Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated ...Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).展开更多
BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heter...BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heterogeneity of this disease.LATS2,a tumor suppressor gene involved in the Hippo signaling pathway,has been identified as a potential prognostic biomarker in gastric cancer.AIM To construct and validate a nomogram model that includes LATS2 expression to predict the survival prognosis of advanced gastric cancer patients following ra-dical surgery,and compare its predictive performance with traditional TNM staging.METHODS A retrospective analysis of 245 advanced gastric cancer patients from the Fourth Hospital of Hebei Medical University was conducted.The patients were divided into a training group(171 patients)and a validation group(74 patients)to deve-lop and test our prognostic model.The performance of the model was determined using C-indices,receiver operating characteristic curves,calibration plots,and decision curves.RESULTS The model demonstrated a high predictive accuracy with C-indices of 0.829 in the training set and 0.862 in the validation set.Area under the curve values for three-year and five-year survival prediction were significantly robust,suggesting an excellent discrimination ability.Calibration plots confirmed the high concordance between the predictions and actual survival outcomes.CONCLUSION We developed a nomogram model incorporating LATS2 expression,which significantly outperformed conven-tional TNM staging in predicting the prognosis of advanced gastric cancer patients postsurgery.This model may serve as a valuable tool for individualized patient management,allowing for more accurate stratification and im-proved clinical outcomes.Further validation in larger patient cohorts will be necessary to establish its generaliza-bility and clinical utility.展开更多
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause o...The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality.The cardiovascular diseases that accompany diabetes include angina,myocardial infarction,stroke,peripheral artery disease,and congestive heart failure.Among the various risk factors generated secondary to hyperglycemic situations,advanced glycation end products(AGEs)are one of the important targets for future diagnosis and prevention of diabetes.In the last decade,AGEs have drawn a lot of attention due to their involvement in diabetic pathophysiology.AGEs can be derived exogenously and endogenously through various pathways.These are a nonhomogeneous,chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein,lipids,and nucleic acid.AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways.At the cellular level,they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation,inflammation,cellular proliferation,and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics.AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins;altering their structure,stability,and functions.Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities.In the present review,we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications.Furthermore,this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.展开更多
AIM:To investigate the efficacy of neoadjuvant chemoradiotherapy(NACRT) for resectability of locally advanced gastric cancer(LAGC).METHODS:Between November 2007 and January 2014,29 patients with LAGC(clinically T3 wit...AIM:To investigate the efficacy of neoadjuvant chemoradiotherapy(NACRT) for resectability of locally advanced gastric cancer(LAGC).METHODS:Between November 2007 and January 2014,29 patients with LAGC(clinically T3 with distal esophagus invasion/T4 or bulky regional node metastasis) that were treated with NACRT followed by D2 gastrectomy were included in this study.Resectability was evaluated with radiologic and endoscopic exams before and after NACRT.Using threedimensional conformal radiotherapy,patients received 45 Gy,with a daily dose of 1.8 Gy.The entire tumor extent and the regional metastatic lymph nodes were included in the gross tumor volume.Patients presenting with a resectable tumor after NACRT received a total or subtotal gastrectomy with D2 dissection.The pathologic tumor response was evaluated using Japanese Gastric Cancer Association histologic evaluation criteria.Postoperative morbidity was evaluated using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0.Overall survival(OS) and progression-free survival(PFS) rates were estimated using a Kaplan-Meier analysis and compared using the log-rank test.RESULTS:All patients were assessed as unresectable cases.Twenty-four patients(24/29; 82.8%) showed LAGC on positron emission tomography-computed tomography(CT) and contrast-enhanced CT,whereas four patients(4/29; 13.8%) with vague invasion orabutment to an adjacent organ underwent diagnostic laparoscopy.One patient(1/29; 3.4%),initially assessed as a resectable case,underwent an "open and closure" after the tumor was found to be unresectable.Abutment to an adjacent organ(34.5%) was the most common reason for NACRT.The clinical response rate one month after NACRT was 44.8%.After NACRT,69%(20/29) of patients had a resectable tumor.Of the 20 patients with a resectable tumor,18 patients(62.1%) underwent a D2 gastrectomy.The R0 resection rate was 94.4% and two patients(2/18; 11.1%) showed a complete response.The median follow-up duration was 13.5 mo.The one-year OS and PFS rates were 72.4 and 48.9%,respectively.The one-year OS,PFS,local failure-free survival,and distant metastasis-free survival were higher in patients with a resectable tumor after NACRT(P < 0.001,P < 0.001,P < 0.001,and P =0.078,respectively).No grade 3-4 late treatment-related toxicities or postoperative mortalities were observed.CONCLUSION:NACRT with D2 gastrectomy showed a high rate of R0 resection and promising local control,which may increase the R0 resection opportunity resulting in survival benefit.展开更多
