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BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.
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Aminas , Esofagite Péptica , Refluxo Gastroesofágico , Úlcera Péptica , Pirróis , Humanos , Método Duplo-Cego , Esomeprazol/efeitos adversos , Esofagite Péptica/tratamento farmacológico , Esofagite Péptica/etiologia , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/complicações , Úlcera Péptica/complicações , Inibidores da Bomba de Prótons/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The application of machine learning (ML) for identifying early gastric cancer (EGC) has drawn increasing attention. However, there lacks evidence-based support for its specific diagnostic performance. Hence, this systematic review and meta-analysis was implemented to assess the performance of image-based ML in EGC diagnosis. METHODS: We performed a comprehensive electronic search in PubMed, Embase, Cochrane Library, and Web of Science up to September 25, 2022. QUADAS-2 was selected to judge the risk of bias of included articles. We did the meta-analysis using a bivariant mixed-effect model. Sensitivity analysis and heterogeneity test were performed. RESULTS: Twenty-one articles were enrolled. The sensitivity (SEN), specificity (SPE), and SROC of ML-based models were 0.91 (95% CI: 0.87-0.94), 0.85 (95% CI: 0.81-0.89), and 0.94 (95% CI: 0.39-1.00) in the training set and 0.90 (95% CI: 0.86-0.93), 0.90 (95% CI: 0.86-0.92), and 0.96 (95% CI: 0.19-1.00) in the validation set. The SEN, SPE, and SROC of EGC diagnosis by non-specialist clinicians were 0.64 (95% CI: 0.56-0.71), 0.84 (95% CI: 0.77-0.89), and 0.80 (95% CI: 0.29-0.97), and those by specialist clinicians were 0.80 (95% CI: 0.74-0.85), 0.88 (95% CI: 0.85-0.91), and 0.91 (95% CI: 0.37-0.99). With the assistance of ML models, the SEN of non-specialist physicians in the diagnosis of EGC was significantly improved (0.76 vs 0.64). CONCLUSION: ML-based diagnostic models have greater performance in the identification of EGC. The diagnostic accuracy of non-specialist clinicians can be improved to the level of the specialists with the assistance of ML models. The results suggest that ML models can better assist less experienced clinicians in diagnosing EGC under endoscopy and have broad clinical application value.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Endoscopia , Aprendizado de MáquinaRESUMO
Pseudouridine synthase 7 (PUS7) may play key roles in cancer development. However, few studies have been conducted in this area. In the present study, we explored the function and potential mechanisms of PUS7 in colorectal cancer (CRC) progression. We found that PUS7 had higher expression in CRC tissues and cell lines. Clinically, high expression of PUS7 was associated with an unfavorable prognosis for CRC patients. Functionally, knockdown of PUS7 suppressed the proliferation of CRC cells in vitro and inhibited tumorigenicity in vivo. Mechanistically, RNA sequencing and coimmunoprecipitation (Co-IP) indicated that PUS7 exhibited oncogenic functions through the interaction of Sirtuin 1 (SIRT1) and activated the Wnt/ß-catenin signaling pathway. Thus, our findings suggest that PUS7 promotes the proliferation of CRC cells by directly stabilizing SIRT1 to activate the Wnt/ß-catenin pathway.
