The Third People's Hospital of Dalian City

Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.

Importance: Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy of RIC for acute moderate ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021. Interventions: Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971). Main Outcomes and Measures: The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group. Conclusions and Relevance: Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention. Trial Registration: ClinicalTrials.gov Identifier: NCT03740971.

The fabricated superhydrophobic–superoleophilic mesh is bent into a V-shape-channel to guarantee floating oils are always in contact with the mesh.

The aim of this study is to find the potential biomarkers from the rat hepatocellular carcinoma (HCC) disease model by using a non-target metabolomics method, and test their usefulness in early human HCC diagnosis. The serum metabolic profiling of the diethylnitrosamine-induced rat HCC model, which presents a stepwise histopathological progression that is similar to human HCC, was performed using liquid chromatography-mass spectrometry. Multivariate data analysis methods were utilized to identify the potential biomarkers. Three metabolites, taurocholic acid, lysophosphoethanolamine 16:0, and lysophosphatidylcholine 22:5, were defined as “marker metabolites,” which can be used to distinguish the different stages of chemical hepatocarcinogenesis. These metabolites represented the abnormal metabolism during the progress of hepatocarcinogenesis, which could also be found in patients. To test their diagnosis potential 412 sera from 262 patients with HCC, 76 patients with cirrhosis and 74 patients with chronic hepatitis B were collected and studied, it was found that 3 marker metabolites were effective for the discrimination of small liver tumor (solitary nodules of less than 2 cm in diameter) patients, achieved a sensitivity of 80.5% and a specificity of 80.1%,which is better than those of α-fetoprotein (53 and 64%, respectively). Moreover, they were also effective for the discrimination of all HCCs and chronic liver disease patients, which could achieve a sensitivity of 87.5% and a specificity of 72.3%, better than those of α-fetoprotein (61.2 and 64%). These results indicate metabolomics method has the potential of finding biomarkers for the early diagnosis of HCC. The aim of this study is to find the potential biomarkers from the rat hepatocellular carcinoma (HCC) disease model by using a non-target metabolomics method, and test their usefulness in early human HCC diagnosis. The serum metabolic profiling of the diethylnitrosamine-induced rat HCC model, which presents a stepwise histopathological progression that is similar to human HCC, was performed using liquid chromatography-mass spectrometry. Multivariate data analysis methods were utilized to identify the potential biomarkers. Three metabolites, taurocholic acid, lysophosphoethanolamine 16:0, and lysophosphatidylcholine 22:5, were defined as “marker metabolites,” which can be used to distinguish the different stages of chemical hepatocarcinogenesis. These metabolites represented the abnormal metabolism during the progress of hepatocarcinogenesis, which could also be found in patients. To test their diagnosis potential 412 sera from 262 patients with HCC, 76 patients with cirrhosis and 74 patients with chronic hepatitis B were collected and studied, it was found that 3 marker metabolites were effective for the discrimination of small liver tumor (solitary nodules of less than 2 cm in diameter) patients, achieved a sensitivity of 80.5% and a specificity of 80.1%,which is better than those of α-fetoprotein (53 and 64%, respectively). Moreover, they were also effective for the discrimination of all HCCs and chronic liver disease patients, which could achieve a sensitivity of 87.5% and a specificity of 72.3%, better than those of α-fetoprotein (61.2 and 64%). These results indicate metabolomics method has the potential of finding biomarkers for the early diagnosis of HCC. Hepatocellular carcinoma (HCC) 1The abbreviations used are:HCChepatocellular carcinomaCLDChronic liver diseasesDENdiethylnitrosamineLPElysophosphoethanolamineTCATaurocholic acidPEphosphoethanolaminePCphosphatidylcholineLPClysophosphatidylcholineHBVhepatitis B virusCTcomputed tomographyMRImagnetic resonance imagingAFPAlpha FetoproteinSDSprague-DawleyPLS-DApartial least squares discriminate analysisTICtotal ion counts chromatogramVIPvariable importance in the projectionHCAhierarchical cluster analysisROCreceiver operating characteristic curveAUCarea under the curveALTAlanine AminotransferaseASTAspertate AminotransferasePEMT 2PE N-methyltransferase 2PUFApoly unsaturated fatty acidFFAFree fatty acid. 1The abbreviations used are:HCChepatocellular carcinomaCLDChronic liver diseasesDENdiethylnitrosamineLPElysophosphoethanolamineTCATaurocholic acidPEphosphoethanolaminePCphosphatidylcholineLPClysophosphatidylcholineHBVhepatitis B virusCTcomputed tomographyMRImagnetic resonance imagingAFPAlpha FetoproteinSDSprague-DawleyPLS-DApartial least squares discriminate analysisTICtotal ion counts chromatogramVIPvariable importance in the projectionHCAhierarchical cluster analysisROCreceiver operating characteristic curveAUCarea under the curveALTAlanine AminotransferaseASTAspertate AminotransferasePEMT 2PE N-methyltransferase 2PUFApoly unsaturated fatty acidFFAFree fatty acid. is a type of malignancy with a high mortality rate worldwide, especially in the East Asian countries (1Gomaa A.I. Khan S.A. Toledano M.B. Waked I. Taylor-Robinson S.D. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis.World J. Gastroenterol. 2008; 14: 4300-4308Crossref PubMed Scopus (542) Google Scholar). In China, chronic hepatitis B virus (HBV) infection and subsequent liver cirrhosis are major precancerous lesions in the majority of HCC cases. An early diagnosis of small HCCs in these precancerous cases may greatly improve the outcome of HCC treatment (2Sakamoto M. Early HCC: diagnosis and molecular markers.J. Gastroenterol. 2009; 44: 108-111Crossref PubMed Scopus (75) Google Scholar). The current screening methods for the high risk population, such as ultrasound or the serum surveillance of tumor markers (mainly α-fetoprotein (AFP)), although effective, are far from ideal (3Ryder S.D. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults.Gut. 2003; 52: iii1-iii8Crossref PubMed Scopus (354) Google Scholar, 4Parikh S. Hyman D. Hepatocellular cancer: a guide for the internist.Am. J. Med. 2007; 120: 194-202Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). For example, a subset of patients with chronic hepatitis and/or cirrhosis exhibit modest elevations (10–500 ng/ml) of serum AFP, which may lead to an incorrect diagnosis (5Pokorski R.J. Ohlmer U. Long-term morbidity and mortality in Chinese insurance applicants infected with the hepatitis B virus.J. Insur. Med. 2001; 33: 143-164PubMed Google Scholar). Hence, new biomarkers for monitoring hepatocarcinogenesis would be of great clinical importance. hepatocellular carcinoma Chronic liver diseases diethylnitrosamine lysophosphoethanolamine Taurocholic acid phosphoethanolamine phosphatidylcholine lysophosphatidylcholine hepatitis B virus computed tomography magnetic resonance imaging Alpha Fetoprotein Sprague-Dawley partial least squares discriminate analysis total ion counts chromatogram variable importance in the projection hierarchical cluster analysis receiver operating characteristic curve area under the curve Alanine Aminotransferase Aspertate Aminotransferase PE N-methyltransferase 2 poly unsaturated fatty acid Free fatty acid. hepatocellular carcinoma Chronic liver diseases diethylnitrosamine lysophosphoethanolamine Taurocholic acid phosphoethanolamine phosphatidylcholine lysophosphatidylcholine hepatitis B virus computed tomography magnetic resonance imaging Alpha Fetoprotein Sprague-Dawley partial least squares discriminate analysis total ion counts chromatogram variable importance in the projection hierarchical cluster analysis receiver operating characteristic curve area under the curve Alanine Aminotransferase Aspertate Aminotransferase PE N-methyltransferase 2 poly unsaturated fatty acid Free fatty acid. Emerging platforms in the biomedical arena provide a new methodology to identify novel biomarkers. Within the framework of systems biology, metabolomics focuses on the quantitative measurement of holistic endogenous metabolites and is increasingly used in clinical fields that focus on the pathophysiological and diagnostic study of diseases (6Nicholson J.K. Lindon J.C. Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica. 1999; 29: 1181-1189Crossref PubMed Scopus (3265) Google Scholar). Metabolic fingerprinting and metabolite biomarkers have been studied for use in the discrimination or diagnosis of carcinoma (7Gowda G.A. Zhang S. Gu H. Asiago V. Shanaiah N. Raftery D. Metabolomics-based methods for early disease diagnostics.Expert Rev. Mol. Diagn. 2008; 8: 617-633Crossref PubMed Scopus (480) Google Scholar, 8Sreekumar A. Poisson L.M. Rajendiran T.M. Khan A.P. Cao Q. Yu J. Laxman B. Mehra R. Lonigro R.J. Li Y. Nyati M.K. Ahsan A. Kalyana-Sundaram S. Han B. Cao X. Byun J. Omenn G.S. Ghosh D. Pennathur S. Alexander D.C. Berger A. Shuster J.R. Wei J.T. Varambally S. Beecher C. Chinnaiyan A.M. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.Nature. 2009; 457: 910-914Crossref PubMed Scopus (1748) Google Scholar), diabetes mellitus (9Li X. Xu Z.L. Lu X. Yang X.H. Yin P. Kong H. Yu Y. Xu G. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry for metabonomics: Biomarker discovery for diabetes mellitus.Anal. Chim. Acta. 2009; 633: 257-262Crossref PubMed Scopus (211) Google Scholar) and inborn analysis to study of inborn of Rev. PubMed Scopus Google Scholar). metabolomics have also been used to for new biomarkers and to the of in diseases G. J. Y. Xu X. Cao H. H. Y. Li on the in liver patients by hepatitis virus.J. 2007; PubMed Scopus Google Scholar, V. E. R. R. P. M. J. and in a model in to a study of Acta. 2007; PubMed Scopus Google Scholar, Y. Y. Y. Y. H. Y. analysis of serum and liver in liver by gas with mass Chim. Acta. 2009; 633: PubMed Scopus Google Scholar, P. D. C. J. X. Lu X. Yang S. Gu J. Xu G. study of hepatitis liver cirrhosis and hepatocellular carcinoma by using and with mass 2009; PubMed Scopus Google Scholar, J. Xu Kong S. Yang Q. of liver cancer using from hepatitis and B. PubMed Scopus Google Scholar, P. to hepatocellular Rev. 2008; PubMed Scopus Google Scholar, Y. Li C. X. X. Y. H. of human hepatocellular carcinoma using NMR in with multivariate data 2007; PubMed Scopus Google Scholar, R. Zhang S. C. J. X. of biomarkers in liver cancer using and gas 2008; PubMed Scopus Google Scholar, J. S. Yin P. X. Lu X. Zhang Xu G. study of liver cancer on liquid to mass spectrometry with and Chim. Acta. 2009; PubMed Scopus Google Scholar, A.I. M. Waked I. Khan S.A. Taylor-Robinson S.D. Metabolic of Hepatocellular in an PubMed Scopus Google Scholar). to these metabolites have been to be for HCC, such as R. Zhang S. C. J. X. of biomarkers in liver cancer using and gas 2008; PubMed Scopus Google Scholar), and a of R. C. J. X. serum on hepatocellular carcinoma patients by chemical by gas 2008; PubMed Scopus Google Scholar). found that serum can be used as biomarkers for different liver diseases M. M. S. A. H. M. S. Y. H. S. H. M. M. as for of Full Text Full Text PDF PubMed Scopus Google Scholar). In metabolomics on HCC on the metabolic profiling of serum and P. D. C. J. X. Lu X. Yang S. Gu J. Xu G. study of hepatitis liver cirrhosis and hepatocellular carcinoma by using and with mass 2009; PubMed Scopus Google Scholar, J. S. Yin P. X. Lu X. Zhang Xu G. study of liver cancer on liquid to mass spectrometry with and Chim. Acta. 2009; PubMed Scopus Google Scholar), found that the of metabolites, such as in and in were different the patients and These a of metabolites that represented the metabolic of HCC patients and the of metabolomics to identify the potential biomarkers of HCC. metabolites or their were for their as biomarkers to the hepatocarcinogenesis and HCC early diagnosis. The in the clinical on and and discovery of biomarkers using these clinical a great of the of the serum In it is to clinical of liver diseases that the stages of chronic and HCC, In the different stages of liver disease in the rat model of HCC can be has been found that and of diethylnitrosamine hepatocarcinogenesis are similar to those of human HCC E. C. D. C. C. R. V. an hepatocellular carcinoma in the rat liver with PubMed Scopus Google Scholar, Y. X. Li D. C. Yu of diethylnitrosamine rat hepatocellular J. 2008; PubMed Scopus Google Scholar). rat model has also been used to the progression of cirrhosis to HCC C. M. M. P. M. M. of in diethylnitrosamine-induced hepatocarcinogenesis in PubMed Scopus Google Scholar, Yu G. H. M. and liver and by and Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. H. of in rat PubMed Scopus Google Scholar). in the a metabolomics was to the rat model to study the metabolic of hepatocarcinogenesis using liquid chromatography-mass spectrometry The “marker metabolites,” which were defined from the rat model, were to distinguish patients with chronic or small HCC to their for small HCC. The study to the for the and of from the The were in X.H. Yin Li H. Xu method for data from liquid use of and for PubMed Scopus Google Scholar). total of Sprague-Dawley were from the and were in the study the of The for the was defined as The model and of these of liver during the The of The were to the model using a of In of were to the were to 2 and To the progression of HCC, from the model and 2 from the were under 2 from 2 all of the were The liver were in and in The and histopathological were used to the progress of the The sera were collected of was from to 2 The sera were The were performed in a all were The serum and are in were from in the were collected and under the was by all The study was by the of the of the serum for the study were collected with from 262 patients with HCC, 76 patients with and 74 patients with hepatitis B. HCC was the tumor The of HCC patients was to and cases. total of HCC patients were in early stages of HCC and patients a than 2 The diagnosis of chronic hepatitis B or cirrhosis was using and of or The and of the in were and the and the of from different were the is in I. The sera were were was to the sera to the and the of the from was in an of the patients with chronic diseases and in a new and acid were from and lysophosphoethanolamine 16:0, lysophosphatidylcholine and were from and taurocholic acid acid acid, acid, acid, acid, acid and were from The was a The rat serum metabolic profiling analysis was performed using a method on a that was to a The used was cm with the of acid and The and methods were in P. D. C. J. X. Lu X. Yang S. Gu J. Xu G. study of hepatitis liver cirrhosis and hepatocellular carcinoma by using and with mass 2009; PubMed Scopus Google Scholar, X.H. Yin Li H. Xu method for data from liquid use of and for PubMed Scopus Google Scholar) and the The was and the rate of the was The total was with and The human serum metabolic were using a that was to an The and the for this were the as those in the high of was used as the The was and the was The rate of the gas was and the rate of the gas was The was using the ion and the mass was The of the was with a rate of the defined the mass of the “marker were less than 2 To the of the metabolites, all of the metabolites in a total ion chromatogram were and using the The were and the total area from was to a of the of all of the metabolites were to this total the of the metabolites, their were to an for the statistical To the and of the were used as in the S. I. R. S. B. human metabolomics a for data and PubMed Scopus Google Scholar, H. R. and for and PubMed Scopus Google Scholar, G.A. of an method for to human 2007; PubMed Scopus Google Scholar). The were from of and with the total of of the were performed on the the The were also and in was used for the The multivariate of the partial least squares analysis with the was The of were used for the of the and the of the and the of the J. Holmes E. in 2007; PubMed Scopus Google Scholar). test was used to the model of the for was used for the statistical The data were using the with as the of statistical was also performed using this A. G. A. R. of serum biomarkers for using J. PubMed Scopus Google Scholar). the the of the were to the discrimination of the operating characteristic curve was by using the The were on the results of the The in this study were those with the sensitivity and different were performed for small HCC and HCC, 3 were The was used for the hierarchical analysis and