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BACKGROUND: High-dose dual therapy (HDDT) is an emerging and promising therapeutic regime for Helicobacter pylori (H. pylori) eradication. However, the pharmacokinetics of the components of HDDT, amoxicillin and proton pump inhibitor, are likely to be affected by body size. In this study, we aimed to find out the impact of body size on the efficacy of HDDT. METHODS: We collected the medical data of 385 treatment-naive patients infected with H. pylori who received HDDT (esomeprazole 20 mg and amoxicillin 750 mg four times daily) for 14 days from July 2020 to December 2021. The associations among the eradication efficacy, adverse events, and variables (sex, age, height, body weight, body mass index (BMI), body surface area (BSA), smoking, drinking, etc.) were analyzed respectively in our study. Among these factors, continuous variables were classified into categorical variables using the cut-off values which were calculated by receiver operating characteristic analysis. RESULTS: The eradication rate of HDDT was 89.9%. There were 55 (14.3%) patients who occurred adverse events during the treatment. Patients with height <170.5 cm, body weight <60.5 kg, BMI <20.55 kg/m2 , BSA <1.69 m2 had a higher eradication rate (92.1% vs. 84.0%, 93.1% vs. 86.8%, 96.0% vs. 87.8%, 93.4% vs. 84.8%, all p < .05). The multivariate analysis showed that BSA ≥1.69 m2 (OR 2.53, 95% CI: 1.28-4.99, p = .007) was the only independent predictor of eradication failure. CONCLUSION: HDDT could achieve better eradication efficacy in patients with small BSA. Clinicians should be aware of the impact of BSA on the H. pylori eradication rate and pay more attention to patients with large BSA.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Quimioterapia Combinada , Amoxicilina/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Tamanho Corporal , Peso Corporal , Resultado do Tratamento , Claritromicina/uso terapêuticoRESUMO
Background: No study on the relationship between common abnormalities of the upper digestive tract and colorectal polyps (CPs) has been conducted. Methods: 33439 patients were enrolled in this cross-sectional study, of which 7700 had available Helicobacter pylori (H.pylori) information. All participants underwent colonoscopy and esophagogastroduodenoscopy (EGD) simultaneously or within six months at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2015 to November 2021. The study assessed whether the risk of CPs was affected by the following gastroesophageal diseases: atrophic gastritis (AG), gastric polyps, Barrett's esophagus and reflux esophagitis, bile reflux, gastric ulcer, gastric mucosal erosion, superficial gastritis, and gastric H.pylori infection. The crude and adjusted odds ratios (ORs) of H.pylori on the occurrence of CPs were computed by logistic regression. Additionally, we also evaluated whether AG had an impact on the relationship between H.pylori infection and CPs. Results: A total of 10600 cases (31.7%) were diagnosed as CPs. Multivariate logistic analysis showed that age, male (OR, 1.80; 95% confidence interval [CI], 1.61 to 2.02), gastric polyps (OR, 1.61; 95% CI, 1.05 to 2.46 for hyperplastic polyps; OR, 1.45; 95% CI, 1.09 to 1.94 for fundic gland polyps), H.pylori infection (OR, 1.21; 95% CI, 1.07 to 1.37) and atrophic gastritis (OR, 1.38; 95% CI, 1.21 to 1.56) were independent risk factors for colorectal polyps. Moreover, the combined effect of H.pylori infection and AG was slightly greater than the sum of their individual effects on the risk of CPs, but there was no additive interaction between them. Conclusions: Gastric conditions including gastric polyps, H.pylori infection, and AG increased the risk of CPs. However, Barrett's esophagus and reflux esophagitis, bile reflux, erosive gastritis, gastric ulcer, and superficial gastritis might not have relationship with CPs occurrence.