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Neoplasias Colorretais , Transferases Intramoleculares , Sirtuína 1 , Via de Sinalização Wnt , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Sirtuína 1/genética , Sirtuína 1/metabolismo , Via de Sinalização Wnt/genética , Transferases Intramoleculares/genética , Transferases Intramoleculares/metabolismoRESUMO
Cuproptosis is a novel programmed cell death pathway that is initiated by direct binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins. Recent studies have demonstrated that cuproptosis-related genes regulate tumorigenesis. However, the potential role and clinical significance of cuproptosis-related long noncoding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) have not been established. We performed a bioinformatics analyses of RNA-sequencing data of HCC patients extracted from The Cancer Genome Atlas (TCGA) dataset to identify and validate a cuproptosis-related lncRNA prognostic signature. Furthermore, we analyzed the clinical significance of the prognostic signature of cuproptosis-related lncRNA in predicting the immunotherapeutic efficacy and the status of the tumor immune microenvironment. The RNA-sequencing data, genomic mutations, and clinical information were downloaded for 374 HCC samples and 50 normal liver samples from TCGA-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Co-expression analysis of Gene-lncRNA pairs with 49 known cuproptosis-related prognostic genes was used to define cuproptosis-related prognostic lncRNAs. We performed the LASSO algorithm and univariate and multivariate Cox regression analysis, respectively, to gradually identify the prognostic risk models of cuproptosis-related lncRNA based on the TCGA-LIHC dataset. Subsequently, the predictive performance of the model was evaluated using receiver operation characteristic (ROC) curves, Kaplan-Meier survival curves, and prognostic nomogram. The analysis of gene-lncRNA co-expression with 49 known cuproptosis-related genes identified 1359 cuproptosis-related lncRNAs in the TCGA-LIHC data set. A prognostic model was constructed with nine cuproptosis-related prognostic lncRNAs (AC007998.3, AC003086.1, AC009974.2, IQCH-AS1, LINC0256 1, AC105345.1, ZFPM2-AS1, AL353708.1 and WAC-AS1) using LASSO regression and Cox regression analyses. Risk scores were calculated for all HCC patient samples based on the four cuproptosis-related lncRNA prognostic models. All HCC patients were divided into high-risk and low-risk subgroups according to a 1:1 ratio column. The Kaplan-Meier survival curve analysis showed that the overall survival rate (OS) of the high-risk group patients was significantly lower than that of the low-risk group. The principal component analysis (PCA) confirmed that the prognostic lncRNA model accurately distinguished between high- and low-risk HCC patients. Furthermore, regression analysis as well as ROC curves confirmed the prognostic value of the risk score. A nomogram with risk scores and other clinicopathological characteristics was constructed. The nomogram accurately predicted the probability of 1-, 3-, and 5-year OS in HCC patients. Tumor mutation burden (TMB) scores were higher for high-risk patients than for low-risk patients. HCC patients in the low-risk group showed lower TIDE scores and greater sensitivity to antitumor drugs than those in the high-risk group. Tumor immune responses and tumor immune cell infiltration were significantly different between the high-risk and low-risk groups of patients with HCC. Our study identified a 9-cuproptosis-related lncRNA signature that accurately predicted prognosis, immunotherapeutic efficacy, and the status of the tumor immune microenvironment in HCC patients. Therefore, this cuproptosis-related lncRNA risk model is a potential prognostic biometric feature in HCC and shows high clinical value in identifying HCC patients who are potentially responsive to immunotherapy.
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BACKGROUND: ColoDefense1.0 assay has demonstrated its excellent sensitivity and specificity for early detection of colorectal cancer (CRC) by detecting the methylation levels of SDC2 and SEPT9, while exhibited limitations on relatively large sample capacity required and limited detection throughput by applying triplicate PCR reactions for each sample. In this study, ColoDefense1.0 was simplified and optimized into ColoDefense2.0 in a single PCR reaction. METHODS: A total 529 stool specimens were collected, and 244 CRC patients, 34 patients with advanced adenomas (AA), 64 with small polyps (SP) and 187 control subjects were divided in training and validation cohorts. Methylation levels of SEPT9 and SDC2 were examined by qPCR reactions in triplicate or single. RESULTS: The stool DNA quantity stored in preservative buffer at 37 °C up to 7 days exhibited no significant decrease. In the training cohort, when the number of replicates reduced from 3 to 1, the overall performance of ColoDefense2.0 was identical to that of ColoDefense1.0, showing sensitivities of 71.4% for AA and 90.8% for all stage CRC with a specificity of 92.9%. In the validation cohort, sensitivities of SP, AA and CRC using ColoDefense2.0 were 25.0%, 55.0% and 88.2%, increased from 14.1% (20.3%), 40.0% (40.0%) and 79.4% (67.6%) using SDC2 (SEPT9) alone; along with an overall specificity of 90.2%, decreased from 94.1% (95.1%) using SDC2 (SEPT9) alone. CONCLUSION: The simplified ColoDefense test maintained the overall performance while reduced the number of PCR reactions to 1/3, and provided an effective and convenient tool to detect early CRC and precancerous lesions and potentially improve the compliance of screening.
