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BACKGROUND: Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS: Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS: In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).
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Angiodisplasia , Hemorragia Gastrointestinal , Fármacos Hematológicos , Enteropatias , Intestino Delgado , Talidomida , Humanos , Angiodisplasia/complicações , Angiodisplasia/tratamento farmacológico , China , Método Duplo-Cego , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/etiologia , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do Tratamento , Enteropatias/complicações , Enteropatias/tratamento farmacológico , Recidiva , Intestino Delgado/irrigação sanguínea , Administração Oral , Fármacos Hematológicos/administração & dosagem , Fármacos Hematológicos/efeitos adversos , Fármacos Hematológicos/uso terapêuticoRESUMO
Chronic obstructive pulmonary disease (COPD) induces serious social and economic burdens due to its high disability and mortality, the pathogenesis of which is highly involved with inflammation, oxidative stress (OS), and mechanism of mucin 5AC (MUC5AC) secretion. Lixisenatide is a selective glucagon-like peptide 1 receptor agonist recently reported to have anti-inflammatory properties. Our study will focus on the potential impact of lixisenatide on lipopolysaccharide (LPS)-induced mucin secretion and inflammation in 16 human bronchial epithelial (16HBE) cells to check its potential function in COPD. 16HBE cells were treated with LPS, with or without lixisenatide (10 and 20 nM) for 1 day. Remarkably declined cell viability, enhanced lactate dehydrogenase release, activated OS, and elevated release of inflammatory cytokines were observed in LPS-treated 16HBE cells, accompanied by the activation of nuclear factor-κB signaling, all of which were signally reversed by lixisenatide. Moreover, elevated expression and release of MUC5AC were observed in LPS-treated 16HBE cells but were markedly repressed by lixisenatide. Furthermore, the repressed nuclear factor erythroid 2-related factor 2 (Nrf2) level in LPS-treated 16HBE cells was notably rescued by lixisenatide. Lastly, following the knockdown of Nrf2, the protective function of lixisenatide on LPS-triggered MUC5AC release in 16HBE cells was significantly abrogated. Collectively, lixisenatide ameliorated LPS-induced expression of mucin and inflammation in bronchial epithelial cells by regulating Nrf2.
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Receptor do Peptídeo Semelhante ao Glucagon 2 , Mucinas , Peptídeos , Doença Pulmonar Obstrutiva Crônica , Humanos , Mucinas/metabolismo , Lipopolissacarídeos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Células Epiteliais/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismoRESUMO
BACKGROUND: To evaluate the long-term efficacy of single-balloon enteroscopy endoscopic retrograde cholangiography (SBE-ERC) for the treatment of biliary obstruction and to analyze the factors affecting the recurrence of benign bilioenteric anastomotic stricture after SBE-ERC treatment. METHODS: The clinical data of patients with biliary diseases treated with SBE-ERC after choledochojejunostomy in our hospital from January 2015 to December 2021 were analyzed retrospectively for the success rates of diagnosis and treatment and the incidence of complications. Patients who were diagnosed with benign bilioenteric anastomotic stricture were followed up. The independent factors affecting recurrence were obtained by univariate and multivariate analyses using the KaplanâMeier method and Cox proportional hazard regression model. RESULTS: A total of 289 SBE-ERCs were performed in 165 patients. The overall success rate was 83.0% (240/289). The incidence of postoperative complications was 5.2% (15/289). The 108 successfully treated patients diagnosed with benign bilioenteric anastomotic stricture were followed up. Twenty-six percent (29/108) of patients had recurrent stricture after SBE-ERC. The biliary patency rates at 1 year, 2 years and 5 years after SBE-ERC were 90.1%, 69.3%, and 53.9%, respectively. Single-factor analysis revealed the absence of intrahepatic biliary gas imaging during endoscopy ( χ 2 =5.366, P = 0.021), a diameter of balloon dilatation during the last endoscopic treatment less than 0.8 cm ( χ 2 =4.552, P = 0.033), and the presence of a thread in the anastomosis ( χ 2 =8.921, P = 0.003) as risk factors for recurrence. A non-indwelling biliary plastic stent ( χ 2 =14.868, P < 0.001) and undergoing only one ERCP treatment ( χ 2 =13.313, P = 0.001) were risk factors for the recurrence of benign stricture after SBE-ERC resection. Multivariate analysis revealed that the absence of a stent (HR = 0.15, 95% CI 0.06-0.40, P = 0.001), absence of intrahepatic biliary gas imaging during endoscopy (HR = 0.39, 95% CI 0.17-0.91, P = 0.03) and the presence of a thread in the anastomosis (HR = 3.69, 95% CI 1.59-8.57, P = 0.002) were independent risk factors for stricture recurrence. CONCLUSIONS: Treating biliary disease after choledochojejunostomy with SBE-ERC is safe and effective, with a good immediate technical success rate and an acceptable incidence of complications. SBE-ERC has long-term efficacy in the treatment of benign bilioenteric anastomotic stricture. The absence of intrahepatic biliary gas imaging during endoscopy, non-indwelling biliary stents and the existence of anastomotic threads are independent risk factors for the recurrence of benign bilioenteric anastomotic stricture.