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Esôfago de Barrett , Refluxo Biliar , Pólipos do Colo , Esofagite Péptica , Gastrite Atrófica , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Úlcera Gástrica , Humanos , Masculino , Estudos Transversais , Esofagite Péptica/epidemiologia , Gastrite Atrófica/complicações , Gastrite Atrófica/epidemiologia , População do Leste Asiático , Gastrite/complicações , Gastrite/epidemiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/diagnósticoRESUMO
BACKGROUND: There is growing evidence that the internet has beneficial effects on the mental health of middle-aged and older people (≥45 years), but the evidence is inconclusive, and the underlying mechanisms are less known. OBJECTIVE: This study aims to explore the relationship between multidimensional (devices, frequency, and purpose) internet use and depression in middle-aged and elderly Chinese, as well as the mediating effect of social participation. Moreover, this study will explore the moderating effect of the regional informatization development level (RIDL) on the relationships between individual internet use, social participation, and depression. METHODS: Data on 17,676 participants aged 45 years or older were obtained from the China Health and Retirement Longitudinal Study (CHARLS) 2018 data set. The 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10) was used to identify the presence of depression. Logistic regression was used to explore the relationship between each dimension of internet use and depression. Multiple linear regression was used to explore the mediating effect of social participation and the moderating effect of the RIDL. RESULTS: The results showed that 28.33% (5008/17,676) of the total population had depression. In terms of regional subgroups, respondents living in the western region exhibited the highest proportion of depression (2041/5884, 34.69%). Internet use was negatively associated with depression (odds ratio 0.613, 95% CI 0.542-0.692; P<.001). Various dimensions of internet use positively contributed to individual social participation and reduced individual depression (devices: ß=-.170, 95% CI -0.209 to -0.127; frequency: ß=-.065, 95% CI -0.081 to -0.047; and purpose: ß=-.043, 95% CI -0.053 to -0.031). In addition, the RIDL weakened the relationship between individual-level internet use and social participation (internet use: F74.12,9.82=7.55, P<.001; devices: F51.65/9.88=5.23, P=.005; frequency: F66.74/10.08=6.62, P=.001; and purpose: F66.52/9.78=6.80, P=.001), and negatively moderated the relationship between the frequency of internet use and depression (frequency: F662.67/188.79=3.51, P=.03). CONCLUSIONS: This study found that different dimensions of internet use are associated with lower levels of depression. Social participation partially mediates the association between multidimensional internet use and depression in the eastern, central, and western regions, respectively. Additionally, the RIDL helps individuals further their internet use and social participation, reducing the impact of depression. However, this effect weakens sequentially from the western region to the central region and then to the eastern region.
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Depressão , Uso da Internet , Idoso , Pessoa de Meia-Idade , Humanos , Estudos Transversais , Depressão/epidemiologia , População do Leste Asiático , Estudos Longitudinais , Participação SocialRESUMO
Background: About 10% of gastric cancer (GC) has been described to be Epstein-Barr virus (EBV) positive. Previous researches have described the association between EBV and GC. However, the association of EBV with atrophic gastritis (AG) is underrecognized. Our study aimed to investigate the relationship between EBV and AG and assess the influence of EBV on gastric function. Methods: A total of 468 pathologically-confirmed chronic gastritis patients underwent circulating EBV DNA test, include 271 non-atrophic gastritis (NAG) and 197 AG patients. Results: In this study, H. pylori infection rate was 33.3%, EBV infection rate was 40%, and co-infection rate was 15%. The EBV DNA-positive was significantly associated with AG (P=0.031, OR= 1.509, 95% CI 1.037-2.194), especially in H. pylori-negative subjects (P=0.044, OR=1.619, 95% CI 1.012-2.589). EBV DNA-positive patients had a lower pepsinogen I (PG I) / pepsinogen II (PG II) ratio (PGR) than EBV DNA-negative patients (P=0.0026), especially in the AG subgroup (P=0.0062). There was no significant association between EBV and H. pylori co-infection with increased risk of AG (P>0.05). Conclusion: EBV infection significantly increased the risk of AG, especially in H. pylori-negative patients. The circulating EBV DNA had a potential in predicting the risk of atrophic gastritis.