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Neoplasias Colorretais , Sindecana-2 , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA , Metilação de DNA , Detecção Precoce de Câncer , Humanos , Sensibilidade e Especificidade , Sindecana-2/genéticaRESUMO
BACKGROUND: Simethicone (SIM) is a commonly used antifoaming agent in the clinic. However, it has not been clarified whether SIM can improve the quality of intestinal preparation and the detection rates of adenomas (ADR) and polyps (PDR). This systematic review and meta-analysis were carried out to mainly evaluate the effect of SIM in bowel preparation for colonoscopy. MATERIALS AND METHODS: An electronic and a manual search of the literature for studies was conducted in PubMed, EMBASE, and Web of Science in all published data before February 1, 2020. The primary outcomes were the quality of bowel preparation and the ADR and PDR. All the data were calculated using a pooled estimate of risk ratio with 95% confidence intervals, and a random-effect model was used for the calculation. RESULTS: Eighteen randomized controlled trials with 7187 patients were included in this meta-analysis. Polyethylene glycol (PEG) with SIM improved colon cleansing (P<0.00001), PDR (P=0.006) and the detection rate of lesions in the right colon (P<0.00001) when compared with PEG alone. There was no difference in the ADR (P=0.68), withdrawal time (P=0.06), cecal intubation rate (P=0.98), and cecal intubation time (P=0.65) between 2 groups. The rate of abdominal bloating rate was higher in the PEG group, but there was no significant difference in vomiting (P=0.65), and abdominal pain (P=0.25). CONCLUSIONS: SIM improves the quality of bowel cleanliness and PDR but not ADR. Besides, SIM improves the detection rate of lesions in the right colon and decreased abdominal bloating, but do not affect vomiting and abdominal pain or cramping.
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Polietilenoglicóis , Simeticone , Catárticos , Ceco , Colonoscopia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Gastric cancer (GC) is fifth most frequently diagnosed cancer and second leading cause of cancer in China. More than 80% of GC are diagnosed at an advanced stage due to low uptake rate of invasive screening method. The performance of methylated SFRP2 test was evaluated in 236 plasma samples, including 92 patients with GC, 16 intestinal metaplasia patients, 26 gastric fundic gland polyp patients, 13 small adenoma patients, 39 hyperplastic polyp patients, and 50 control patients. The sensitivity of plasma methylated SFRP2 was compared to serum CEA, CA72-4, CA19-9, and CA242 results in 79 patients with GC. The sensitivities for detecting GC and gastric intestinal metaplasia by methylated SFRP2 test were 60.9% and 56.3% with a specificity of 86.0%. Methylated SFRP2 test had significantly higher positive detection rate for patients with GC than gastric fundic gland polyp, small adenoma, and hyperplastic polyp patients. In 79 patients with GC, the sensitivities of CEA, CA72-4, CA19-9, and CA242 for detecting GC were 22.8%, 16.5%, 12.7%, and 11.4%. In comparison, the sensitivity of methylated SFRP2 test for detecting GC was 58.2%. Plasma methylated SFRP2 test may become a valuable tool for the noninvasive detection of GC and precursor lesions and showed higher sensitivity than serum tumor markers.
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Biomarcadores Tumorais/genética , Metilação de DNA , Detecção Precoce de Câncer/métodos , Proteínas de Membrana/genética , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/metabolismo , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/metabolismo , Estudos de Casos e Controles , Estudos de Viabilidade , Feminino , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/química , Pessoa de Meia-Idade , Curva ROC , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Adulto JovemRESUMO
BACKGROUND/AIMS: gastric cancer is a serious health concern with high morbidity and mortality. Therefore, it is urgent to find novel targets for gastric cancer diagnosis and treatment. METHODS: qRT-PCR and immunohistochemistry assays were used to detect GTPBP4 expression in gastric cancer tissues, and gastric cancer and gastric epithelial cells. Lentivirus infection was used to construct GTPBP4 stable knockdown cells. Annexin V/PI apoptosis, CCK8, EdU incorporation and cell clone formation analysis were performed to evaluate the effects of GTPBP4 on gastric cancer cell proliferation and apoptosis. Further RNA-based high-throughput sequencing and co-IP assays were constructed to explore the related mechanisms contributing to GTPBP4-mediated effects. RESULTS: GTPBP4 expression was significantly increased in gastric cancer tissues compared with that in adjacent normal tissues, and positively correlated with gastric cancer stages. Meanwhile, GTPBP4 level was markedly upregulated in gastric cancer cells than in gastric epithelial cells. Additionaly, stable knockdown of GTPBP4 inhibited cell proliferation and promoted cell apoptosis. Mechanistically, p53 and its related signaling were significantly activated in GTPBP4 stable knockdown cells. And GTPBP4 interacted with p53 in gastric cancer cells. CONCLUSIONS: our results provide insights into mechanistic regulation and linkage of the GTPBP4-p53 in gastric cancer, and also a valuable potential target for gastric cancer.