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BACKGROUND AND AIMS: Many studies of gastric gastrointestinal stromal tumors (g-GISTs) following endoscopic resection (ER) have typically focused on tumor size, with most tumors at low risk of aggressiveness after risk stratification. There have been few systematic studies on the oncologic outcomes of intermediate- or high-risk g-GISTs after ER. METHODS: From January 2014 to January 2020, we retrospectively collected patients considered at intermediate- or high-risk of g-GISTs according to the modified NIH consensus classification system. The primary outcome was overall survival (OS). RESULTS: Six hundred and seventy nine (679) consecutive patients were diagnosed with g-GISTs and treated by ER between January 2014 and January 2020 in three hospitals in Shanghai, China. 43 patients (20 males and 23 females) were confirmed at intermediate-or high-risk. The mean size of tumors was 2.23 ± 1.01 cm. The median follow-up period was 62.02 ± 15.34 months, with a range of 28 to 105 months. There were no recurrences or metastases, even among patients having R1 resections. The 5-year OS rate was 97.4% (42/43). CONCLUSION: ER for intermediate- or high-risk gastric small GISTs is a feasible and safe method, which allows for a wait-and-see approach before determining the necessity for imatinib adjuvant or surgical treatment. This approach to g-GISTs does require that patients undergo close follow-up.
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Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Idoso , Adulto , Resultado do Tratamento , Gastroscopia/métodos , Taxa de Sobrevida , China/epidemiologia , Idoso de 80 Anos ou mais , Medição de Risco , Gastrectomia/métodosRESUMO
Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.
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Carcinoma Ductal Pancreático , Fluoruracila , Imunoterapia , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Animais , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Camundongos , Humanos , Imunoterapia/métodos , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Lipossomos/química , Cinurenina/metabolismo , Interferon gama/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêuticoRESUMO
PURPOSE: Chronic gastritis is observed in almost half world population. Traditional medications against chronic gastritis might produce adverse effects, so alternative nutritional strategies are needed to prevent the aggravation of gastric mucosal damage. The aim of this study is to evaluate the protective effect of the combination of wheat peptides and fucoidan (WPF) on adults diagnosed with chronic superficial gastritis in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Participants were randomized to receive WPF (N = 53) or placebo (N = 53) once daily for 45 days. Pathological grading of gastric mucosal damage was scored using gastroscopy. Fecal samples were collected for the determination of calprotectin, short chain fatty acids (SCFA) levels and metagenomics analysis. Questionnaires for self-reported gastrointestinal discomforts, life quality and food frequency were collected throughout the study. RESULTS: WPF intervention reduced gastric mucosal damage in 70% subjects (P < 0.001). Significantly less stomach pain (P < 0.001), belching (P = 0.028), bloating (P < 0.001), acid reflux (P < 0.001), loss of appetite (P = 0.021), increased food intake (P = 0.020), and promoted life quality (P = 0.014) were reported in the WPF group. WPF intervention significantly decreased fecal calprotectin level (P = 0.003) while slightly increased fecal SCFAs level (P = 0.092). In addition, we found altered microbiota composition post-intervention with increased Bifidobacterium pseudocatenulatum (P = 0.032), Eubacterium siraeum (P = 0.036), Bacteroides intestinalis (P = 0.024) and decreased Prevotella copri (P = 0.055). CONCLUSIONS: WPF intervention could be utilized as a nutritional alternative to mitigate the progression of chronic gastritis. Furthermore, WPF played an important role in altering gut microbial profile and SCFA production, which might benefit the lower gastrointestinal tract.
