BACKGROUND Hypersplenism and esophageal varices bleeding are the major complications of portal hypertension(PHT).In recent years,increasing attention has been given to spleen preservation operations.The mode and long-...BACKGROUND Hypersplenism and esophageal varices bleeding are the major complications of portal hypertension(PHT).In recent years,increasing attention has been given to spleen preservation operations.The mode and long-term effects of subtotal splenectomy and selective pericardial devascularization for PHT remain controversial.AIM To investigate the clinical efficacy and safety of subtotal splenectomy combined with selective pericardial devascularization for the treatment of PHT.METHODS This was a retrospective study of 15 patients with PHT who underwent subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization in the Department of Hepatobiliary Surgery,Qilu Hospital of Shandong University from February 2011 to April 2022.Fifteen propensity score-matched patients with PHT who underwent total splenectomy at the same time served as the control group.The patients were followed for up to 11 years after surgery.We compared the postoperative platelet levels,perioperative splenic vein thrombosis,and serum immunoglobulin levels between the two groups.Abdominal enhanced computed tomography was used to evaluate the blood supply and function of the residual spleen.The operation time,intraoperative blood loss,evacuation time,and hospital stay were compared between the two groups.RESULTS The postoperative platelet level of patients in the subtotal splenectomy group was significantly lower than that in the total splenectomy group(P<0.05),and the postoperative portal system thrombosis rate in the subtotal splenectomy group was also much lower than that in the total splenectomy group.The levels of serum immunoglobulins(IgG,IgA,and IgM)showed no significant differences after surgery compared with before surgery in the subtotal splenectomy group(P>0.05),but serum immunoglobulin IgG and IgM levels decreased dramatically after total splenectomy(P<0.05).The operation time in the subtotal splenectomy group was longer than that in the total splenectomy group(P<0.05),but there were no significant differences in the amount of intraoperative blood loss,evacuation time,or hospital stay between the two groups.CONCLUSION Subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization is a safe and effective surgical treatment for patients with PHT,not only correcting hypersplenism but also preserving splenic function,especially immunological function.展开更多
AIM: To investigate the effect of surgery and chemotherapy for gastric cancer with multiple synchronous liver metastases (GCLM). METHODS: A total of 114 patients were entered in this study, and 20 patients with multip...AIM: To investigate the effect of surgery and chemotherapy for gastric cancer with multiple synchronous liver metastases (GCLM). METHODS: A total of 114 patients were entered in this study, and 20 patients with multiple synchronous liver metastases were eligible. After screening with preoperative chemotherapy, 20 patients underwent curative gastrectomy and hepatectomy for GCLM; 14 underwent major hepatectomy, and the remaining six underwent minor hepatectomy. There were 94 patients without aggressive treatment, and they were in the non-operative group. Two regimens of perioperative chemotherapy were used: S-1 and cisplatin (SP) in 12 patients, and docetaxel, cisplatin and 5-fluorouracil (DCF) in eight patients. These GCLM patients were given preoperative chemotherapy consisting of two courses chemotherapy of SP or DCF regimens. After chemotherapy, gastrectomy and hepatectomy were preformed. Evaluation of patient survival was by follow-up contact using telephone and outpatient records. All patients were assessed every 3 mo during the first year and every 6 mo thereafter. RESULTS: Twenty patients underwent gastrectomy and hepatectomy and completed their perioperative chemotherapy and hepatic arterial infusion before and after surgery. Ninety-four patients had no aggressive treatment of liver metastases because of technical difficulties with resection and severe cardiopulmonary dysfunction. In the surgery group, there was no toxicity greater than grade 3 during the course of chemotherapy. The response rate was 100% according to the Response Evaluation Criteria in Solid Tumors Criteria. For all 114 patients, the overall survival rate was 8.0%, 4.0%, 4.0% and 4.0% at 1, 2, 3 and 4 years, respectively, with a median survival time (MST) of 8.5 mo (range: 0.5-48 mo). For the 20 patients in the surgery group, MST was 22.3 mo (range: 4-48 mo). In the 94 patients without aggressive treatment, MST was 5.5 mo (range: 0.5-21 mo). There was a significant difference between the surgery and unresectable patients (P = 0.000). Three patients in surgery group were still alive at the end of the cut-off date. CONCLUSION: Perioperative weekly DCF and SP achieved a good response, and combined with surgery, they could improve prognosis of GCLM.展开更多
Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the d...Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.展开更多
AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 sample...AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry.Correlations between NGF-TrkA expression and clinicopathological features were analyzed byχ2 test.Moreover,we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis.With experiments in vitro,we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-βstimulation.RESULTS:We found that NGF and TrkA expression was significantly related with differentiation(P=0.024)and intraneural invasion(P=0.003),respectively.Additionally,double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC(P=0.003).Moreover,we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion.CONCLUSION:NGF-TrkA double higher expression is an independent prognostic factor in IHCC.NGF-TrkA pathway can promote IHCC progression,indicating that NGF-TrkA may become a potential drug target.展开更多
AIM:To introduce an air insufflation procedure and to investigate the effectiveness of air insufflation in preventing pancreatic fistula(PF).of 185 patients underwent pancreaticoduodenectomy(PD)at our institution,and ...AIM:To introduce an air insufflation procedure and to investigate the effectiveness of air insufflation in preventing pancreatic fistula(PF).of 185 patients underwent pancreaticoduodenectomy(PD)at our institution,and 74 patients were not involved in this study for various reasons.The clinical outcomes of 111 patients were retrospectively analyzed.The air insufflation test was performed in 46 patients to investigate the efficacy of the pancreaticojejunal anastomosis during surgery,and 65 patients who did not receive the air insufflation test served as controls.Preoperative assessments and intraoperative outcomes were compared between the 2 groups.Univariate and multivariate analyses were performed to identify the risk factors for PF.RESULTS:The two patient groups had similar baseline demographics,preoperative assessments,operative factors,pancreatic factors and pathological results.The overall mortality,morbidity,and PF rates were1.8%,48.6%,and 26.1%,respectively.No significant differences were observed in either morbidity or mortality between the two groups.The rate of clinical PF(grade B and grade C PF)was significantly lower in the air insufflation test group,compared with the nonair insufflation test group(6.5%vs 23.1%,P=0.02).Univariate analysis identified the following parameters as risk factors related to clinical PF:estimated blood loss;pancreatic duct diameter≤3 mm;invagination anastomosis technique;and not undergoing air insufflation test.By further analyzing these variables with multivariate logistic regression,estimated blood loss,pancreatic duct diameter≤3 mm and not undergoing air insufflation test were demonstrated to be independent risk factors.CONCLUSION:Performing an air insufflation test could significantly reduce the occurrence of clinical PF after PD.Not performing an air insufflation test was an independent risk factor for clinical PF.展开更多
BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-infla...BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-inflammatory and immunomodulatory properties.However,little is known about the regulation of PPAR-γactivity in modulating cell crosstalk in NAFLD.AIM To investigate whether the regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocytespecific PPAR-γknockout mice and incubated with free fatty acids(FFAs).Macrophages were incubated with conditioned medium(CM)from lipid-laden hepatocytes with or without a PPAR-γagonist.Wild-type C57BL/6J mice were fed a high-fat(HF)diet and administered rosiglitazone.RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs.CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway.A PPAR-γagonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization.Hepatocyte-specific PPAR-γdeficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes,which further promoted M1 macrophage polarization.Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSION Upregulation of PPAR-γactivity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1βpathway.展开更多