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Proteínas de Ligação ao GTP/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo , Idoso , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Progressão da Doença , Feminino , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Regulação para CimaRESUMO
BACKGROUND/AIMS: The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is overexpressed in numerous cancers. However, whether MALAT1 is regulated and the related mechanisms in gastric cancer remain unclear. METHODS: Immunohistochemistry and qRT-PCR analyses were used to detect the expression levels of UPF1 and MALAT1 in gastric cancer and adjacent normal tissues. MTT, cell cycle, apoptosis and transwell assays were performed to examine the effects of UPF1 on cell cycle progression, cell proliferation, apoptosis, migration and invasion. Additionally, sodium bisulfate sequencing was used to test the promoter hypermethylation on UPF1 in gastric tumor tissues. Finally, RNA immunoprecipitation and luciferase reporter analyses demonstrated that UPF1 directly bound with MALAT1. RESULTS: The expression of UPF1 was significantly downregulated in gastric cancer and negatively correlated with MALAT1 expression. Patients with lower expression of UPF1 had poorer prognosis than those with higher expression. Overexpression of UPF1 inhibited cell proliferation, cell cycle progression, cell migration and invasion, and promoted cell apoptosis in gastric cancer cells. Moreover, the UPF1-mediated inhibition of gastric cancer progression was reversed by overexpression of MALAT1. A profound downregulation of UPF1 in gastric tumor tissues was due to promoter hypermethylation. Overexpression of UPF1 increased nonsense-mediated mRNA decay (NMD) efficiency and thus led to downregulation of MALAT1. CONCLUSION: Our results demonstrate that UPF1 is a potential modulator of MALAT1 and that UPF1/MALAT1 pathway could be a therapeutic target for gastric cancer.
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RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Transativadores/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Metilação de DNA , Progressão da Doença , Regulação para Baixo , Transição Epitelial-Mesenquimal , Humanos , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Helicases , Interferência de RNA , Estabilidade de RNA , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Transativadores/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
AIM: To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus (PVN) on ulcerative colitis (UC) in rats and to explore the relevant mechanisms. METHODS: 2,4,6-Trinitrobenzenesulfonic acid (100 mg/kg in 50% ethanol) was instilled into the colon of adult male SD rats to induce UC. A colonic damage score (CDS) was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion. RESULTS: Microinjection of glutamate (3, 6 and 12 µg) into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid (0.3 µg) was microinjected into PVN or into the nucleus tractus solitarius (NTS) that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V1 receptor antagonist DPVDAV (200 ng) was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. CONCLUSION: The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.
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Colite Ulcerativa/tratamento farmacológico , Ácido Glutâmico/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Masculino , Microinjeções/métodos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Acute necrotic collection (ANC), acute peripancreatic fluid collection (APFC), pleural effusion, and ascites are common early complications of acute pancreatitis. This study aimed to investigate the relationship between 12 serum cytokines and the early complications and severity of acute pancreatitis (AP). METHODS: We retrospectively analyzed the clinical data of 307 patients with AP, and divided them into severe group and mild-to-moderate group according to the revised Atlanta classification. Propensity score matching was used to control for confounding factors. Binary logistic regression analysis was used to explore the relationship between cytokine levels and early complications of AP. RESULTS: Serum levels of interleukin (IL)-1ß, IL-5, IL-6, IL-8, IL-10, IL-17, and tumor necrosis factor-α were significantly higher in the severe acute pancreatitis (SAP) group than in the non-SAP group (p < .05). After adjusting for confounding factors, the upper quartiles of IL-6, IL-8, and IL-10 were associated with an increased risk of ANC compared with those in the lowest quartile (IL-6: quartile 3, odds ratio [OR] = 3.99, 95% confidence interval [CI] = 1.95-8.16; IL-8: quartile 4, OR = 2.47, 95% CI = 1.27-4.84; IL-10: quartile 2, OR = 2.22, 95% CI = 1.09-4.56). APFC was associated with high serum levels of IL-6 (quartile 3, OR = 1.32, 95% CI = 1.02-1.72), pleural effusions were associated with high serum levels of IL-1ß, IL-6, IL-8, and IL-10 (IL-1ß: quartile 4, OR = 2.36, 95% CI = 1.21-4.58; IL-6: quartile 3, OR = 4.67, 95% CI = 2.27-9.61; IL-8: quartile 3, OR = 2.95, 95% CI = 1.51-5.79; IL-10: quartile 4, OR = 3.20, 95% CI = 1.61-6.36), and high serum levels of IL-6 and IL-10 were associated with an increased risk of ascites (IL-6: quartile 3, OR = 3.01, 95% CI = 1.42-6.37; IL-10: quartile 3, OR = 2.57, 95% CI = 1.23-5.37). CONCLUSION: Serum cytokine levels, including IL-1ß, IL-6, IL-8, and IL-10 may be associated with the occurrence of early complications of AP. In daily clinical practice, IL-6 may be the most worthwhile cytokine to be detected.