analysis for The method was performed to R. G. analysis of to the 2001; PubMed Scopus Google Scholar). of of these of liver or a of the tumor during the total of from the model and from the were for to the all of the that were the of the study of the liver as in the The progression of hepatocarcinogenesis in this model was the the cirrhosis and the HCC The and were the characteristic of the and HCC In and were that were stages with on the the sera from of the and the were collected for a metabolic analysis the rat serum total ion of the the and the the different cirrhosis and carcinoma These the metabolic the different the and of all a total of metabolite were in the data for the statistical To model and the in the rat a partial least squares discriminate analysis of the data for of the lesions was were and the and were and of the data was on the results of the test H. R. and for and PubMed Scopus Google Scholar) was and the was in the the of the the the The that metabolites such as were the metabolites such as and were an ideal it be to the disease and have or from the To the of the a test was performed the and model with the was found that and the model and the the the cirrhosis and carcinoma total of metabolites in least of liver disease These metabolites could better the metabolic of the and were also to the stages of the liver diseases and using a model was and was The model achieved a better cirrhosis and which was all the were used in the model that was on with the metabolites were to the variable importance in the projection a total of with a were and the chemical of were on the metabolite J. X. J. Yin P. P. Lu X. R. Xu G. for the and of biomarkers in a study for the discovery of risk for diabetes by the and mass 2008; PubMed Scopus Google Scholar, C. J. R. G. M. E. Lu X. Xu J. method for profiling of method and to 2008; PubMed Scopus Google Scholar). was that these metabolites could also be found in the data from the human metabolic the results that were from the rat may be to patients. To the potential biomarkers from the with a a was the of the in the model with the in the metabolites a characteristic of that the of the progression of hepatocarcinogenesis. For example, and from to In the of the metabolite were in the metabolites in all of the model such as acid metabolites, such as and in the model To the of the was performed to the potential the These metabolites were to their which were on the different The metabolites were major were fatty acid and and was fatty and was all with different of and cluster was was and on the results and X.H. Yin Li H. Xu method for data from liquid use of and for PubMed Scopus Google Scholar), the characteristic metabolites were from cluster 22:5, 16:0, and which to to The metabolites in the cluster also similar The metabolic of these characteristic metabolites during are in The of to during the early of HCC and greatly as the tumor with the The of with the of the in it in The of as the cirrhosis and during the of HCC and during this it the and the The of during the of in the of HCC during the and in the tumor The of with that in the especially The analysis for method R. G. analysis of to the 2001; PubMed Scopus Google Scholar) was used to the The results that 16:0, and were the metabolites for the of the model and the and are the metabolites for the carcinoma and to the and in and and a similar metabolic a was as a marker from the for and was For the of HCC markers in was of similar the model and the in or stages they a metabolic to the metabolites in cluster such as The of can the risk of metabolites 22:5, 16:0, and were as markers for to the of the metabolites and the analysis a discrimination is in were a data to the model and a test data for and were to the of the and of the and of the were in the and of the and 87.5% of the in the test were also using the model the HCC were from using 22:5, of the HCC and of the were and the was and in the test of the and of the cirrhosis were using all metabolites, and with hepatitis was from HCC rat model also similar of using the model The that were in the stages and were also using the of the were as and of the were to be To test the usefulness of the marker metabolites for human HCC especially small HCC from and chronic 412 serum from 262 patients with HCC, 76 patients with cirrhosis and 74 patients with chronic hepatitis B were using the and the of the marker metabolites were For the patients with small HCC (solitary nodules with a of less than 2 the marker metabolites a sensitivity of 80.5% and a specificity of the results of ng/ml) for these patients were and 64%, the curve analysis of the marker metabolites an of which was than that of the of metabolic markers and achieved an of all HCC were the sensitivity of the HCC diagnosis with marker metabolites was and the specificity was was used as a for the of the HCC and of the were The curve analysis that the of the marker metabolites was which was than that of The results were to the were also which were represented on The are for small HCC and for all the patients. these were a sensitivity of and specificity of could be achieved for the diagnosis of small HCC. a sensitivity of and specificity of could be achieved for discrimination of all HCC patients. a of was of 262 HCC patients were of these patients a of the metabolite markers than the the of HCC. the for the patients with cases for the In the use of the 3 marker metabolites the specificity and the diagnostic of the metabolic markers Early or diagnosis of HCC would be for the and HCC patients with chronic liver diseases a HCC an to the early biomarkers of the and of HCC. The metabolomics a of the and can be used to the metabolic that in different J.K. Lindon J.C. 2008; PubMed Scopus Google Scholar). The of the study was that a metabolomics study of hepatocarcinogenesis would provide early or metabolic markers for HCC, the serum metabolic profiling analysis of rat of HCC was the of this The results that the rat HCC model was The progression of hepatocarcinogenesis could be the the cirrhosis and the carcinoma The study was on the metabolic in the rat using a in and are major factors in model Moreover, these factors are to the the metabolites were using a statistical analysis and the were also to the stages of liver diseases which provide for the of marker using to with were The metabolites that metabolic fatty were during in the model these metabolic the of metabolites of these metabolites and represented the major metabolic results that the of metabolism is of great importance during the and were in the of which the abnormal metabolism of unsaturated fatty such as acid and acid, could in the of C. of by the endogenous of PubMed Scopus Google Scholar). The of has been as the early in the liver S. C. in fatty acid with liver and the progression of nodules in rat 2001; PubMed Scopus Google Scholar). as a from liver by fatty acid in and the from M. Y. M. of fatty and in 2001; PubMed Scopus Google Scholar, A.M. S.A. A. of diethylnitrosamine-induced in J. Gastroenterol. 2009; PubMed Scopus Google Scholar). in the metabolism of The of were by such as PE N-methyltransferase 2 which the of PE to in the liver is the of is or in HCC and may the of PE or for the high of PE or B. M. A. A. of N-methyltransferase in human hepatocellular 2003; PubMed Scopus Google Scholar). the of PE to in and which the or in the model with the used clinical liver of and the for the of PE could be to hepatocellular are from in the and in and The high of in the would be for hepatocellular in HCC and chronic liver diseases could also be on the of in the diagnosis of PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar), the of the marker metabolites to discriminate liver diseases in was The results for these metabolites to be used as markers for the of HCC and chronic liver The model in the different disease stages were to their which is is to the progression of HCC. the in the stages variable on the The from or and were the discrimination of the or was of the of cirrhosis or in and were as the and were as the HCC. is for the the results are for subsequent markers for the or diagnosis of HCC. 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In these metabolic the of metabolism during hepatocarcinogenesis, which for and of of HCC. The study also the of metabolomics to the metabolic that during the biological in with