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Antiulcerosos/farmacologia , Gastrite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Peptídeos/farmacologia , Polissacarídeos/farmacologia , Triticum , Adulto , China , Doença Crônica , Método Duplo-Cego , Fezes/microbiologia , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Endothelial cells have been shown to be in response to a variety of local and systemic stimuli, and are able to transition between quiescent and activated states. Endothelial cell activation is critical for the pathogenesis of various cardiovascular diseases. However, the expression changes of long non-coding RNAs (lncRNAs) are still unknown in the process of endothelial cell activation. Thus, this study was aimed to investigate expression changes of lncRNA before and after endothelial cell activation. MATERIALS AND METHODS: In an experimental model of peripheral venous congestion, endothelial cells were activated and analyzed with Affymetrix HG-U133 plus2.0 microarray. We analyzed these microarray data and reannotated the microarray probes for lncRNA. RESULTS: According to the definition of absolute fold change>2 and p value <0.05, 27 differentially expressed lncRNAs were identified and only 1 lncRNA transcript, ENST00000509256 was down-regualted. Co-expression network of lncRNA and mRNA were constructed to predict function of the dysregulated lncRNA. Gene set enrichment analyses suggested that these ENST00000509256 was associated with many important functions, such as cell-cell signaling and regulation of cell differentiation. CONCLUSION: Many lncRNAs are dysregulated upon endothelial cell activation and further experiments are needed to identify the potential biological functions of these lncRNAs.
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Células Endoteliais/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/metabolismo , Células Cultivadas , Bases de Dados Factuais , Células Endoteliais/citologia , Redes Reguladoras de Genes , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , TranscriptomaRESUMO
BACKGROUND/AIMS: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms. METHODS: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis. RESULTS: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models. CONCLUSION: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer.
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Antígenos de Superfície/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Interferência de RNA , Terapêutica com RNAi , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Intraosseous epithelioid hemangioma (EH) is a rare intermediate vascular neoplasm, characterized by locally aggressive and rarely metastasizing behavior. Occasionally, EH of bone can behave strangely and may simulate malignant neoplasm. Here, we report two cases of EH of bone. Of interest was the fact that the computed tomography and magnetic resonance images from one case showed an osteolytic lesion in the right scapula, with multiple swollen lymph nodes in the right supraclavicular and axillary areas. Another patient exhibited a local recurrence in the cervical vertebrae. The initial radiological diagnosis of both cases was metastatic tumor. EH should be included in the differential diagnosis of a radiographic osteolytic lesion with an aggressive appearance. Also, we reviewed the literature that reported EH of bone and summarized their radiological appearances. The cases of EH of bone that exhibited involvement of regional or draining lymph nodes were also summarized.