Background:Clear cell renal carcinoma(ccRCC)is notorious for its highly unfavorable prognosis,closely related to immune cell infiltration(ICI).MYB Proto-Oncogene Like 2(MYBL2)is elevated in multiple types of human can...Background:Clear cell renal carcinoma(ccRCC)is notorious for its highly unfavorable prognosis,closely related to immune cell infiltration(ICI).MYB Proto-Oncogene Like 2(MYBL2)is elevated in multiple types of human cancer and is recognized as a crucial role in tumorigenesis.In the present study,we aimed to determine the roles of MYBL2 in the prognostic outcomes of ccRCC.Methods:We analyzed the GSE100666 dataset from the Gene Expression Omnibus(GEO)database and found that the expression of MYBL2 was significantly higher in ccRCC subjects than in normal controls.Next,RNA sequencing data related to ccRCC were retrieved from The Cancer Genome Atlas(TCGA)database and the levels of MYBL2 were compared between tumor and peri-tumor tissues.The correlation between MYBL2 and clinicopathological parameters was assessed by logistic analysis.The Kaplan-Meier method,Cox-regression analysis,and nomograms,were applied to investigate the potential clinical benefits of MYBL2 in ccRCC.We also evaluated the correlation between MYBL2 and immune cell infiltration with a single-sample gene set enrichment analysis(ssGSEA).The association between MYBL2 and immune checkpoints was determined via the TIMER and TISIDB databases.Finally,correlation analysis was conducted to predict upstream non-coding RNAs(ncRNAs)regulating MYBL2,and a completing endogenous RNA(ceRNA)network was constructed to visualize the long non-coding RNAs(lncRNAs)-microRNAs(miRNAs)-MYBL2 axis in ccRCC.Finally,further analysis of upstream lncRNAs was carried out to validate the accuracy of the network.Results:MYBL2 was significantly over-expressed in ccRCC(P<0.001).High levels of MYBL2 expression in ccRCC correlated with a worse T stage,a more advanced N stage,a higher M stage,a more deleterious pathological stage,and higher histological grades.MYBL2 was identified as a risk factor for disease-specific survival(hazard ratio(HR)=2.73,P<0.001),overall survival(HR=1.91,P<0.001),and progression-free interval(HR=2.03,P<0.001).MYBL2 also positively associated with multiple types of immune cells and checkpoints.Finally,two ceRNA axes,PVT1-miR-30e-5p-MYBL2 and LINC00511-miR-29c-3p-MYBL2 were detected as the most promising upstream ncRNAs regulating MYBL2 in ccRCC,and we also validated the expression of MYBL2 and PVT1 by launching qRT-PCR.We found that the expression of MYBL2 was significantly higher in 786-O than in human kidney-2 cell line HK-2(P<0.001)and the expression of PVT1 was significantly higher in Caki-1 than in HK-2(P<0.001).Conclusion:Our study revealed that ncRNAs might upregulated the expression of MYBL2 in ccRCC and that this was associated with an unfavorable prognosis and immune infiltration.展开更多
To investigate the clinical application of vancomycin blood concentration monitoring in critically ill patients and the influence of the ABCB1 gene polymorphism on vancomycin dnug concentrations to guide clinically ra...To investigate the clinical application of vancomycin blood concentration monitoring in critically ill patients and the influence of the ABCB1 gene polymorphism on vancomycin dnug concentrations to guide clinically rational usage of vancomycin.The vancomycin blood concentration monitoring data on 141 critically ill patients in our hospital from November 2016 to March 2017 were analyzed and 68 patients who received the same dosages of vancomycin were subjected to ABCB1 genotyping.The results showed that among the 141 critically ill patients,68(48.22%)showed sub-target concentrations of vancomycin,averaging 5.58±2.54μg/mL;29 patients(20.56%)had higher than target concentrations,with an average value of 33.01±9.38μg/mL;and 44 cases(31.21%)were in the normal concentration range,with an average of 14.72±2.75μg/mL.The vancomycin concentrations in 1236TT-genotype patients were significantly higher than those of the 1236CC and 1236CT-genotype patients.The concentrations in the 2677AA-genotype patients were significantly higher than those in the 2677AT,2677GA,2677GG and 2677GT patients.Vancomycin concentrations in 3435CT patients were significantly higher than those in 3435CC,but slightly lower than those in 3435TT patients.The ABCB11236C>T,2677G>T/A and 3435C>T gene mutations may affect vancomycin blood concentrations.At the same time,other factors such as gender,age,co-morbidities and other transporters possiblely play the roles in influencing the concentration of vancomycin in patients.All these factors finally cause individual differences.展开更多