BackgroundDeep learning has been widely used for glaucoma diagnosis. However, there is no clinically validated algorithm for glaucoma incidence and progression prediction. This study aims to develop a clinically feasible deep-learning system for predicting and stratifying the risk of glaucoma onset and progression based on color fundus photographs (CFPs), with clinical validation of performance in external population cohorts.MethodsWe established data sets of CFPs and visual fields collected from longitudinal cohorts. The mean follow-up duration was 3 to 5 years across the data sets. Artificial intelligence (AI) models were developed to predict future glaucoma incidence and progression based on the CFPs of 17,497 eyes in 9346 patients. The area under the receiver operating characteristic (AUROC) curve, sensitivity, and specificity of the AI models were calculated with reference to the labels provided by experienced ophthalmologists. Incidence and progression of glaucoma were determined based on longitudinal CFP images or visual fields, respectively.ResultsThe AI model to predict glaucoma incidence achieved an AUROC of 0.90 (0.81-0.99) in the validation set and demonstrated good generalizability, with AUROCs of 0.89 (0.83-0.95) and 0.88 (0.79-0.97) in external test sets 1 and 2, respectively. The AI model to predict glaucoma progression achieved an AUROC of 0.91 (0.88-0.94) in the validation set, and also demonstrated outstanding predictive performance with AUROCs of 0.87 (0.81-0.92) and 0.88 (0.83-0.94) in external test sets 1 and 2, respectively.ConclusionOur study demonstrates the feasibility of deep-learning algorithms in the early detection and prediction of glaucoma progression.FUNDINGNational Natural Science Foundation of China (NSFC); the High-level Hospital Construction Project, Zhongshan Ophthalmic Center, Sun Yat-sen University; the Science and Technology Program of Guangzhou, China (2021), the Science and Technology Development Fund (FDCT) of Macau, and FDCT-NSFC.