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Hemangioendotelioma Epitelioide/diagnóstico por imagem , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , RadiografiaRESUMO
BACKGROUND & AIMS: Controlled attenuation parameter (CAP) is a non-invasive method for evaluating hepatic steatosis. However, larger skin capsular distance (SCD) can affect the accuracy. The aim of this study was to investigate the impact of SCD on the diagnostic performance of CAP and liver stiffness measurement (LSM). METHODS: Of 101 patients with non-alcoholic fatty liver disease (NAFLD) and 280 patients with chronic hepatitis B (CHB) who underwent liver biopsy were prospectively recruited. CAP, LSM and SCD were performed using FibroScan with M probe. The areas under receiver operating characteristics curves (AUROCs) were calculated to determine the diagnostic efficacy. The optimal thresholds were defined by the maximum Youden index. RESULTS: SCD (B 30.34, P < 0.001) and hepatic steatosis (B 23.04, P < 0.001) were independently associated with CAP by multivariate analysis. The AUROCs were slightly higher for SCD <25 mm compared to those for SCD ≥25 mm for steatosis ≥5% (0.88 vs. 0.81), >33% (0.90 vs. 0.85) and >66% (0.84 vs. 0.72). For SCD <25 mm, the optimal CAP cut-offs for differentiating steatosis ≥5%, >33% and >66% were 255.0 dB/m, 283.5 dB/m and 293.5 dB/m. However, cut-offs were elevated by approximately 60-70 dB/m for SCD ≥25 mm. When stratified by fibrosis grade, LSM was significantly affected by SCD ≥25 mm for advanced fibrosis (≥F3) in NAFLD, but not in CHB. CONCLUSION: CAP is a promising tool for detecting and quantifying hepatic steatosis. SCD ≥25 mm may cause overestimation of steatosis. Similarly, SCD ≥25 mm affects the detection of advanced fibrosis by LSM in NAFLD patients.
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Técnicas de Imagem por Elasticidade/métodos , Hepatite B Crônica/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Pele/patologia , Adulto , Área Sob a Curva , Biópsia , Índice de Massa Corporal , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Curva ROC , Índice de Gravidade de DoençaRESUMO
PURPOSE: To evaluate the diagnostic values of autofluorescence imaging (AFI) combined with narrow band imaging (NBI) in diagnosing early gastric cancer and precancerous lesions. METHODS: 140 patients were investigated for lesions such as gastric mucosal roughness, erosion, plaque, abnormal color, bump or pitting by conventional endoscopy. AFI endoscope was used for the observation, and the endoscopic diagnosis was performed according to the fluorescence forms under the endoscopic AFI mode, as well as the changes of gastric mucosal capillaries and gastric pits under the NBI mode. The corresponding lesions were also biopsied for pathological examination. RESULTS: 78 patients were diagnosed as gastritis (including superficial and atrophic gastritis), 45 as intestinal metaplasia, 6 as dysplasia, and 11 as early gastric cancer. The sensitivity and specificity of AFI-NBI combination were 88.89 and 91.58% in the diagnosis of intestinal metaplasia; 83.33 and 98.51% for dysplasia; and 90.91 and 99.22% for early gastric cancer. All of them were significantly higher than the simple fluorescence endoscopy. CONCLUSIONS: The AFI-NBI combination could improve the detection rate of early gastric cancer and precancerous lesions.
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Imagem de Banda Estreita/métodos , Imagem Óptica/métodos , Lesões Pré-Cancerosas/diagnóstico , Neoplasias Gástricas/diagnóstico , Idoso , Feminino , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologiaRESUMO
PURPOSE: To evaluate the diagnostic values of Auto Fluorescence Imaging (AFI) combined with Narrow Band Imaging (NBI) in the diagnosis of the intraepithelial neoplasia of Barrett's esophagus (BE). METHODS: Seventy four suspicious BE intraepithelial lesions were assessed in 50 patients by AFI, who were further subjected to NBI mode to observe the changes of gastric mucosal capillaries and gastric pits. The corresponding lesions were biopsied for pathological examination. RESULTS: Among the 74 AFI-diagnosed cases of suspicious lesions, 44 (59.5%) were high-grade intraepithelial neoplasias (BEHGIN), while the remaining 30 cases (40.5%) were false-positive. The NBI-diagnostic results of these 44 BEHGIN lesions were as follows: 39 cases were confirmed and 5 were suspicious; among the 30 false-positive BEHGIN cases, NBI gave 7 false-positive cases. The false-positive rates decreased from 40.5% of AFI to 9.5% (7/74) of NBI-AFI (p<0.05). The positive predictive value of AFI in BEHGIN was 59.5% (44/74), while that of AFI-NBI combination was 84.8% (39/46; p<0.05). CONCLUSIONS: The AFI-NBI combination technology could significantly improve (p<0.05) the detection rate of BEHGIN.