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Citocinas , Pancreatite , Humanos , Interleucina-10 , Doença Aguda , Ascite/etiologia , Interleucina-6 , Interleucina-8 , Estudos Retrospectivos , Pancreatite/complicações , Hospitais , Interleucina-1betaRESUMO
OBJECTIVES: No studies have evaluated the relationship between lifestyle and Pepsinogen (PG)I, PGII and Gastrin (G)17 in patients with anxiety. Using data from the Affiliated Hospital of Xuzhou Medical University study, we aimed to identify factors associated with anxiety. METHODS: We conducted a retrospective cross-sectional observational study involving 779 Chinese healthy checkup participants (301 males; mean age, 47.60±16.17 years) who underwent stomach-related health examinations. RESULTS: Anxiety was defined as a Hamilton Anxiety Scale (HAM-A) Scale score ≥14. The odds ratios, with 95% confidence intervals, were calculated using binary logistic analysis to assess the risk of anxiety and healthy checkup participants while adjusting for several covariates. In the HAM-A≥14 group (anxiety group), sex, PGII and pickled dishes were independent influencing factors. Binary logistic regression analysis revealed a significant difference in anxiety risk between the high PGII group and the low PGII group for females (P=0.005). There was also a significant difference in anxiety risk between the groups consuming pickled and non-pickled food for females (P=0.010). Logistic regression analysis indicated a higher risk of anxiety in females aged ≤50 years who belonged to the high PGII + no pickled foods group. CONCLUSIONS: Our study revealed that in females aged ≤50 years, high levels of PGII and no pickled foods were associated with a higher risk of anxiety.
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AIM: To investigate the effects of microinjection of the GABA(A) receptor agonist muscimol into cerebellar fastigial nucleus (FN) on stress-induced gastric mucosal damage and the underlying mechanism in rats. METHODS: Stress-induced gastric mucosal damage was induced in adult male SD rats by restraining and immersing them in cold water for 3 h. GABA(A) receptor agonist or antagonist was microinjected into the lateral FN. The decussation of superior cerebellar peduncle (DSCP) was electrically destroyed and the lateral hypothalamic area (LHA) was chemically ablated by microinjection of kainic acid. The pathological changes in the gastric mucosa were evaluated using TUNEL staining, immunohistochemistry staining and Western blotting. RESULTS: Microinjection of muscimol (1.25, 2.5, and 5.0 µg) into FN significantly exacerbated the stress-induced gastric mucosal damage in a dose-dependent manner, whereas microinjection of GABA(A) receptor antagonist bicuculline attenuated the damage. The intensifying effect of muscimol on gastric mucosal damage was abolished by electrical lesion of DSCP or chemical ablation of LHA performed 3 d before microinjection of muscimol. Microinjection of muscimol markedly increased the discharge frequency of the greater splanchnic nerve, significantly increased the gastric acid volume and acidity, and further reduced the gastric mucosal blood flow. In the gastric mucosa, further reduced proliferation cells, enhanced apoptosis, and decreased anti-oxidant levels were observed following microinjection of muscimol. CONCLUSION: Cerebellar FN participates in the regulation of stress-induced gastric mucosal damage, and cerebello-hypothalamic circuits contribute to the process.