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Coinfecção , Infecções por Vírus Epstein-Barr , Gastrite Atrófica , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Coinfecção/complicações , Coinfecção/epidemiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Gastrite Atrófica/complicações , Infecções por Helicobacter/complicações , Herpesvirus Humano 4/genética , Humanos , Pepsinogênio C , Neoplasias Gástricas/epidemiologiaRESUMO
Histidine-rich calcium binding protein (HRC) is markedly overexpressed in hepatocellular carcinoma (HCC) and is significantly correlated with metastasis. Anoikis resistance and endoplasmic reticulum (ER) stress may have a critical effect on survival before metastasis. However, the potential functions of HRC in anoikis resistance in HCC remain unknown. Here, we uncovered the clinical value of HRC and its functional significance on anoikis in HCC. The positive expression of HRC was observably correlated with tumor size, tumor encapsulation, and tumor-node-metastasis (TNM) stage. The expression of HRC increased in HCC cells cultured in suspension. HRC enhanced the anoikis resistance of HCC, and promoted the HCC metastasis in vivo. Mechanistically, the anoikis resistance was probably dependent on endoplasmic reticulum stress. Modulating HRC level changed the ERS to affect anoikis resistance by acting protein kinase RNA-like ER kinase (PERK)-eIF2a-ATF4-CHOP signaling axis. In conclusion, we define HRC as a novel candidate oncogene involved in anoikis resistance and HCC metastasis, and provide a new potential therapeutic target for HCC.
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Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator 4 Ativador da Transcrição/metabolismo , Adulto , Anoikis , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Progressão da Doença , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/metabolismoRESUMO
This study evaluates the impact of health information technology in accessing medical resources and identifies its role in improving health equity. We used 262, 771 records from the electronic medical records and outpatient appointment systems of three clinics for logistic regression to analyze the impact of information technology on patients' access to medical care. We interviewed a few health professionals to gauge their reactions and to validate and understand our quantitative results. The proportion of inpatients affected by information technology is low, accounting for only 16.7% (N = 43, 870). The difference between rural and urban groups is statistically significant, and rural households are more susceptible to information technology. In addition, distance has a significant positive effect. We demonstrate an inverted U-shaped relationship between severity of disease and the impact of information technology. Moreover, our interview results are consistent with our quantitative results. Quantitative and interview results suggest that health information technology plays a positive role in accessing medical care for patients with rural household and those in remote areas. Meanwhile, this effect is complex for patients with different severities of illnesses. Governments and managers should vigorously promote health information technology for healthcare delivery in the future and focus their attention on patients with serious diseases.
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Registros Eletrônicos de Saúde , Equidade em Saúde , Tecnologia da Informação , Adulto , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Alocação de RecursosRESUMO
Activation of the platelet-derived growth factor (PDGF)/PDGF beta receptor (PDGFßR) axis has a critical role in liver fibrosis. However, the mechanisms that regulate the PDGF signaling are yet to be elucidated. The present study demonstrates that paired related homeobox protein 1 (Prrx1) is involved in PDGF-dependent hepatic stellate cell (HSCs) migration via modulation of the expression of metalloproteinases MMP2 and MMP9. PDGF elevated the level of Prrx1 through the activation of ERK/Sp1 and PI3K/Akt/Ets1 pathways. In vivo, an adenoviral-mediated Prrx1 shRNA administration attenuated liver fibrosis in thioacetamide-induced fibrotic models. These studies reveal a role of Prrx1 as a modulator of PDGF-dependent signaling in HSCs, and inhibiting its expression may offer a therapeutic approach for hepatic fibrosis.