Neurological diseases,such as intractable pain,Parkinson’s disease,and depression,have imposed significant health and economic burden globally.According to the World Health Organization(WHO),approximately one billion...Neurological diseases,such as intractable pain,Parkinson’s disease,and depression,have imposed significant health and economic burden globally.According to the World Health Organization(WHO),approximately one billion people,one-sixth of the global population,are afflicted with neurological diseases.These disorders have become the primary contributors to disability-adjusted life-years(DALYs)and are ranked as the second leading cause of death[1].The economic losses caused by brain diseases can exceed trillions of dollars every year in major countries.Thus,developing and applying innovative neuroscience technology for the treatment of brain diseases has been a central goal in large-scale brain research projects with a budget of billions of dollars,like the China Brain Project[2],the EU’s Human Brain Project,Japan’s Brain/MINDS Project,the US’s BRAIN Initiative[3].展开更多
Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy...Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.展开更多
Viruses evolve rapidly and continuously threaten animal health and economy,posing a great demand for rapid and efficient genome editing technologies to study virulence mechanism and develop effective vaccine.We presen...Viruses evolve rapidly and continuously threaten animal health and economy,posing a great demand for rapid and efficient genome editing technologies to study virulence mechanism and develop effective vaccine.We present a highly efficient viral genome manipulation method using CRISPR-guided cytidine deaminase.We cloned pseudorabies virus genome into bacterial artificial chromosome,and used CRISPR-guided cytidine deaminase to directly convert cytidine(C)to uridine(U)to induce premature stop mutagenesis in viral genes.The editing efficiencies were 100%.Comprehensive bioinformatic analysis revealed that a large number of editable sites exist in pseudorabies virus(PRV)genomes.Notably,in our study viral genome exists as a plasmid in E.coli,suggesting that this method is virus species-independent.This application of base-editing provided an alternative approach to generate mutant virus and might accelerate study on virulence and vaccine development.展开更多
基金Supported by Chinese Postdoctoral Science Foundation,No. 2022M711911
文摘BACKGROUND Hypersplenism and esophageal varices bleeding are the major complications of portal hypertension(PHT).In recent years,increasing attention has been given to spleen preservation operations.The mode and long-term effects of subtotal splenectomy and selective pericardial devascularization for PHT remain controversial.AIM To investigate the clinical efficacy and safety of subtotal splenectomy combined with selective pericardial devascularization for the treatment of PHT.METHODS This was a retrospective study of 15 patients with PHT who underwent subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization in the Department of Hepatobiliary Surgery,Qilu Hospital of Shandong University from February 2011 to April 2022.Fifteen propensity score-matched patients with PHT who underwent total splenectomy at the same time served as the control group.The patients were followed for up to 11 years after surgery.We compared the postoperative platelet levels,perioperative splenic vein thrombosis,and serum immunoglobulin levels between the two groups.Abdominal enhanced computed tomography was used to evaluate the blood supply and function of the residual spleen.The operation time,intraoperative blood loss,evacuation time,and hospital stay were compared between the two groups.RESULTS The postoperative platelet level of patients in the subtotal splenectomy group was significantly lower than that in the total splenectomy group(P<0.05),and the postoperative portal system thrombosis rate in the subtotal splenectomy group was also much lower than that in the total splenectomy group.The levels of serum immunoglobulins(IgG,IgA,and IgM)showed no significant differences after surgery compared with before surgery in the subtotal splenectomy group(P>0.05),but serum immunoglobulin IgG and IgM levels decreased dramatically after total splenectomy(P<0.05).The operation time in the subtotal splenectomy group was longer than that in the total splenectomy group(P<0.05),but there were no significant differences in the amount of intraoperative blood loss,evacuation time,or hospital stay between the two groups.CONCLUSION Subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization is a safe and effective surgical treatment for patients with PHT,not only correcting hypersplenism but also preserving splenic function,especially immunological function.