Background Solid components of part-solid nodules (PSNs) at CT are reflective of invasive adenocarcinoma, but studies describing radiomic features of PSNs and the perinodular region are lacking. Purpose To develop and to validate radiomic signatures diagnosing invasive lung adenocarcinoma in PSNs compared with the Brock, clinical-semantic features, and volumetric models. Materials and Methods This retrospective multicenter study (https://ClinicalTrials.gov, NCT03872362) included 291 patients (median age, 60 years; interquartile range, 55–65 years; 191 women) from January 2013 to October 2017 with 297 PSN lung adenocarcinomas split into training (n = 229) and test (n = 68) data sets. Radiomic features were extracted from the different regions (gross tumor volume [GTV], solid, ground-glass, and perinodular). Random-forest models were trained using clinical-semantic, volumetric, and radiomic features, and an online nodule calculator was used to compute the Brock model. Performances of models were evaluated using standard metrics such as area under the curve (AUC), accuracy, and calibration. The integrated discrimination improvement was applied to assess model performance changes after the addition of perinodular features. Results The radiomics model based on ground-glass and solid features yielded an AUC of 0.98 (95% confidence interval [CI]: 0.96, 1.00) on the test data set, which was significantly higher than the Brock (AUC, 0.83 [95% CI: 0.72, 0.94]; P = .007), clinical-semantic (AUC, 0.90 [95% CI: 0.83, 0.98]; P = .03), volumetric GTV (AUC, 0.87 [95% CI: 0.78, 0.96]; P = .008), and radiomics GTV (AUC, 0.88 [95% CI: 0.80, 0.96]; P = .01) models. It also achieved the best accuracy (93% [95% CI: 84%, 98%]). Both this model and the model with added perinodular features showed good calibration, whereas adding perinodular features did not improve the performance (integrated discrimination improvement, −0.02; P = .56). Conclusion Separating ground-glass and solid CT radiomic features of part-solid nodules was useful in diagnosing the invasiveness of lung adenocarcinoma, yielding a better predictive performance than the Brock, clinical-semantic, volumetric, and radiomics gross tumor volume models. Online supplemental material is available for this article. See also the editorial by Nishino in this issue. Published under a CC BY 4.0 license