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Quimiotaxia/fisiologia , Células Estreladas do Fígado/metabolismo , Proteínas de Homeodomínio/metabolismo , Cirrose Hepática/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Linhagem Celular , Proteínas de Homeodomínio/genética , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Transdução de SinaisRESUMO
Patients with hepatocellular carcinoma (HCC) usually present at advanced stages and do not benefit from surgical resection, so drug therapy should deserve a prominent place in unresectable HCC treatment. But chemotherapy agents, such as doxorubicin, cisplatin, and paclitaxel, frequently encounter important problems such as low specificity and non-selective biodistribution. Recently, the development of nanotechnology led to significant breakthroughs to overcome these problems. Decorating the surfaces of nanoparticulate-based drug carriers with homing devices has demonstrated its potential in concentrating chemotherapy agents specifically to HCC cells. In this paper, we reviewed the current status of active targeting strategies for nanoparticulate systems based on various receptors such as asialoglycoprotein receptor, transferrin receptor, epidermal growth factor receptor, folate receptor, integrin, and CD44, which are abundantly expressed on the surfaces of hepatocytes or liver cancer cells. Furthermore, we pointed out their merits and defects and provided theoretical references for further research.
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Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Portadores de Fármacos/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Receptor de Asialoglicoproteína/antagonistas & inibidores , Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/metabolismo , Portadores de Fármacos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Técnicas de Transferência de Genes , Humanos , Neoplasias Hepáticas/metabolismo , Terapia de Alvo Molecular , Interferência de RNARESUMO
BACKGROUND/AIM: Metastasis contributes to the poor prognosis of hepatocellular carcinoma (HCC). However, the mechanism through which a primary HCC cell develops into a metastatic phenotype is not well understood. In this study, we set out to elucidate how blood vessel epicardial substance (BVES), a novel adhesion molecule regulating tight junction formation, mediates invasion and metastasis in human HCC cells. METHODS: qRT-PCR, western blot and IHC were used to detect the expression of BVES in HCC samples and HCC cell lines. Small interfering RNAs (siRNAs) against human BVES were synthesized and used to transfect Huh7 cells. Then, the interference efficiency and the expression of mesenchymal marker vimentin and epithelial marker E-cadherin were measured by qRT-PCR and western blot. F-actin cytoskeleton was detected using TRITC-conjugated phalloidin. After inhibition of BVES, wound healing experiment and transwell assay were used to analyze the migratory and invasive ability of Huh7 cells. RESULTS: BVES was down-regulated in human HCC tissues and HCC cell lines with high metastatic potential. After BVES inhibition, Huh7 cells exhibited some morphological changes including cytoskeleton rearrangement and junctional disruption. Cell migration and invasion were increased concomitant with increased expression of vimentin, IL-6, MMP2, MMP9 and decreased expression of E-cadherin. Finally, we found the expression of epithelial-mesenchymal transition (EMT) transcription factors Snail1 and Twist1 was significantly increased in BVES knockdown cells. CONCLUSIONS: Our results suggest that down-regulation of BVES in HCC induces EMT, thus promoting invasion and metastasis in HCC cells.
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Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Citoesqueleto de Actina/patologia , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas Musculares , Invasividade Neoplásica , Interferência de RNA , RNA Interferente PequenoRESUMO
BACKGROUND: Hypoxia is often found in solid tumors and is associated with tumor progression and poor clinical outcomes. We elucidated the mechanism by which netrin-1 released under hypoxic stress can induce epithelial-mesenchymal transition (EMT) to promote invasion in hepatocellular carcinoma (HCC) cells. METHODS: The expression of netrin-1 and the dependent receptors UNC5H and deleted in colorectal cancer (DCC) in HCC was examined by immunohistochemistry or western blot. The HepG2 cells were cultured in 21% O2 (normoxia) or 1% O2 (hypoxia) for 24 h. The release of netrin-1 from hypoxic cells was detected by ELISA. Expression of E-cadherin and vimentin were examined by western blot. Inverted microscopy or confocal microscopy was used to show the cell morphology or cytoskeletal rearrangements. Cell invasion induced by hypoxia was analyzed by Transwell chamber. Cytokine IL-8 and IL-10 mRNA levels were assessed by real-time PCR. RESULTS: The expression of netrin-1 was increased in HCC tissue and cell lines. The dependent receptors UNC5H and DCC were decreased in most HCC cell lines. Hypoxia induced netrin-1 release in a time-dependent manner. EMT induction was found to occur in hypoxic HCC cells in a process that was dependent on the extracellular release of netrin-1. Moreover, overexpression of netrin-1 resulted in EMT induction in normoxic tumor cells. Cytoskeletal rearrangements were found to occur and cell invasion was increased in cells with netrin-1 overexpression. Lastly, mRNA of IL-8 and IL-10 were also increased after recombinant human netrin-1 treatment. CONCLUSION: These results suggest that in hypoxic HCC cells, netrin-1 activates downstream signaling pathways to induce EMT activation with subsequent production of multiple inflammatory mediators which in turn promotes cancer invasion.