文摘AIM: To investigate the effect of surgery and chemotherapy for gastric cancer with multiple synchronous liver metastases (GCLM). METHODS: A total of 114 patients were entered in this study, and 20 patients with multiple synchronous liver metastases were eligible. After screening with preoperative chemotherapy, 20 patients underwent curative gastrectomy and hepatectomy for GCLM; 14 underwent major hepatectomy, and the remaining six underwent minor hepatectomy. There were 94 patients without aggressive treatment, and they were in the non-operative group. Two regimens of perioperative chemotherapy were used: S-1 and cisplatin (SP) in 12 patients, and docetaxel, cisplatin and 5-fluorouracil (DCF) in eight patients. These GCLM patients were given preoperative chemotherapy consisting of two courses chemotherapy of SP or DCF regimens. After chemotherapy, gastrectomy and hepatectomy were preformed. Evaluation of patient survival was by follow-up contact using telephone and outpatient records. All patients were assessed every 3 mo during the first year and every 6 mo thereafter. RESULTS: Twenty patients underwent gastrectomy and hepatectomy and completed their perioperative chemotherapy and hepatic arterial infusion before and after surgery. Ninety-four patients had no aggressive treatment of liver metastases because of technical difficulties with resection and severe cardiopulmonary dysfunction. In the surgery group, there was no toxicity greater than grade 3 during the course of chemotherapy. The response rate was 100% according to the Response Evaluation Criteria in Solid Tumors Criteria. For all 114 patients, the overall survival rate was 8.0%, 4.0%, 4.0% and 4.0% at 1, 2, 3 and 4 years, respectively, with a median survival time (MST) of 8.5 mo (range: 0.5-48 mo). For the 20 patients in the surgery group, MST was 22.3 mo (range: 4-48 mo). In the 94 patients without aggressive treatment, MST was 5.5 mo (range: 0.5-21 mo). There was a significant difference between the surgery and unresectable patients (P = 0.000). Three patients in surgery group were still alive at the end of the cut-off date. CONCLUSION: Perioperative weekly DCF and SP achieved a good response, and combined with surgery, they could improve prognosis of GCLM.
基金This study was supported by the Ministry of Science and Technology of China(No.2016YFC1305800)the National Natural Science Foundation of China(No.31771114 and No.31929002)+1 种基金the Innovative Research Groups of the National Natural Science Foundation of China(No.81721005)the Academic Frontier Youth Team Project to Xiao-chuan WANG from Huazhong University of Science and Technology。
文摘Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.
基金Supported by National Natural Science Foundation of China,No.81172044
文摘AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry.Correlations between NGF-TrkA expression and clinicopathological features were analyzed byχ2 test.Moreover,we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis.With experiments in vitro,we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-βstimulation.RESULTS:We found that NGF and TrkA expression was significantly related with differentiation(P=0.024)and intraneural invasion(P=0.003),respectively.Additionally,double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC(P=0.003).Moreover,we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion.CONCLUSION:NGF-TrkA double higher expression is an independent prognostic factor in IHCC.NGF-TrkA pathway can promote IHCC progression,indicating that NGF-TrkA may become a potential drug target.
文摘AIM:To introduce an air insufflation procedure and to investigate the effectiveness of air insufflation in preventing pancreatic fistula(PF).of 185 patients underwent pancreaticoduodenectomy(PD)at our institution,and 74 patients were not involved in this study for various reasons.The clinical outcomes of 111 patients were retrospectively analyzed.The air insufflation test was performed in 46 patients to investigate the efficacy of the pancreaticojejunal anastomosis during surgery,and 65 patients who did not receive the air insufflation test served as controls.Preoperative assessments and intraoperative outcomes were compared between the 2 groups.Univariate and multivariate analyses were performed to identify the risk factors for PF.RESULTS:The two patient groups had similar baseline demographics,preoperative assessments,operative factors,pancreatic factors and pathological results.The overall mortality,morbidity,and PF rates were1.8%,48.6%,and 26.1%,respectively.No significant differences were observed in either morbidity or mortality between the two groups.The rate of clinical PF(grade B and grade C PF)was significantly lower in the air insufflation test group,compared with the nonair insufflation test group(6.5%vs 23.1%,P=0.02).Univariate analysis identified the following parameters as risk factors related to clinical PF:estimated blood loss;pancreatic duct diameter≤3 mm;invagination anastomosis technique;and not undergoing air insufflation test.By further analyzing these variables with multivariate logistic regression,estimated blood loss,pancreatic duct diameter≤3 mm and not undergoing air insufflation test were demonstrated to be independent risk factors.CONCLUSION:Performing an air insufflation test could significantly reduce the occurrence of clinical PF after PD.Not performing an air insufflation test was an independent risk factor for clinical PF.