damage through the AMPK/C/EBP β/miR-1a-3p/GRP94 pathway, which indicates that metformin may be applied for the treatment of I/R injury.

Background: ) receptor agonist, having the possibility to be an ideal sedative drug for procedural sedation. At present, there are few studies on the effect of RT on respiratory depression in elderly patients. We aimed to evaluate the effect of RT on respiratory depression in elderly patients undergoing gastroscopy. Methods: This prospective, randomized, single-blinded trial recruited patients from eight centers in China between May 2022 and July 2022. A total of 346 elderly patients undergoing gastroscopy were randomly divided into RT group (0.2 mg/kg) or propofol group (1.5 mg/kg), respectively. The primary outcome was the incidence of respiratory depression. Secondary outcomes include the incidence of sedative-related adverse events, the success rate of sedation, time to fully alert, time to loss of consciousness (LOC), time to ready for discharge, as well as the the patients, endoscopists and anethetists' satisfaction. Results: The incidence of respiratory depression was significantly reduced in the RT group compared with the propofol group (9.8% vs 17.9%, P=0.042). The time of LOC and fully alert in the RT group were longer than that in the propofol group (P < 0.05). The incidences of hypotention (50.9% vs 32.4%, P=0.001) and hypotension requiring treatment (5.8% vs 1.7%, P=0.031) were significantly higher in the propofol group than that in the RT group. The incidence and severity of injection pain were more frequently recorded in the propofol group than that in the RT group (40.5% vs 12.1%, P<0.05). There were no statistically significant differences between the two groups in terms of sedation success rates, time to ready for discharge, endoscopists and anethetists' satisfaction and other sedative-related adverse events. Conclusion: RT may be a suitable alternative sedative agent for elderly patients undergoing gastroscopy due to its safety profile.

One of the key roadblocks in UCNP development is its extremely limited choices of excitation wavelengths. We report a generic design to program UCNPs to possess highly tunable dye characteristic excitation bands. Using such distinctive properties, we were able to develop a new excitation wavelength selective security imaging. This work unleashed the greater freedom of the excitation wavelengths of the upconversion nanoparticles and we believe it is a game-changer in the field and this method will enable numerous applications that are currently limited by existing UCNPs.