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Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Hepáticas/metabolismo , Invasividade Neoplásica/genética , Fatores de Crescimento Neural/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Fatores de Crescimento Neural/genética , Netrina-1 , Oxigênio , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Proteínas Supressoras de Tumor/genéticaRESUMO
Irritable bowel syndrome (IBS) is a chronic, recurrent disorder that is characterized by abdominal pain associated with defecation. IBS was previously considered to manifest without any structural alterations until the discovery of post-infection IBS. An increasing body of published evidence indicates that immune activation plays an important role in the development of IBS. Nevertheless, the pathophysiology of IBS, including mainly visceral hypersensitivity and gastrointestinal dysmotility, has not yet been explicitly elucidated. The observation of potential inflammatory degenerative neuropathy, including neuronal degeneration, spearheaded research on autoimmune responses targeting the enteric nervous system. Subsequently, several autoantibodies were detected in the sera of IBS patients, among which some were presumed to exert a pathogenic influence or be associated with the etiology of gastrointestinal dysmotility in IBS. Moreover, certain specific autoantibodies evidently served as biomarkers to facilitate the differentiation between IBS and other related diseases. Therefore, we aimed to present an overview of autoantibodies reported in the sera of IBS patients and highlight their significance in diagnosing and comprehending the pathophysiology of IBS. Consequently, we propose a therapeutic strategy from an autoimmune perspective.
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ETHNOPHARMACOLOGICAL RELEVANCE: Currently, the clinical treatment is limited and difficult to achieve satisfactory results for ulcerative colitis (UC). The role of traditional Chinese medicine (TCM) in the treatment of UC is very complex. Kuijie decoction (KJD) as a classic TCM, is widely used in the clinical treatment of UC, but the mechanism of its action is still unclear. AIM OF THE STUDY: This study is to investigate the protective effects of KJD on UC and the underlying mechanisms. MATERIALS AND METHODS: The experimental model of UC was induced by DSS, and KJD was introduced into the model at the same time. Clinical symptoms, including the body weight, colon length and colon histopathological, were used to measure the severity of colitis. The expression of inflammatory cytokines and tight junction proteins was quantified. The effect of KJD on intestinal flora and intestinal metabolism was determined by 16S rRNA and untargeted metabolomics analysis, respectively. The proportion of Th17 cells and Tregs in the spleen was examined by flow cytometry. RESULTS: Mice treated with KJD showed significantly alleviated clinical symptoms and histological damage, such as more body weight gain, lower disease activity index (DAI) score, and longer colon length. The administration of KJD also led to the down-regulation of inflammatory mediators, upregulation of the expression of ZO-1, occludin and decreased claudin-2, as well as altered microbiota composition against DSS challenges (especially an increase of Lachnospiraceae). KJD enhanced the percentage of Treg cells but decreased the proportion of Th17 cells to maintain intestinal homeostasis by improving gut microbiota metabolism. CONCLUSIONS: In summary, KJD maintained intestinal epithelial homeostasis by regulating epithelial barrier function, intestinal flora, and restoring Th17/Treg balance. KJD has the potential to be a Chinese medicine treatment for UC.