基金the National Natural Science Foundation of China,No.81770572.
文摘BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-inflammatory and immunomodulatory properties.However,little is known about the regulation of PPAR-γactivity in modulating cell crosstalk in NAFLD.AIM To investigate whether the regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocytespecific PPAR-γknockout mice and incubated with free fatty acids(FFAs).Macrophages were incubated with conditioned medium(CM)from lipid-laden hepatocytes with or without a PPAR-γagonist.Wild-type C57BL/6J mice were fed a high-fat(HF)diet and administered rosiglitazone.RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs.CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway.A PPAR-γagonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization.Hepatocyte-specific PPAR-γdeficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes,which further promoted M1 macrophage polarization.Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSION Upregulation of PPAR-γactivity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1βpathway.
基金supported by the Key Medical Research Projects of Jiangsu Commission of Health(ID:2022013).
文摘Background:Clear cell renal carcinoma(ccRCC)is notorious for its highly unfavorable prognosis,closely related to immune cell infiltration(ICI).MYB Proto-Oncogene Like 2(MYBL2)is elevated in multiple types of human cancer and is recognized as a crucial role in tumorigenesis.In the present study,we aimed to determine the roles of MYBL2 in the prognostic outcomes of ccRCC.Methods:We analyzed the GSE100666 dataset from the Gene Expression Omnibus(GEO)database and found that the expression of MYBL2 was significantly higher in ccRCC subjects than in normal controls.Next,RNA sequencing data related to ccRCC were retrieved from The Cancer Genome Atlas(TCGA)database and the levels of MYBL2 were compared between tumor and peri-tumor tissues.The correlation between MYBL2 and clinicopathological parameters was assessed by logistic analysis.The Kaplan-Meier method,Cox-regression analysis,and nomograms,were applied to investigate the potential clinical benefits of MYBL2 in ccRCC.We also evaluated the correlation between MYBL2 and immune cell infiltration with a single-sample gene set enrichment analysis(ssGSEA).The association between MYBL2 and immune checkpoints was determined via the TIMER and TISIDB databases.Finally,correlation analysis was conducted to predict upstream non-coding RNAs(ncRNAs)regulating MYBL2,and a completing endogenous RNA(ceRNA)network was constructed to visualize the long non-coding RNAs(lncRNAs)-microRNAs(miRNAs)-MYBL2 axis in ccRCC.Finally,further analysis of upstream lncRNAs was carried out to validate the accuracy of the network.Results:MYBL2 was significantly over-expressed in ccRCC(P<0.001).High levels of MYBL2 expression in ccRCC correlated with a worse T stage,a more advanced N stage,a higher M stage,a more deleterious pathological stage,and higher histological grades.MYBL2 was identified as a risk factor for disease-specific survival(hazard ratio(HR)=2.73,P<0.001),overall survival(HR=1.91,P<0.001),and progression-free interval(HR=2.03,P<0.001).MYBL2 also positively associated with multiple types of immune cells and checkpoints.Finally,two ceRNA axes,PVT1-miR-30e-5p-MYBL2 and LINC00511-miR-29c-3p-MYBL2 were detected as the most promising upstream ncRNAs regulating MYBL2 in ccRCC,and we also validated the expression of MYBL2 and PVT1 by launching qRT-PCR.We found that the expression of MYBL2 was significantly higher in 786-O than in human kidney-2 cell line HK-2(P<0.001)and the expression of PVT1 was significantly higher in Caki-1 than in HK-2(P<0.001).Conclusion:Our study revealed that ncRNAs might upregulated the expression of MYBL2 in ccRCC and that this was associated with an unfavorable prognosis and immune infiltration.