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Núcleos Cerebelares/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Muscimol/farmacologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Núcleos Cerebelares/patologia , Agonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/farmacologia , Mucosa Gástrica/irrigação sanguínea , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiologia , Masculino , Microinjeções , Muscimol/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIMS: Toll-like receptor 4 (TLR4) contributes to ethanol-induced gastric mucosal injury. This study aimed to determine its precise role in this pathogenic state and the related signaling pathway. METHODS: Ethanol-induced gastric mucosal injury models were generated in TLR4(-/-) mice (C3H/HeJ: point mutation; C57BL/10ScNJ: gene deletion), their respective TLR4(+/+) wild-type counterparts, and heterozygous TLR4(+/-) mice. Lipopolysaccharide (LPS) or pyrrolidine dithiocarbamate (PDTC) was injected intraperitoneally 1 h or 30 min before ethanol administration. At 1 h post-ethanol treatment, gastric or serum specimens were evaluated. RESULTS: Ethanol intra-gastric administration induced significant gastric mucosal injury in all mice, but the damaged area was larger in TLR4(-/-) mice. LPS preconditioning and up-regulated TLR4 expression led to significantly larger areas of gastric mucosal damage. Upon ethanol administration, TLR4(+/+), and not TLR4(-/-), mice showed significant increases in TLR4, myeloid differentiation factor 88 (MyD88), cytoplasmic high mobility group box 1 (HMGB1), and nuclear factor-kappa B p65 (NF-κB p65). PDTC pretreatment significantly attenuated the ethanol-induced gastric mucosal damaged areas, inhibited nuclear NF-κB p65 expression, and suppressed HMGB1 translocation out of the nucleus. In addition, PDTC pretreatment reduced ethanol-stimulated expression of the inflammatory modulators, interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α), in serum. CONCLUSIONS: Both deficient and excessive expression of TLR4 promotes ethanol-induced gastric mucosal injury. The underlying mechanism involves the MyD88/NF-κB signaling pathway and the HMGB1, TLR4 activator ligand. The increased expression of HMGB1 may lead to increased secretion and binding to TLR4, further stimulating the TLR4/MyD88/NF-κB signaling pathway and aggravating the ethanol-induced gastric mucosal injury.
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Etanol/efeitos adversos , Mucosa Gástrica/lesões , Predisposição Genética para Doença/genética , Gastropatias/induzido quimicamente , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo , Animais , Citocinas/sangue , Modelos Animais de Doenças , Etanol/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Proteína HMGB1/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Mutação Puntual/genética , Transdução de Sinais/fisiologia , Gastropatias/genética , Gastropatias/metabolismo , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/metabolismoRESUMO
OBJECTIVE: To construct self-inactivating (SIN) lentiviral vector carrying human soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene and to observe the effects of sTRAIL gene on apoptosis in SGC-7901 cells, so as to assess the value of sTRAIL in gene therapy for gastric cancer. METHODS: The bicistronic SIN lentiviral transfer plasmid containing sTRAIL gene and internal ribosomal entry site-green fluorescent protein gene (IRES-GFP) was constructed. Recombinant lentivirus containing sTRAIL were packaged using liposome by lentiviral packing system. Several cell lines including HL-7702, HLF-1 and SGC-7901 cells were infected with the viral supernatant. Flow cytometry was used to measure apoptosis of cells and recombinant sTRAIL. protein was assayed by ELISA at 24 h after infection. RESULTS: The lentiviral transfer plasmid pXZ208-sTRAIL was constructed, and the virus titres were above 10(6) IU/mL in the supernatant. SGC-7901 cells were efficiently infected by recombinant virus. The apoptosis rate of SGC-7901 cells was increased with the virus multiplicity of infection (MOI) increasing. When the MOI was > or = 0.5, a dose-dependent apoptosis rate was observed. At MOI of 6.0, the highest apoptosis rate (29.12 +/- 2.87)% was observed, while the expression of sTRAIL in the supernatant was only (34.08 +/- 3.43) ng/mL. However, no significant apoptosis was observed in HL-7702 cells and HLF-1 cells. CONCLUSION: Recombinant lentivirus carrying human sTRAIL gene can efficiently infected SGC-7901 cells, which induced apoptosis in SGC-7901 cells in vitro by secreting bioactive sTRAIL protein. However, this effect is not seen in normal cells.