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Colite Ulcerativa , Microbioma Gastrointestinal , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , RNA Ribossômico 16S , Linfócitos T Reguladores , Células Th17 , Peso Corporal , Medicina Tradicional Chinesa , Redes e Vias MetabólicasRESUMO
OBJECTIVE: This meta-analysis aimed to comprehensively explore the risk factors for inadequate bowel preparation (IBP). METHODS: We searched the Embase, PubMed, Web of Science, and The Cochrane Library databases up to August 24, 2023, to identify observational studies and randomized controlled trials (RCTs) that examined risk factors for IBP. A random effects model was used to pool the adjusted odds ratios and 95% confidence intervals. RESULTS: A total of 125 studies (91 observational studies, 34 RCTs) were included. Meta-analyses of observational studies revealed that three preparation-related factors, namely, characteristics of last stool (solid or brown liquid), incomplete preparation intake, and incorrect diet restriction, were strong predictors of IBP. The other factors were moderately correlated with IBP incidence, including demographic variables (age, body mass index, male sex, Medicaid insurance, and current smoking), comorbidities (diabetes, liver cirrhosis, psychiatric disease, Parkinson's disease, previous IBP, poor mobility, inpatient, and Bristol stool form 1/2), medications (tricyclic antidepressants, opioids, antidepressants, narcotics, antipsychotics, and calcium channel blockers), and preparation-related factors (preparation-to-colonoscopy interval not within 3 to 5/6 h, nonsplit preparation, and preparation instructions not followed). No colonoscopy indications were found to be related to IBP. Meta-analyses of RCTs showed that education, constipation, stroke/dementia, and discomfort during preparation were also moderately associated with IBP. Most of the other findings were consistent with the pooled results of observational studies. However, primarily due to imprecision and inconsistency, the certainty of evidence for most factors was very low to moderate. CONCLUSIONS: We summarized five categories of risk factors for IBP. Compared to demographic variables, comorbidities, medications, and colonoscopy indications, preparation-related elements were more strongly associated with IBP. These findings may help clinicians identify high-risk individuals and provide guidance for IBP prevention.
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Catárticos , Colonoscopia , Humanos , Fatores de Risco , Colonoscopia/métodos , Catárticos/administração & dosagemRESUMO
Background: Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism. Methods: MyD88 knockout (MyD88-/-) mice and the MyD88 inhibitor (TJ-M2010-5) were used to investigate the impact of MyD88 on acute dextran sodium sulfate (DSS)-induced colitis. Disease activity index, colon length, histological score, and inflammatory cytokines were examined to evaluate the severity of colitis. RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism. Results: In an acute DSS-colitis model, the severity of colitis was not alleviated in MyD88-/- mice and TJ-M2010-5-treated mice, despite significantly lower levels of NF-κB activation being exhibited compared to control mice. Meanwhile, 16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the nucleotide oligomerization domain-like receptors (NLRs) signaling pathway in colitis mice following MyD88 suppression. Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ-M2010-5 ameliorated the disease severity, which was not improved solely by MyD88 inhibition. After treatment with broad-spectrum antibiotics, downregulation of the NLR signaling pathway was observed. Conclusion: Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota, leading to NLR-mediated immune activation and intestinal inflammation.
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BACKGROUND: N6-methyladenosine (m6A) methylation modification exists in Epstein-Barr virus (EBV) primary infection, latency, and lytic reactivation. It also modifies EBV latent genes and lytic genes. EBV-associated gastric cancer (EBVaGC) is a distinctive molecular subtype of GC. We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC. AIM: To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC. METHODS: First, The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC (EBVnGC). Second, we identified Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of m6A-related differentially expressed genes. We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment (TME). Finally, cell counting kit-8 cell proliferation test, transwell test, and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1 (IGFBP1) in EBVaGC cell lines. RESULTS: m6A methylation regulators were involved in the occurrence and development of EBVaGC. Compared with EBVnGC, the expression levels of m6A methylation regulators Wilms tumor 1-associated protein, RNA binding motif protein 15B, CBL proto-oncogene like 1, leucine rich pentatricopeptide repeat containing, heterogeneous nuclear ribonucleoprotein A2B1, IGFBP1, and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC (P < 0.05). The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher (P = 0.046). GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC. Compared with EBVnGC, the infiltration of activated CD4+ T cells, activated CD8+ T cells, monocytes, activated dendritic cells, and plasmacytoid dendritic cells were significantly upregulated in EBVaGC (P < 0.001). In EBVaGC, the expression level of proinflammatory factors interleukin (IL)-17, IL-21, and interferon-γ and immunosuppressive factor IL-10 were significantly increased (P < 0.05). In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line (SNU719) than in an EBVnGC cell line (AGS) (P < 0.05). IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719. Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS. CONCLUSION: m6A regulators could remodel the TME of EBVaGC, which is classified as an immune-inflamed phenotype and referred to as a "hot" tumor. Among these regulators, we demonstrated that IGFBP1 affected proliferation, migration, and apoptosis.