在WRFDA-3DVar(Weather Research and Forecasting model’s 3-dimensional variational data assimilation)的框架下,添加了新的探测器AMSR2(Advanced Microwave Scanning Radiometer 2)微波辐射率资料的同化模块,实现了AMSR2辐射率资...在WRFDA-3DVar(Weather Research and Forecasting model’s 3-dimensional variational data assimilation)的框架下,添加了新的探测器AMSR2(Advanced Microwave Scanning Radiometer 2)微波辐射率资料的同化模块,实现了AMSR2辐射率资料在中小尺度同化系统中的有效使用。台风"山神"(Son-Tinh)直接同化AMSR2资料的个例试验结果表明,AMSR2资料可以很好的探测出台风的形态,并且与没有同化该资料的控制试验相比,同化AMSR2辐射率资料可以有效提高模式分析场的质量,进一步提高了台风中心气压,最大风速和台风路径的预报。展开更多
Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an...Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection.In the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)2.The soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.展开更多
Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglyc...Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglycemia.The above,over time,affects other systems of the human body by causing tissue hypoxia,low-grade inflammation,and oxidative stress,which lay the pathophysiological groundwork for cancer.The leading causes of death globally are T2DM and cancer.Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death(i.e.,damage-associated molecular patterns)such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products(RAGE)-a multiligand receptor involved in inflammatory and metabolic and neoplastic processes.This review analyzes the latest advanced reports on the role of RAGE in the development of obesity,T2DM,and cancer,with an aim to understand the intracellular signaling mechanisms linked with cancer initiation.This review also explores inflammation,oxidative stress,hypoxia,cellular senescence,RAGE ligands,tumor microenvironment changes,and the“cancer hallmarks”of the leading tumors associated with T2DM.The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.展开更多
Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
A patient with advanced gastric cancer complicated with pyloric obstruction was treated using D2 ＋ radical resection combined with perioperative chemotherapy, and had satisfying outcomes. The perioperative chemothera...A patient with advanced gastric cancer complicated with pyloric obstruction was treated using D2 ＋ radical resection combined with perioperative chemotherapy, and had satisfying outcomes. The perioperative chemotherapy regimen was Taxol and S1 （tegafur, gimeracil, and oteracil）. Three cycles of neoadjuvant chemotherapy were delivered before surgery, and three cycles of adjuvant therapy after surgery. PR was achieved after chemotherapy. D2 ＋ dissection of stations 8p, 12b, 12p, 13 and 14v lymph nodes was performed on September 10, 2012.展开更多
文摘Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).
文摘BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heterogeneity of this disease.LATS2,a tumor suppressor gene involved in the Hippo signaling pathway,has been identified as a potential prognostic biomarker in gastric cancer.AIM To construct and validate a nomogram model that includes LATS2 expression to predict the survival prognosis of advanced gastric cancer patients following ra-dical surgery,and compare its predictive performance with traditional TNM staging.METHODS A retrospective analysis of 245 advanced gastric cancer patients from the Fourth Hospital of Hebei Medical University was conducted.The patients were divided into a training group(171 patients)and a validation group(74 patients)to deve-lop and test our prognostic model.The performance of the model was determined using C-indices,receiver operating characteristic curves,calibration plots,and decision curves.RESULTS The model demonstrated a high predictive accuracy with C-indices of 0.829 in the training set and 0.862 in the validation set.Area under the curve values for three-year and five-year survival prediction were significantly robust,suggesting an excellent discrimination ability.Calibration plots confirmed the high concordance between the predictions and actual survival outcomes.CONCLUSION We developed a nomogram model incorporating LATS2 expression,which significantly outperformed conven-tional TNM staging in predicting the prognosis of advanced gastric cancer patients postsurgery.This model may serve as a valuable tool for individualized patient management,allowing for more accurate stratification and im-proved clinical outcomes.Further validation in larger patient cohorts will be necessary to establish its generaliza-bility and clinical utility.