Assuntos
Apoptose/genética , Lentivirus/genética , Neoplasias Gástricas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/genética , Transfecção , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lentivirus/metabolismo , Neoplasias Gástricas/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/biossínteseRESUMO
BACKGROUND: Existing predictive models often focus solely on overall survival (OS), neglecting the bias that other causes of death might introduce into survival rate predictions. To date, there is no strict predictive model established for cancer-specific survival (CSS) in patients with intermediate and advanced colon cancer after receiving surgery and chemotherapy. METHODS: We extracted the data from the Surveillance, Epidemiology, and End Results (SEER) database on patients with stage-III and -IV colon cancer treated with surgery and chemotherapy between 2010 and 2015. The cancer-specific survival (CSS) was assessed using a competitive risk model, and the associated risk factors were identified via univariate and multivariate analyses. A nomogram predicting 1-, 3-, and 5-year CSS was constructed. The c-index, area under the curve (AUC), and calibration curve were adopted to assess the predictive performance of the model. Additionally, the model was externally validated. RESULTS: A total of 18 risk factors were identified by univariate and multivariate analyses for constructing the nomogram. The AUC values of the nomogram for the 1-, 3-, and 5-year CSS prediction were 0.831, 0.842, and 0.848 in the training set; 0.842, 0.853, and 0.849 in the internal validation set; and 0.815, 0.823, and 0.839 in the external validation set. The C-index were 0.826 (se: 0.001), 0.836 (se: 0.002) and 0.763 (se: 0.013), respectively. Moreover, the calibration curve showed great calibration. CONCLUSION: The model we have constructed is of great accuracy and reliability, and can help physicians develop treatment and follow-up strategies that are beneficial to the survival of the patients.
RESUMO
In recent years, the involvement of E3 ubiquitin ligase constitutive photomorphogenesis 1 (COP1) in the tumorigenesis of gastric cancer (GC) has been elucidated. However, the exact underlying mechanism remains to be clarified. In the present study, the expression profiles of COP1 in GC were derived from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, followed by verification via immunohistochemical staining (IHC), Western blotting (WB), and quantitative real-time polymerase chain reaction (qRT-PCR) reaction assays on clinical samples. In vitro, the gain- and loss-of-function experiments of COP1 protein were conducted to explore its role in GC cell lines HGC-27 and SGC-7901. Furthermore, we screened the interaction protein of COP1 by yeast two-hybrid experiment and verified their combination by co-immunoprecipitation (co-IP). We preliminary explored the possible underlying mechanisms of COP1 protein in GC cell lines via WB. COP1 was upregulated in GC tissues compared with the corresponding non-carcinoma tissues. In vitro, the upregulation of COP1 protein promoted the proliferation and migration of GC cells. The yeast two-hybrid experiment and co-IP indicated that Cadherin 18 (CDH18) could constitute a complex with COP1. Moreover, cells with COP1 over-expression showed low levels of CDH18 expression, with the intracellular PI3K/AKT pathway activated and the malignancy of GC cell lines enhanced. Our findings demonstrated that COP1 promoted the GC tumorigenesis by downregulated CDH18 with the involvement of PI3K/AKT signaling pathway in cell lines, suggesting the potential of COP1 as a prognostic biomarker and therapeutic target for GC.
Assuntos
Caderinas , Neoplasias Gástricas , Ubiquitina-Proteína Ligases , Humanos , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saccharomyces cerevisiae , Transdução de Sinais , Neoplasias Gástricas/patologia , Caderinas/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND: Target gastrointestinal cancers (GICs), encompassing esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC), originate within a single readily accessible luminal organ system and are diagnosable using endoscopy. However, endoscopy is an invasive procedure with low compliance and no plasma-based DNA methylation assay for the early detection of GICs. METHODS: Nine potential DNA methylation markers were identified and evaluated in tissue (n=60) and plasma (n=155) cohorts to select the most suitable markers. A training cohort (n=244) and a validation cohort (n=199), including GICs patients, benign tumors, gastrointestinal polyps, and controls, were enrolled to develop and validate a DNA methylation panel. An independent prospective cohort (n=158) was used to validate the panel's performance and compare it with blood protein tumor markers. RESULTS: Six out of nine candidate methylation markers with excellent discrimination abilities in both tissue and plasma cohorts were selected for the DNA methylation panel. The panel demonstrated high AUC values of 0.937 (EC), 0.968 (GC), and 0.987 (CRC) in training cohort, and achieved AUC values of 0.921 (EC), 0.921 (GC), and 0.959 (CRC) in validation cohort. Notably, it achieved impressive AUC values of 0.971 and 0.843 for identifying stage I GICs in the training and validation cohorts, respectively. In the prospective cohort, the six-marker panel showed comparable AUC values to CEA, AFP, and CA19-9 (0.935, 0.769, 0.663, and 0.668, respectively). CONCLUSION: This study successfully developed and validated a novel, robust, sensitive, and specific plasma-based DNA methylation panel, offering a promising strategy for the early detection of GICs.