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KIAA1199, a major glycosaminoglycan component of the extracellular matrix, was reported to induce a fibrosis-like process. However, the relationship between KIAA1199 and liver fibrosis remains unclear. The liver fibrosis mouse model was established with carbon tetrachloride (CCl4). Here, we found that KIAA1199 was upregulated in CCl4-induced liver fibrosis. The expression of KIAA1199 was also increased in TGF-ß-stimulated LX-2 cells. To clarify the impact of KIAA1199 in hepatic stellate cells (HSCs), we downregulated the expression of KIAA1199 in LX-2 cells by RNA interference. Cell proliferation, apoptosis, and migration were determined by CCK-8, flow cytometry, and transwell assay. We found that KIAA1199 knockdown reduced the expression of fibrosis markers α-SMA and COL1A1. Depletion of KIAA1199 inhibited cell proliferation by downregulating cyclin B1 and cyclin D1 and promoted cell apoptosis by upregulating Bax and downregulating Bcl-2. Moreover, KIAA1199 knockdown decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression to inhibit the migration ability of LX-2 cells. Silencing KIAA1199 also suppressed the epithelial-mesenchymal transition phenomenon. Collectively, our study revealed that KIAA1199 knockdown alleviated the activation, proliferation, and migration of HSCs, while promoting apoptosis of HSCs, which suggests that KIAA1199 may be a potential regulator of liver fibrosis.
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Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and has an increasing incidence worldwide. The management of HCC still has many restrictions, despite the fact that there are now numerous treatment options, including liver transplantation/resection, locoregional treatments (LRT), and systemic medication. As a turning point in the history of cancer treatment, the discovery of the immune checkpoints and the development of their inhibitors provide new hope for HCC patients. However, limited objective response rate and insignificant overall survival improvement are still urgent problems to be solved for immune checkpoint inhibitors (ICIs). Combination therapies are considered a solution for improving the effectiveness and response rate of ICIs, and several forms of combination treatments are currently being actively researched. In this review, we summarize the mainstream combination strategies, explain their theoretical basis, introduce several important and ongoing clinical trials, and suggest some potential future paths in this area at the conclusion of the review. AVAILABILITY OF DATA AND MATERIALS: Not applicable.