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Esôfago de Barrett/complicações , Carcinoma in Situ/diagnóstico , Neoplasias Esofágicas/diagnóstico , Imagem de Banda Estreita/métodos , Adulto , Idoso , Reações Falso-Positivas , Feminino , Fluorescência , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: It has recently been reported that thymosin beta-4 (Tß4) has anti-fibrogenic effects in human hepatic stellate cells (HSCs) in vitro, but the mechanisms underlying these effects remain unclear. The aim of this study was to investigate the roles of Tß4 in the proliferation, migration, and activation of HSCs. METHODS: Enzyme-linked immunosorbent assays (ELISA), immunohistochemistry, and western blot assays were utilized to determine the expression levels of Tß4 in serum, liver tissues, and LX-2 cells. Tß4 was depleted in LX-2 cells using small interfering RNAs (siRNAs). Cell proliferation was analyzed using cell counting kit-8 (CCK-8) viability assays, and cell migration was investigated using wound-healing and transwell migration assays. RESULTS: The expression of Tß4 was significantly reduced during the progression of liver fibrosis. The depletion of Tß4 significantly promoted the proliferation and migration of LX-2 cells via the activation of the PI3K/Akt signaling pathway. The pro-migratory and pro-proliferative effects of Tß4 depletion in LX-2 cells can be counteracted by treatment with the Akt inhibitor MK-2206. In addition, Tß4 depletion was also associated with the activation of HSCs via the enhanced expression of α-smooth muscle actin (α-SMA) and vimentin. CONCLUSIONS: Our results suggest that Tß4 participates in liver fibrosis by inhibiting the migration, proliferation, and activation of HSCs and that Tß4 may be an effective target in the treatment of liver fibrosis.
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Movimento Celular/fisiologia , Proliferação de Células , Células Estreladas do Fígado/citologia , Timosina/fisiologia , Actinas/metabolismo , Animais , Linhagem Celular , Progressão da Doença , Humanos , Cirrose Hepática/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Timosina/genética , Vimentina/metabolismoRESUMO
OBJECTIVE: To evaluate the controlled attenuation parameter (CAP) assessment of fatty liver and choose a cut-off value of hepatic steatosis more than 5%. METHODS: Consecutive patients, 18 years or older, who had undergone percutaneous liver biopsy and CAP measurement were recruited from five liver healthcare centers in China. All enrollees were categorized as hepatic steatosis grade S0 (<5%) or S1 (5%). An M-probe equipped FibroScan 502 was used to capture CAP values. Receiver operating characteristic (ROC) curves were plotted, and the areas under (AU) the curves were calculated to determine the diagnostic efficacy. The CAP cut-off values at the optimal thresholds were defined by maximum Youden indices; sensitivity and specificity were also calculated. RESULTS: A total of 332 patients were enrolled in the study, including 67 patients with non-alcoholic fatty liver disease (NAFLD) and 265 with chronic hepatitis B (CHB) viru: infection. The median age (inter quartile range, IQR) of the study cohort was 39.0 (32.0-50.5) years-old. There were 46 males (68.7%) in the NAFLD group, with a median age of 37.0 (28.0-45.0) years-old, and 182 males (68.7%) in the CHB group; the differences between the two groups in median age and male: female ratio did not reach statistical significance. Multivariate linear regression analysis identified steatosis grade and body mass index (BMI) as independently associated with CAP. The median (IQR) CAP values among patients with S0 and S1 grade steatosis were 215.0 (190.0-241.0) dB/m and 294.0 (255.0-325.5) dB/m (P<0.001), respectively. For all patients, when BMI was <25 kg/m2, the ability of the AUROC of the CAP to discriminate hepatic steatosis more than or equal to 5% was 0.853, and the optimal cut-off value was 244.5 dB/m; however, when BMI≥25 kg/m2, the AUROC was 0.835 and the optimal cut-off value 269.5 dB/m. CONCLUSION: CAP can identify hepatic steatosis more than or equal to 5% and is applicable for the diagnosis of fatty liver if it is adjusted for BMI.
