity of 90.5% (95% CI, 84.1%-95.4%), and a specificity of 85.3% (95% CI, 77.1%-90.9%) in the testing dataset. The diagnostic performance of novice endoscopists was comparable to those of expert endoscopists with the DCNN model's assistance (accuracy: 84.6% vs. 85.5%, sensitivity: 85.7% vs. 87.4%, specificity: 83.3% vs. 83.0%). The mean pairwise kappa value of endoscopists was increased significantly with the DCNN model's assistance (0.430-0.629 vs. 0.660-0.861). The diagnostic duration reduced considerably with the assistance of the DCNN model from 4.35s to 3.01s. The correlation between the perseverance of effort and diagnostic accuracy of endoscopists was diminished using the DCNN model (r: 0.470 vs. 0.076). CONCLUSIONS: An AI-assisted system was established and found useful for novice endoscopists to achieve comparable diagnostic performance with experts.
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OBJECTIVE: Hox transcript antisense intergenic RNA (HOTAIR), a lncRNA, functions as a critical regulator in cancer development. A plenty of case-control studies were conducted to assess the actual relationship of HOTAIR gene generic variants on cancer susceptibility, yet conflicting conclusions remain. Herein, we carried out this up-to-date meta-analysis to get a better understanding of such relationship by incorporating all eligible case-control studies. MATERIALS AND METHODS: Six widely investigated polymorphisms were included in this meta-analysis: rs920778, rs4759314, rs7958904, rs874945, rs1899663, and rs12826786. We retrieved relevant studies from databases PubMed, EMBASE, Medline, CNKI and Wanfang update to June 2020. We applied odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the relationship strengths. RESULTS: Our findings indicate that rs920778, rs4759314, rs874945, rs12826786 polymorphism significantly increased with susceptibility to overall cancer. However, rs7958904, rs1899663 under any five genetic models could not impact susceptibility to overall cancer. Furthermore, altered cancer risk was detected when the data were stratified by cancer type, ethnicity, the source of controls, and HWE in all the SNPs. CONCLUSIONS: These findings of the meta-analysis suggest that HOTAIR polymorphisms may predispose to cancer susceptibility.
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Cholangiocarcinoma (CCA) is a fatal disease with dismal survival rates. Long non-coding RNA (lncRNA) expression profiling as potential prognostic biomarkers play critical roles in tumor initiation, development, and poor prognosis. Identifying specific lncRNA to predict the prognosis of CCA patients in the early stages is very important for improving a patient's survival. In the current study, we aimed to establish a novel risk-stratification lncRNA signature panel in CCA. The initial lncRNA discovery was identified in The Cancer Genome Atlas database (TCGA cohort). The Cox regression analysis was used to establish the lncRNA prognostic model and the receiver operating characteristic (ROC) curve analysis was performed to assess the specificity and sensitivity of the model. This was followed by independent validation of the lncRNA signature in the CCA patients from the First Affiliated Hospital of Wenzhou Medical University (WMU cohort). Furthermore, by using the Gene Ontology function and Kyoto Encyclopedia Gene and Genome pathway enrichment analysis, we explored the potential function of prognosis lncRNA. Finally, five lncRNA (HULC; AL359715.5; AC006504.8; AC090114.2; AP00943.4) were screened to establish the predictive model that significantly associated with poor overall survival(HR:4.879;95%CI,1.587-14.996;p=0.006). This five-lncRNA signature model showed excellent accuracy in the TCGA cohort (AUC=0.938), and also robustly predicted survival in the validation WMU cohort(AUC=0.816). Functional enrichment analysis suggested prognostic lncRNA was primarily associated with CCA-related biological processes. Our data established a novel lncRNA signature model for CCA risk-stratification and robust identification of CCA patients with poor molecular genotypes. Moreover, it revealed new molecular mechanisms of CCA.
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Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , ARN Largo no Codificante/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , ARN Largo no Codificante/metabolismo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. METHODS: A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. RESULTS: We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. CONCLUSIONS: This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.