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Background: Contradictory evidence suggested gastric xanthelasma (GX) was associated with some upper gastrointestinal (GI) diseases. Additionally, no research has been performed on the relationship between esophageal/duodenal xanthelasma and upper GI diseases. Methods: Individuals who underwent esophagogastroduodenoscopy at Tongji Hospital, Tongji Medical College, participated in this retrospective study. This study evaluated whether the risk of GX or esophageal/duodenal xanthelasma was influenced by the following gastroesophageal diseases: superficial gastritis, gastric polyp, bile reflux, peptic ulcer, reflux esophagitis, Barrett's esophagus, esophageal cancer, atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia, gastric cancer, and Helicobacter pylori (H. pylori) infection. Furthermore, subgroup analysis was conducted to establish the relationship between the number of GX and upper GI diseases. Results: Of the 69,071 subjects reviewed, 1,220 (1.77%) had GX, and 54 (0.08%) had esophageal/duodenal xanthelasma. There was no difference in the prevalence of upper GI diseases between patients with and without esophageal/duodenal xanthelasma. Nevertheless, compared with non-xanthelasma patients, GX patients had a greater proportion of AG, IM, dysplasia, gastric cancer, and H. pylori infection and a lower incidence of superficial gastritis (p < 0.05). The multivariate logistic regression analysis indicated AG (OR = 1.83, 95%CI: 1.56-2.16), IM (OR = 2.42, 95%CI: 2.41-2.85), and H. pylori infection (OR = 1.32, 95%CI: 1.17-1.50) were independent risk factors for GX. In addition, patients with multiple GXs had a higher rate of AG and IM than those with single GX. Conclusion: Esophageal/duodenal xanthelasma may not be associated with upper GI diseases, and further research is needed to support this hypothesis. Notably, GX, especially multiple GXs, may be a more easily detected warning sign of AG, IM, or H. pylori infection.
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BACKGROUND: Chronic liver injury contributes to liver fibrosis, which is characterized by the excessive deposition of extracellular matrix (ECM) components. ECM is mainly composed of myofibroblasts. Recently, macrophage-to-myofibroblasts transition (MMT), has been identified as a novel origin for myofibroblasts. However, the potential functions of MMT in chronic liver injury and liver fibrosis remain unknown. METHODS: To clarify the transformation of fibrotic cells in hepatic fibrosis, liver specimens were collected from people at different stages in the progression of hepatic fibrosis and stained with immunofluorescence. Models of hepatic fibrosis such as the CCL4 model, HFD-induced NAFLD model, MCD-induced NAFLD model and ethanol-induced AFLD model were demonstrated and were stained with immunofluorescence. RESULTS: Here, we uncovered macrophages underwent MMT in clinical liver fibrosis tissue samples and multiple animal models of chronic liver injury. MMT cells were found in specimens from patients with liver fibrosis on the basis of co-expression of macrophage (CD68) and myofibroblast (a-SMA) markers. Moreover, macrophages could transform into myofibroblasts in CCL4-induced liver fibrosis model, high-fat diet (HFD) and methionine-choline-deficient diet (MCD)-induced nonalcoholic fatty liver diseases (NAFLD) model, and ethanol-induced alcoholic fatty liver diseases (AFLD) model. In addition, we highlighted that MMT cells mainly had a predominant M2 phenotype in both human and experimental chronic liver injury. CONCLUSIONS: Taken together, MMT acts a crucial role in chronic liver injury and liver fibrosis.
Assuntos
Miofibroblastos , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Miofibroblastos/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Macrófagos , Fígado/patologia , Cirrose Hepática/patologia , Fibrose , Etanol , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: Gastric precancerous conditions such as atrophic gastritis (AG) and intestinal metaplasia (IM) are considered independent risk factors for gastric cancer (GC). The suitable endoscopic monitoring interval is unclear when we attempt to prevent GC development. This study investigated the appropriate monitoring interval for AG/IM patients. METHODS: Totally, 957 AG/IM patients who satisfied the criteria for evaluation between 2010 and 2020 were included in the study. Univariate and multivariate analyses were used to determine the risk factors for progression to high-grade intraepithelial neoplasia (HGIN)/GC in AG/IM patients, and to determine an appropriate endoscopic monitoring scheme. RESULTS: During follow-up, 28 AG/IM patients developed gastric neoplasia lesions including gastric low-grade intraepithelial neoplasia (LGIN) (0.7%), HGIN (0.9%), and GC (1.3%). Multivariate analysis identified H. pylori infection (P=0.022) and extensive AG/IM lesions (P=0.002) as risk factors for HGIN/GC progression (P=0.025). CONCLUSION: In our study, HGIN/GC was present in 2.2% of AG/IM patients. In AG/IM patients with extensive lesions, a 1-2-year surveillance interval is recommended for early detection of HIGN/GC in AG/IM patients with extensive lesions.