Cancer has emerged as a formidable challenge in the 21st century, impacting society, public health, and the economy. Conventional cancer treatments often exhibit limited efficacy and considerable side effects, particularly in managing the advanced stages of the disease. Photodynamic therapy (PDT), a contemporary non-invasive therapeutic approach, employs photosensitizers (PS) in conjunction with precise light wavelengths to selectively target diseased tissues, inducing the generation of reactive oxygen species and ultimately leading to cancer cell apoptosis. In contrast to conventional therapies, PDT presents a lower incidence of side effects and greater precision in targeting. The integration of intelligent nanotechnology into PDT has markedly improved its effectiveness, as evidenced by the remarkable synergistic antitumor effects observed with the utilization of multifunctional nanoplatforms in conjunction with PDT. This paper provides a concise overview of the principles underlying PS and PDT, while also delving into the utilization of nanomaterial-based PDT in the context of cancer treatment.

Fascioliasis is a common parasitic disease in livestock in China. However, human fascioliasis is rarely reported in the country. Here we describe an outbreak of human fascioliasis in Yunnan province. We reviewed the complete clinical records of 29 patients and performed an epidemiological investigation on the general human population and animals in the outbreak locality. Our findings support an outbreak due to Fasciola gigantica with a peak in late November, 2011. The most common symptoms were remittent fever, epigastric tenderness, and hepatalgia. Eosinophilia and tunnel-like lesions in ultrasound imaging in the liver were also commonly seen. Significant improvement of patients' condition was achieved by administration of triclabendazole®. Fasciola spp. were discovered in local cattle (28.6%) and goats (26.0%). Molecular evidence showed a coexistence of F. gigantica and F. hepatica. However, all eggs seen in humans were confirmed to be F. gigantica. Herb (Houttuynia cordata) was most likely the source of infections. Our findings indicate that human fascioliasis is a neglected disease in China. The distribution of triclabendazole®, the only efficacious drug against human fascioliasis, should be promoted.

Hepatocellular carcinoma (HCC) was the most common primary liver cancer, and its resistance to anti-tumor drugs often caused the death of patients suffering with HCC. Matrix stiffness was reported to be closely related to tumor chemoresistance; however, the relationship between HCC drug resistance and three-dimensional (3D) matrix stiffness is still unclear at present. In this study, alginate gel (ALG) beads with controllable matrix stiffness were used to mimic tumor tissue rigidity, and the role of 3D matrix stiffness in regulating the chemoresistance of HCC cells was investigated by using these ALG beads. It was found that HCC cells in ALG beads with 105 kPa stiffness had highest resistance to paclitaxel, 5-FU, and cisplatin. Although the mechanism was still uncovered, ABC transporters and endoplasmic reticulum stress-related molecules were highly expressed in ALG bead-encapsulated HCC cells compared with two-dimensional-cultured cells, which suggested a very complex mechanism underlying HCC drug resistance in 3D culture conditions. In addition, to mimic the specific stiffness of HCC tumor tissue, or other tumor tissues in vivo, response surface methodology (RSM) was used to build up a prediction mathematical model so that ALG beads with desired matrix stiffness could be prepared by simply changing three factors: molecular weight, G content, and alginate concentration.

// Yu-Long Lan 1,2,3,4,* , Xun Wang 1,4,* , Jia-Cheng Lou 1 , Xiao-Chi Ma 2 and Bo Zhang 1 1 Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China 2 Department of Pharmacy, Dalian Medical University, Dalian, China 3 Department of Physiology, Dalian Medical University, Dalian, China 4 Department of Neurosurgery, The Third People&rsquo;s Hospital of Dalian, Non-Directly Affiliated Hospital of Dalian Medical University, Dalian, China * These authors have contributed equally to this work Correspondence to: Bo Zhang, email: // Xiao-Chi Ma, email: // Keywords : AQP4, orthogonal arrays of particles, glioma, expression, regulation Received : November 25, 2016 Accepted : February 22, 2017 Published : March 08, 2017 Abstract Aquaporin 4 (AQP4) is the major water channel expressed in the central nervous system and is primarily expressed in astrocytes. Recently, accumulated evidence has pointed to AQP4 as a key molecule that could play a critical role in glioma development. Discoveries of the role of AQP4 in cell migration suggest that AQP4 could be a significant factor regarding glioma malignancies. However, the AQP4 expression levels in glioma have not been fully elucidated; furthermore, the correlation of AQP4 expression with glioma malignancy remains controversial. Here, we review the expression pattern and predictive significance of AQP4 in malignant glioma. The molecular mechanism of AQP4 as it pertains to the migration and invasion of human glioma cells has been summarized. In addition, the important roles of AQP4 in combating drug resistance as well as potential pharmacological blockers of AQP4 have been systematically discussed. More research should be conducted to elucidate the potential roles of AQP4 in malignant glioma for identifying the tumor type, progression stages and optimal treatment strategies. The observed experimental results strongly emphasize the importance of this topic for future investigations.