基金supported by the Department of Science and Technology of Jiangxi Province(20161BBG70181)the Department of Health Science and Technology project of Jiangxi Province(20151022)+1 种基金the National Natural Science Foundation of China(81660620)Innovation and Entrepreneurship Training Program for College Students(20190402367).
文摘To investigate the clinical application of vancomycin blood concentration monitoring in critically ill patients and the influence of the ABCB1 gene polymorphism on vancomycin dnug concentrations to guide clinically rational usage of vancomycin.The vancomycin blood concentration monitoring data on 141 critically ill patients in our hospital from November 2016 to March 2017 were analyzed and 68 patients who received the same dosages of vancomycin were subjected to ABCB1 genotyping.The results showed that among the 141 critically ill patients,68(48.22%)showed sub-target concentrations of vancomycin,averaging 5.58±2.54μg/mL;29 patients(20.56%)had higher than target concentrations,with an average value of 33.01±9.38μg/mL;and 44 cases(31.21%)were in the normal concentration range,with an average of 14.72±2.75μg/mL.The vancomycin concentrations in 1236TT-genotype patients were significantly higher than those of the 1236CC and 1236CT-genotype patients.The concentrations in the 2677AA-genotype patients were significantly higher than those in the 2677AT,2677GA,2677GG and 2677GT patients.Vancomycin concentrations in 3435CT patients were significantly higher than those in 3435CC,but slightly lower than those in 3435TT patients.The ABCB11236C>T,2677G>T/A and 3435C>T gene mutations may affect vancomycin blood concentrations.At the same time,other factors such as gender,age,co-morbidities and other transporters possiblely play the roles in influencing the concentration of vancomycin in patients.All these factors finally cause individual differences.
基金supported by the Beijing Natural Science Foundation(JQ22018)the National Natural Science Foundation of China(32071061).
文摘Neurological diseases,such as intractable pain,Parkinson’s disease,and depression,have imposed significant health and economic burden globally.According to the World Health Organization(WHO),approximately one billion people,one-sixth of the global population,are afflicted with neurological diseases.These disorders have become the primary contributors to disability-adjusted life-years(DALYs)and are ranked as the second leading cause of death[1].The economic losses caused by brain diseases can exceed trillions of dollars every year in major countries.Thus,developing and applying innovative neuroscience technology for the treatment of brain diseases has been a central goal in large-scale brain research projects with a budget of billions of dollars,like the China Brain Project[2],the EU’s Human Brain Project,Japan’s Brain/MINDS Project,the US’s BRAIN Initiative[3].
基金This work was supported by Grants from the National Natural Science Foundation of China(31771290 and 81702454)the Beijing National Science Foundation(5222033)+1 种基金the Military Logistics Scientific Research Foundation of China(BWS17J027)the National Basic Scientific Research Program of China(JCKY2019548B001).
文摘Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
基金This work was supported by the National Key Research and Development Program(2016YFD0500105)the Natural Science Foundation of China(31770191).
文摘Viruses evolve rapidly and continuously threaten animal health and economy,posing a great demand for rapid and efficient genome editing technologies to study virulence mechanism and develop effective vaccine.We present a highly efficient viral genome manipulation method using CRISPR-guided cytidine deaminase.We cloned pseudorabies virus genome into bacterial artificial chromosome,and used CRISPR-guided cytidine deaminase to directly convert cytidine(C)to uridine(U)to induce premature stop mutagenesis in viral genes.The editing efficiencies were 100%.Comprehensive bioinformatic analysis revealed that a large number of editable sites exist in pseudorabies virus(PRV)genomes.Notably,in our study viral genome exists as a plasmid in E.coli,suggesting that this method is virus species-independent.This application of base-editing provided an alternative approach to generate mutant virus and might accelerate study on virulence and vaccine development.