文摘The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality.The cardiovascular diseases that accompany diabetes include angina,myocardial infarction,stroke,peripheral artery disease,and congestive heart failure.Among the various risk factors generated secondary to hyperglycemic situations,advanced glycation end products(AGEs)are one of the important targets for future diagnosis and prevention of diabetes.In the last decade,AGEs have drawn a lot of attention due to their involvement in diabetic pathophysiology.AGEs can be derived exogenously and endogenously through various pathways.These are a nonhomogeneous,chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein,lipids,and nucleic acid.AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways.At the cellular level,they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation,inflammation,cellular proliferation,and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics.AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins;altering their structure,stability,and functions.Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities.In the present review,we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications.Furthermore,this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
文摘AIM:To investigate the efficacy of neoadjuvant chemoradiotherapy(NACRT) for resectability of locally advanced gastric cancer(LAGC).METHODS:Between November 2007 and January 2014,29 patients with LAGC(clinically T3 with distal esophagus invasion/T4 or bulky regional node metastasis) that were treated with NACRT followed by D2 gastrectomy were included in this study.Resectability was evaluated with radiologic and endoscopic exams before and after NACRT.Using threedimensional conformal radiotherapy,patients received 45 Gy,with a daily dose of 1.8 Gy.The entire tumor extent and the regional metastatic lymph nodes were included in the gross tumor volume.Patients presenting with a resectable tumor after NACRT received a total or subtotal gastrectomy with D2 dissection.The pathologic tumor response was evaluated using Japanese Gastric Cancer Association histologic evaluation criteria.Postoperative morbidity was evaluated using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0.Overall survival(OS) and progression-free survival(PFS) rates were estimated using a Kaplan-Meier analysis and compared using the log-rank test.RESULTS:All patients were assessed as unresectable cases.Twenty-four patients(24/29; 82.8%) showed LAGC on positron emission tomography-computed tomography(CT) and contrast-enhanced CT,whereas four patients(4/29; 13.8%) with vague invasion orabutment to an adjacent organ underwent diagnostic laparoscopy.One patient(1/29; 3.4%),initially assessed as a resectable case,underwent an "open and closure" after the tumor was found to be unresectable.Abutment to an adjacent organ(34.5%) was the most common reason for NACRT.The clinical response rate one month after NACRT was 44.8%.After NACRT,69%(20/29) of patients had a resectable tumor.Of the 20 patients with a resectable tumor,18 patients(62.1%) underwent a D2 gastrectomy.The R0 resection rate was 94.4% and two patients(2/18; 11.1%) showed a complete response.The median follow-up duration was 13.5 mo.The one-year OS and PFS rates were 72.4 and 48.9%,respectively.The one-year OS,PFS,local failure-free survival,and distant metastasis-free survival were higher in patients with a resectable tumor after NACRT(P < 0.001,P < 0.001,P < 0.001,and P =0.078,respectively).No grade 3-4 late treatment-related toxicities or postoperative mortalities were observed.CONCLUSION:NACRT with D2 gastrectomy showed a high rate of R0 resection and promising local control,which may increase the R0 resection opportunity resulting in survival benefit.
文摘在WRFDA-3DVar(Weather Research and Forecasting model’s 3-dimensional variational data assimilation)的框架下,添加了新的探测器AMSR2(Advanced Microwave Scanning Radiometer 2)微波辐射率资料的同化模块,实现了AMSR2辐射率资料在中小尺度同化系统中的有效使用。台风"山神"(Son-Tinh)直接同化AMSR2资料的个例试验结果表明,AMSR2资料可以很好的探测出台风的形态,并且与没有同化该资料的控制试验相比,同化AMSR2辐射率资料可以有效提高模式分析场的质量,进一步提高了台风中心气压,最大风速和台风路径的预报。
文摘Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection.In the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)2.The soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.
基金Supported by the Founding Proyectos de Impulso a la Investigación to Hernandez-Nazara ZH from Universidad de Guadalajara,Mexico,No.PIN 2020-I.
文摘Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglycemia.The above,over time,affects other systems of the human body by causing tissue hypoxia,low-grade inflammation,and oxidative stress,which lay the pathophysiological groundwork for cancer.The leading causes of death globally are T2DM and cancer.Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death(i.e.,damage-associated molecular patterns)such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products(RAGE)-a multiligand receptor involved in inflammatory and metabolic and neoplastic processes.This review analyzes the latest advanced reports on the role of RAGE in the development of obesity,T2DM,and cancer,with an aim to understand the intracellular signaling mechanisms linked with cancer initiation.This review also explores inflammation,oxidative stress,hypoxia,cellular senescence,RAGE ligands,tumor microenvironment changes,and the“cancer hallmarks”of the leading tumors associated with T2DM.The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
文摘A patient with advanced gastric cancer complicated with pyloric obstruction was treated using D2 ＋ radical resection combined with perioperative chemotherapy, and had satisfying outcomes. The perioperative chemotherapy regimen was Taxol and S1 （tegafur, gimeracil, and oteracil）. Three cycles of neoadjuvant chemotherapy were delivered before surgery, and three cycles of adjuvant therapy after surgery. PR was achieved after chemotherapy. D2 ＋ dissection of stations 8p, 12b, 12p, 13 and 14v lymph nodes was performed on September 10, 2012.