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Biomarcadores de Tumor/genética , Proliferación Celular/genética , Metilación de ADN , Transición Epitelial-Mesenquimal/genética , Histonas/genética , Hipoxia/fisiopatología , Metástasis de la Neoplasia/genética , Neoplasias Pancreáticas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , PronósticoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Our previous study found that peroxisome proliferator activated receptor gamma (PPARγ) was capable of enhancing glycolysis in PDAC cells. However, whether PPARγ could promote PDAC progression remains unclear. In our present study, PPARγ was positively associated with tumor size and poor prognosis in PDAC patients. Functional assays demonstrated that PPARγ could promote the proliferation of pancreatic cancer cells in vitro and in vivo. Additionally, flow cytometry results showed that PPARγ decreased mitochondrial reactive oxygen species (mitochondrial ROS) production, stabilized mitochondrial membrane potential (MMP) and inhibited cell apoptosis via up-regulating superoxide dismutase 2 (SOD2), followed by the inhibition of ATG4D-mediated mitophagy. Meanwhile, the activation of PPARγ might reduce pancreatic cancer cell stemness to improve PDAC chemosensitivity via down-regulating ATG4D. Thus, these results revealed that PPARγ/SOD2 might protect against mitochondrial ROS-dependent apoptosis via inhibiting ATG4D-mediated mitophagy to promote pancreatic cancer proliferation, further improving PDAC chemosensitivity.
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Background: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is a key enzyme associated with a variety of metabolic processes, including glucose metabolism. We recently uncovered that glucose metabolism played an essential role in promoting metastasis of pancreatic ductal adenocarcinoma (PDAC). As ALDH1A3 labels an aggressive subtype of PDAC, we hypothesized that ALDH1A3 functionally promoted PDAC metastasis via its metabolic effect on glucose metabolism. Methods: Expression of ALDH1A3 was detected in human PDAC tissues by immunohistochemistry. ALDH1A3 was knocked down or overexpressed in PDAC cells by either shRNA or overexpression vector. The functional roles of ALDH1A3 were characterized in vitro and in vivo. Transcriptional profiling via RNA-sequencing was used to explore the possible underlying molecular mechanisms. Glucose uptake, extracellular lactate, and ATP production were measured to access the metabolic influence of ALDH1A3 on PDAC cells. Results: ALDH1A3 was associated with poor prognosis in PDAC patients. Functionally, ALDH1A3 promoted PDAC metastasis in vitro and in vivo. Further studies revealed that ALDH1A3 activated PI3K/AKT/mTOR signaling pathway and its downstream target-PPARγ (peroxisome proliferator-activated receptor gamma). This led to increase the expression of HK2 (hexokinase 2), which subsequently enhanced the glycolysis in PDAC cells. Additionally, the pharmacological inhibition of PPARγ activity in ALDH1A3-positive cells impaired glycolytic genes expression, PI3K/AKT/mTOR activity and cellular glycolysis. Conclusions: ALDH1A3 promotes PDAC metastasis via its metabolic influence on glucose metabolism. PPARγ and its downstream PI3K/AKT/mTOR signaling pathway maybe involved in this process.
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BACKGROUND AND AIMS: In recent years, with the development of endoscopic techniques, endoscopic resection is widely used for duodenal papillary adenomas, but conventional endoscopic resection has a high rate of incomplete resection and recurrence. On this basis, we have employed a novel modified endoscopic papillectomy (ESP). In this study, we evaluated the feasibility and advantages of this ESP for the treatment of duodenal major papilla adenoma. METHODS: A total of 56 patients with duodenal major papilla adenoma confirmed by endoscopic ultrasonography, intraluminal ultrasound and gastroscopic biopsy from October 2007 to June 2017 were collected in the Department of Gastroenterology, Nanjing Drum Tower Hospital. The diameter of the adenoma ranged from 1.41 to 2.02 cm. 16 cases were given the conventional method and 40 cases underwent the modified ESP procedure in which a small incision was made by cutting current when anchoring the snare tip on the distal side of the adenoma. RESULTS: En bloc resection rate was significantly higher in the modified group (100%, 40/40) than that in the conventional group (81.3%, 13/16; P = 0.02). However, no significance was seen between the modified group and the conventional group in complete resection rate (92.5%, 37/40 vs 93.8%, 15/16; P = 1.00). There was no significant difference in the number and difficulty of postoperative pancreatic and biliary stents placement between the two groups (P = 0.20). Total bleeding occurrence was much lower in the modified group (37.5%, 15/40 vs 87.5%, 14/16; P = 0.001), and no significant differences were found in other short-term complications and the 3, 6, 12 and 24 months recurrences rate between the conventional and modified ESP groups. CONCLUSIONS: The modified ESP improves the treatment outcome of duodenal major papilla adenoma with higher en bloc resection rate and lowering bleeding rate.