In this study, an ultra fast LC/IT-TOF MS (UFLC/IT-TOF MS)-based serum lipidomics method was employed to characterize the serum lipid profile of patients with chronic hepatitis B, cirrhosis, and hepatocellular carcinoma (HCC). After data collection and processing, 96 lipids including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, triacylglycerides, and cholesterol esters were identified and used for subsequent data analysis. Partial least squares-discriminant analysis revealed that patients with liver diseases had distinctly different serum lipid profile from that of healthy controls; while cirrhosis and HCC patients had a similar serum lipid profile, but different from that of hepatitis patients. The ANOVA analysis found 75 of the 96 identified lipids to be abnormally regulated, among which most of these lipids were downregulated in cirrhosis and HCC patients compared with those of healthy controls and hepatitis patients, while hepatitis patients induced several lipids downregulated and others upregulated compared with those of healthy controls, indicating the aberrant lipid metabolism in patients with liver diseases. This work demonstrated the utility of UFLC/IT-TOF MS-based serum lipidomics as a powerful tool to investigate the lipid metabolism of liver diseases.

OBJECTIVE: To investigate the anti-inflammatory and antioxidant effect of curcumin on lung lesion induced by intestinal ischemia reperfusion injury (IIR). METHODS: Rats were divided into four groups: sham, intestinal IIR (IIR), 1 mg/kg of curcumin treatment group (1 mg/kg), and 5 mg/kg of curcumin treatment group (5 mg/kg). Curcumin was given respectively (1 mg/kg and 5 mg/kg) following the above doses. IIR was produced by 1 h of intestinal ischemia followed by 2 h of reperfusion. Rats were sacrificed at the end of reperfusion and lung tissues were collected for biochemical and histopathological examination in 4 groups. Lung tissues histology and bronchoalveolar lavage fluid (BALF) protein were assayed. Serum IL-6, lung superoxide dismutase (SOD) and myeloperoxidase (MPO) were measured. The expression level of NF-κB and ICAM-1 (including immunohistochemical analysis and western blot analysis) were also measured. RESULTS: Lung tissue injury induced by IIR was obviously observed through pathology and BALF protein. MPO activity, IL-6 level and ICAM-1 expression were significantly increased with the elevation of NF-κB, simultaneously, SOD activity was decreased. With Treatment of curcumin, pathology and BALF protein of lung tissue were improved clearly. Inflammatory indexes (MPO activity, IL-6 level and ICAM-1) were improved and antioxidant index (SOD activity) was enhanced paralleled with NF-κB. CONCLUSION: Using curcumin effectively prevented IIR-induced lung injury. Anti-inflammatory and antioxidant effects of curcumin could be observed by inhibiting the pathway of NF-κB.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 μg/kg bolus over 3-5 minutes followed by an infusion of 1.0 μg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Most diabetic patients develop diabetic peripheral neuropathy (DPN). DPN is related to the increase of inflammatory cells in peripheral nerves, abnormal cytokine expression, oxidative stress, ischemia ,and pro-inflammatory changes in bone marrow. We summarized the progress of immune-inflammatory mechanism and treatment of DPN in recent years. Immune inflammatory mechanisms include TNF-α, HSPs, PARP, other inflammatory factors, and the effect of immune cells on DPN. Treatment includes tricyclic antidepressants and other drug therapy, immune and molecular therapy, and non-drug therapy such as exercise therapy, electrotherapy, acupuncture, and moxibustion. The pathogenesis of DPN is complex. In addition to strictly controlling blood glucose, its treatment should also start from other ways, explore more effective and specific treatment schemes for various causes of DPN, and find new targets for treatment will be the direction of developing DPN therapeutic drugs in the future.

miR-152, as a tumor suppressor, has been reported to be downregulated in a number of cancer cell lines and tumor tissues, including breast cancer. This study aimed to investigate the role of miR-152 in human breast cancer and its underlying mechanisms. Human breast cancer cell line HCC1806 was transfected with hsa-miR-152-3p mimic, inhibitor, or scrambled negative controls. The efficiency of miR-152-3p transfection was evaluated by quantitative real-time PCR, and the effects on cell viability and apoptosis as well as on the PI3K/AKT signaling pathway were investigated by MTT assay, flow cytometry, and Western blot analysis, respectively. The binding effect of miR-152-3p on PIK3CA 3'-UTR was also investigated. The results suggested that miR-152-3p mimic transfection inhibited cell viability while inducing apoptosis of HCC1806 cells. Furthermore, miR-152-3p negatively regulated PIK3CA expression via binding to the 3'-UTR of PIK3CA and decreased the phosphorylation levels of AKT (Ser473) and RPS6 (Ser235/236) in HCC1806 cells. miR-152-3p inhibitor transfection showed the opposite effects. In conclusion, miR-152-3p might serve as a tumor suppressor in human breast cancer cells via negatively regulating PIK3CA expression to inhibit the activation of AKT and RPS6, leading to suppression of HCC1806 cell proliferation.

BACKGROUND: Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally? METHOD: Symptoms at their lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾ 30 years, with recurrent DSM-IV MD. Latent class analysis (LCA) was performed in Mplus. RESULTS; Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n = 27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct. CONCLUSIONS: MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences.

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.