Assuntos
Neoplasias Colorretais , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Metilação de DNA , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Estudos Prospectivos , Neoplasias Esofágicas/genética , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND AND AIMS: The effect of linked color imaging (LCI) compared with white light imaging (WLI) is conflicting. The aim of this meta-analysis is to compare the efficacy of LCI versus WLI for the adenoma detection. METHODS: PubMed, Embase, Google Scholar and Cochrane Library were searched up to the end of Aug 18, 2021. All randomized controlled trials (RCTs) comparing LCI with WLI were included. Dichotomous data were pooled to obtain the relative risk (RR) with a 95% confidence interval (CI), whereas continuous data were pooled using a mean difference (MD) with 95%CI. RESULTS: A total of 10 RCTs involving 5,510 patients were included. The use of LCI was associated with a statistically significant improvement in adenoma detection rate (ADR), polyp detection rate (PDR), mean adenomas per patient (MAP) and mean polyp per patient (MPP) when compared to WLI (ADR: RR=1.15, 95%CI: 1.07-1.23, p=0.0001, PDR: RR=1.15, 95%CI: 1.08-1.22, p<0.0001; MAP: MD=0.18, 95%CI: 0.09- 0.28, p=0.0002; MPP: MD=0.13, 95%CI: 0.01, 0.25, p=0.03). When stratified by size, LCI group had a higher detection rate of small adenomas (<10 mm) than the WLI group. Besides, LCI showed a significant decrease in adenoma miss rate (AMR) when compared to WLI. There were no statistically significant differences between the two groups in advanced ADR (AADR), sessile serrated lesion detection rate (SDR), cecal intubation rate, insertion time, and withdrawal time. CONCLUSIONS: The pooled evidence suggests that LCI can significantly improve the detection of ADR, especially for small adenomas (<10 mm). Moreover, the AMR were significantly lower using LCI compared with WLI.
Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Adenoma/diagnóstico por imagem , Adenoma/patologia , Ceco , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/patologia , Colonoscopia/métodos , Neoplasias Colorretais/patologia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Aim:Helicobacter pylori (Hp) infection has a connection with metabolic syndrome (MetS). Pepsinogen II (PGII) is a marker for gastric epithelial function. The present research was aimed at determining the associations among serum PGII levels, Hp infection and MetS in healthy subjects. Methods: This cross-sectional study enrolled 1242 healthy people, including 545 subjects with asymptomatic Hp infection and 697 subjects without Hp infection. Based on the number of MetS components present, subjects with Hp infection were assigned to the following groups: group 1, no component (126 subjects); group 2, one or two components (260 subjects); and group 3, three or more components (159 subjects). Physical measurements and biochemical indices were recorded. Serum PGII levels were recorded using ELISA. SPSS and GraphPad Prism were used for statistical analyses. Results: Among subjects with Hp infection, serum PGII was evidently downregulated in group 3 compared with group 1 (14.95 ± 8.24 vs 17.97 ± 9.08 µg/l; p = 0.015). Serum PGII levels were correlated with an increased risk of MetS (odds ratio: 0.867; 95% CI: 0.772-0.974; p = 0.016), as indicated by the multivariate logistic regression analysis. Grouping subjects with Hp infection according to quartiles of serum PGII levels identified an evident difference in MetS prevalence among the four quartile-based groups (p = 0.047). Conclusions: Among healthy subjects with asymptomatic Hp infection, serum PGII levels were lower in those with MetS than in those without MetS. Serum PGII levels showed an independent and negative correlation with the risk of MetS in healthy subjects with Hp infection.