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Fígado Gorduroso , Adulto , Área Sob a Curva , Bile , Biópsia , Índice de Massa Corporal , China , Feminino , Hepatite B Crônica , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Extratos de TecidosRESUMO
Sertraline hydrochloride belongs to the selective serotonin reuptake inhibitor class of antidepressants, which can cause respiratory depression, hypotension, malignant vomiting, liver function impairment, and other symptoms when taken in excess. To our knowledge, reports of sertraline hydrochloride overdose causing diabetes insipidus in patients are rare. This report describes a unique case of a 17-year-old female patient who developed diabetes insipidus after a one-time oral intake of 20 sertraline hydrochloride tablets (50 mg/tablet) during the later course of treatment. Her symptoms were effectively relieved after treatment with pituitrin.
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An increasing number of studies have reported the close relation of the hemoglobin glycation index (HGI) with metabolism, inflammation, and disease prognosis. However, the prognostic relationship between the HGI and patients with sepsis remains unclear. Thus, this study aimed to analyze the association between the HGI and all-cause mortality in patients with sepsis using data from the MIMIC-IV database. In this study, 2605 patients with sepsis were retrospectively analyzed. The linear regression equation was established by incorporating glycated hemoglobin (HbA1c) and fasting plasma glucose levels. Subsequently, the HGI was calculated based on the difference between the predicted and observed HbA1c levels. Furthermore, the HGI was divided into the following three groups using X-tile software: Q1 (HGI ≤ - 0.50%), Q2 (- 0.49% ≤ HGI ≤ 1.18%), and Q3 (HGI ≥ 1.19%). Kaplan-Meier survival curves were further plotted to analyze the differences in 28-day and 365-day mortality among patients with sepsis patients in these HGI groups. Multivariate corrected Cox proportional risk model and restricted cubic spline (RCS) were used. Lastly, mediation analysis was performed to assess the factors through which HGI affects sepsis prognosis. This study included 2605 patients with sepsis, and the 28-day and 365-day mortality rates were 19.7% and 38.9%, respectively. The Q3 group had the highest mortality risk at 28 days (HR = 2.55, 95% CI: 1.89-3.44, p < 0.001) and 365 days (HR = 1.59, 95% CI: 1.29-1.97, p < 0.001). In the fully adjusted multivariate Cox proportional hazards model, patients in the Q3 group still displayed the highest mortality rates at 28 days (HR = 2.02, 95% CI: 1.45-2.80, p < 0.001) and 365 days (HR = 1.28, 95% CI: 1.08-1.56, p < 0.001). The RCS analysis revealed that HGI was positively associated with adverse clinical outcomes. Finally, the mediation effect analysis demonstrated that the HGI might influence patient survival prognosis via multiple indicators related to the SOFA and SAPS II scores. There was a significant association between HGI and all-cause mortality in patients with sepsis, and patients with higher HGI values had a higher risk of death. Therefore, HGI can be used as a potential indicator to assess the prognostic risk of death in patients with sepsis.
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Hemoglobinas Glicadas , Sepse , Humanos , Sepse/mortalidade , Sepse/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Idoso , Hemoglobinas Glicadas/análise , Estimativa de Kaplan-Meier , Glicemia/análise , Modelos de Riscos Proporcionais , Análise de Sobrevida , Idoso de 80 Anos ou maisRESUMO
Background: Pesticides are widely used in agricultural activities. Although pesticide use is known to cause damage to the human body, its relationship with thyroid function remains unclear. Therefore, this study aimed to investigate the association between pesticide exposure and thyroid function. Methods: The Chinese database used included 60 patients with pyrethroid poisoning and 60 participants who underwent health checkups between June 2022 and June 2023. The NHANES database included 1,315 adults enrolled from 2007 to 2012. The assessed pesticide and their metabolites included 2,4-dichlorophenoxyacetic acid (2,4-D), 4-fluoro-3-phenoxybenzoic acid (4F3PB), para-nitrophenol (PN), 3-phenoxybenzoic acid (3P), and trans-dichlorovinyl-dimethylcyclopropane carboxylic acid (TDDC). The evaluated indicators of thyroid function were measured by the blood from the included population. The relationship between pesticide exposure and thyroid function indexes was investigated using linear regression, Bayesian kernel machine regression (BKMR), restricted cubic spline (RCS), and weighted quantile sum (WQS) models. Results: The Chinese data showed that pesticide exposure was negatively correlated with the thyroid function indicators FT4, TT4, TgAb, and TPOAb (all p < 0.05). The BKMR model analysis of the NHANES data showed that the metabolic mixture of multiple pesticides was negatively associated with FT4, TSH, and Tg, similar to the Chinese database findings. Additionally, linear regression analysis demonstrated positive correlations between 2,4-D and FT3 (p = 0.041) and 4F3PB and FT4 (p = 0.003), whereas negative associations were observed between 4F3PB and Tg (p = 0.001), 4F3PB and TgAb (p = 0.006), 3P and TgAB (p = 0.006), 3P and TPOAb (p = 0.03), PN and TSH (p = 0.003), PN and TT4 (p = 0.031), and TDDC and TPOAb (p < 0.001). RCS curves highlighted that most pesticide metabolites were negatively correlated with thyroid function indicators. Finally, WQS model analysis revealed significant differences in the weights of different pesticide metabolites on the thyroid function indexes. Conclusion: There is a significant negative correlation between pesticide metabolites and thyroid function indicators, and the influence weights of different pesticide metabolites on thyroid function indicators are significantly different. More research is needed to further validate the association between different pesticide metabolites and thyroid disease.
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Inquéritos Nutricionais , Praguicidas , Testes de Função Tireóidea , Glândula Tireoide , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido 2,4-Diclorofenoxiacético/toxicidade , China , Bases de Dados Factuais , População do Leste Asiático , Exposição Ambiental/efeitos adversos , Praguicidas/toxicidade , Glândula Tireoide/efeitos dos fármacosRESUMO
BACKGROUND: Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM: To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS: RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS: In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION: We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Prognóstico , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Processamento de Proteína Pós-Traducional , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Ácido Láctico/metabolismo , Simportadores/genética , Simportadores/metabolismo , Proliferação de Células/genética , Perfilação da Expressão Gênica , Masculino , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Feminino , Animais , TranscriptomaRESUMO
Objectives: Portal hypertension (PH) frequently gives rise to severe and life-threatening complications, including hemorrhage accompanied by the rupture of esophageal and gastric varices. In contrast to the guidelines for the management of PH in adults, the optimal endoscopic management of variceal bleeding for secondary prophylaxis in children remains unclear. The present study evaluated the efficacy and safety of endoscopic variceal ligation (EVL) and endoscopic sclerotherapy (EST) to control gastroesophageal variceal bleeding in children. Methods: This retrospective study included children with gastroesophageal variceal bleeding who underwent EST or EVL at Xinhua Hospital, Shanghai Jiaotong University School of Medicine, between February 2013 and March 2020. Short-term hemostasis rate and long-term rebleeding rate were evaluated. Adverse events related to the procedures, such as esophageal ulcer, esophageal stricture, abnormal embolization, pneumonia and perforation, were also recorded. Results: EVL (n = 8) and EST (n = 13) were performed successfully in all pediatric patients diagnosed with moderate to severe esophageal varices concurrent with gastric varices. Hemostasis was achieved during episodes of upper gastrointestinal bleeding. The mean volume of each single aliquot of cyanoacrylate injected was 0.3 ± 0.1â ml (range: 0.1-0.5â ml). Varices were eradicated in six (75%) of the eight patients who underwent EVL after a median 2 (range: 1-4) procedures and a median time of 3.40 months (range: 1.10-13.33 months). Eleven (52.4%) of the 21 patients developed rebleeding events, with the mean duration of hemostasis being 11.1 ± 11.6 months (range 1.0-39.2 months). No treatment-related complications, for example, distal embolism, occurred except for abdominal pain in one patient (4.8%). Conclusions: EST, alone or in combination with EVL, is an effective and safe method of managing gastroesophageal variceal hemorrhage in children undergoing secondary prophylaxis.
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Purpose: Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy. Methods: The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody. Results: QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors. Conclusion: QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses.