Objectives:This study aimed to observe the disintegration of clopidogrel and ticagrelor in vitro solution with different pH levels and in human digestive tract.Methods:(1)In vitro study:0.9% normal saline was mixed with hydrochloric acid and sodium bicarbonate respectively to mimic fasting gastric fluid,postprandial gastric fluid,gastric fluid after taking acid-inhibiting agent,acid-free gastric fluid and small intestine fluid.The disintegration of clopidogrel and ticagrelor in different pH solutions was observed.(2)In vivo study:12 patients who were admitted to the Department of Geriatric,Peking University First Hospital from 2022.11 to 2023.6 were included and underwent magnetic controlled capsule endoscopy.We observed the disintegration of clopidogrel(n=6)and ticagrelor(n=6)in the digestive tract.Results:(1)In vitro study:clopidogrel began to disintegrate earlier than ticagrelor([21.67±7.53]s vs.[40.00±6.33]s,P=0.001),but clopidogrel disintegrated more slowly than ticagrelor([23.00±9.38]min vs.[8.33±1.97]min,P=0.011).Clopidogrel disintegrated faster in alkaline solution than in acidic and neutral solution([11.50±4.95]min vs.[28.75±2.50]min,P=0.004),and the disintegration rate of ticagrelor in alkaline solutions is comparable to that in acidic and neutral solutions([7.00±1.41]min vs.[9.00±2.00]min,P=0.285).(2)In vivo study:In the study population,the morphology of clopidogrel and ticagrelor began to change after passing through the esophagus,of which 3 cases(clopidogrel 1 case,ticagrelor 2 cases)were in powder state when passing through the cardia,and the remaining 9 cases were basically intact when entering the stomach and completely disintegrated in the stomach.The complete disintegration time of Clopidogrel varied significantly among individuals,ranging from 8 to 33 min,with an average of(18.80±10.38)min,while the complete disintegration time of ticagrelor ranged from 3 to 6 min,with an average of(4.25±1.26)min.Clopidogrel disintegrated slower than ticagrelor(P=0.034).Conclusions:In vitro study,clopidogrel disintegrated more slowly than ticagrelor in solutions at different pH levels.Compared with clopidogrel,the disintegration rate of ticagrelor was less affected by pH.After oral administration of clopidogrel and ticagrelor,clopidogrel disintegrated more slowly than ticagrelor.The difference of complete disintegration time between individuals of ticagrelor was smaller and the disintegration rate was faster.

AIM:To observe the role of enoyl-coenzyme A hydratase/L-3-hydroxyacyl-coenzyme A dehydroge-nase(Ehhadh)in renal tubulointerstitial inflammation in high-fat diet(HFD)fed mice,and to explore its molecular mecha-nism.METHODS:Twenty-four C57BL/6N mice were randomly divided into 4 groups:standard diet(SD)group,HFD group,HFD with Ehhadh overexpression(HFD+Ehh)group and HFD with blank vector(HFD+Vec)group.Each group consisted of 6 mice.The HFD mice were fed with a diet containing 60%fat,20%protein,and 20%carbohydrates for 16 weeks.Briefly,at the end of 8 weeks,the mice in HFD+Ehh or HFD+Vec group were injected with adeno-associated virus 9(AAV9)-Ehhadh or AAV9-vector via the tail vein,and then continued another 8-week HFD feeding.At the end of the experiments,the renal function and morphological changes were observed.The protein expression levels of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1 p10,interleukin-1β(IL-1β)and IL-18 in the kidney were detected by Western blot and immunohistochemistry.Immunofluorescence staining was used to detect the colocalization of Ehhadh and peroxisomal biogenesis factor 14(Pex14).ELISA was used to detect the content of IL-1β and IL-18 in the urine.Lipid droplet formation in renal tissues was detected by Nile red staining.Absolute quantitative lip-idomic analysis were used to detect the differential lipid species in renal cortices of the mice in SD,HFD and HFD+Ehh groups.RESULTS:Compared with SD group,the expression of Ehhadh protein was significantly decreased in the peroxi-some of renal tubular epithelium cells in HFD-fed mice(P<0.01).Overexpression of Ehhadh significantly improved renal function(P<0.01)and alleviated the morphological changes of renal tubular epithelial cells in HFD group.Moreover,it significantly inhibited the expression of inflammatory cytokines IL-1β and IL-18 and macrophage infiltration in renal tu-bule interstitium of HFD-fed mice(P<0.01).At the same time,Ehhadh overexpression inhibited HFD-induced NLRP3 inflammasome activation(P<0.01).It also attenuated lipid deposition in renal tubular epithelium cells(P<0.01)and promoted the β-oxidation of long-chain fatty acid such as cholesterol and phospholipids in peroxisomes.CONCLUSION:The Ehhadh inhibits tubulointerstitial inflammation by promoting long-chain fatty acid β-oxidation in peroxisomes and in-hibiting the activation of NLRP3 inflammasome in HFD-fed mice.

AIM:To observe the role of enoyl-coenzyme A hydratase/L-3-hydroxyacyl-coenzyme A dehydroge-nase(Ehhadh)in renal tubulointerstitial inflammation in high-fat diet(HFD)fed mice,and to explore its molecular mecha-nism.METHODS:Twenty-four C57BL/6N mice were randomly divided into 4 groups:standard diet(SD)group,HFD group,HFD with Ehhadh overexpression(HFD+Ehh)group and HFD with blank vector(HFD+Vec)group.Each group consisted of 6 mice.The HFD mice were fed with a diet containing 60%fat,20%protein,and 20%carbohydrates for 16 weeks.Briefly,at the end of 8 weeks,the mice in HFD+Ehh or HFD+Vec group were injected with adeno-associated virus 9(AAV9)-Ehhadh or AAV9-vector via the tail vein,and then continued another 8-week HFD feeding.At the end of the experiments,the renal function and morphological changes were observed.The protein expression levels of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1 p10,interleukin-1β(IL-1β)and IL-18 in the kidney were detected by Western blot and immunohistochemistry.Immunofluorescence staining was used to detect the colocalization of Ehhadh and peroxisomal biogenesis factor 14(Pex14).ELISA was used to detect the content of IL-1β and IL-18 in the urine.Lipid droplet formation in renal tissues was detected by Nile red staining.Absolute quantitative lip-idomic analysis were used to detect the differential lipid species in renal cortices of the mice in SD,HFD and HFD+Ehh groups.RESULTS:Compared with SD group,the expression of Ehhadh protein was significantly decreased in the peroxi-some of renal tubular epithelium cells in HFD-fed mice(P<0.01).Overexpression of Ehhadh significantly improved renal function(P<0.01)and alleviated the morphological changes of renal tubular epithelial cells in HFD group.Moreover,it significantly inhibited the expression of inflammatory cytokines IL-1β and IL-18 and macrophage infiltration in renal tu-bule interstitium of HFD-fed mice(P<0.01).At the same time,Ehhadh overexpression inhibited HFD-induced NLRP3 inflammasome activation(P<0.01).It also attenuated lipid deposition in renal tubular epithelium cells(P<0.01)and promoted the β-oxidation of long-chain fatty acid such as cholesterol and phospholipids in peroxisomes.CONCLUSION:The Ehhadh inhibits tubulointerstitial inflammation by promoting long-chain fatty acid β-oxidation in peroxisomes and in-hibiting the activation of NLRP3 inflammasome in HFD-fed mice.

Objectives:This study aimed to observe the disintegration of clopidogrel and ticagrelor in vitro solution with different pH levels and in human digestive tract.Methods:(1)In vitro study:0.9% normal saline was mixed with hydrochloric acid and sodium bicarbonate respectively to mimic fasting gastric fluid,postprandial gastric fluid,gastric fluid after taking acid-inhibiting agent,acid-free gastric fluid and small intestine fluid.The disintegration of clopidogrel and ticagrelor in different pH solutions was observed.(2)In vivo study:12 patients who were admitted to the Department of Geriatric,Peking University First Hospital from 2022.11 to 2023.6 were included and underwent magnetic controlled capsule endoscopy.We observed the disintegration of clopidogrel(n=6)and ticagrelor(n=6)in the digestive tract.Results:(1)In vitro study:clopidogrel began to disintegrate earlier than ticagrelor([21.67±7.53]s vs.[40.00±6.33]s,P=0.001),but clopidogrel disintegrated more slowly than ticagrelor([23.00±9.38]min vs.[8.33±1.97]min,P=0.011).Clopidogrel disintegrated faster in alkaline solution than in acidic and neutral solution([11.50±4.95]min vs.[28.75±2.50]min,P=0.004),and the disintegration rate of ticagrelor in alkaline solutions is comparable to that in acidic and neutral solutions([7.00±1.41]min vs.[9.00±2.00]min,P=0.285).(2)In vivo study:In the study population,the morphology of clopidogrel and ticagrelor began to change after passing through the esophagus,of which 3 cases(clopidogrel 1 case,ticagrelor 2 cases)were in powder state when passing through the cardia,and the remaining 9 cases were basically intact when entering the stomach and completely disintegrated in the stomach.The complete disintegration time of Clopidogrel varied significantly among individuals,ranging from 8 to 33 min,with an average of(18.80±10.38)min,while the complete disintegration time of ticagrelor ranged from 3 to 6 min,with an average of(4.25±1.26)min.Clopidogrel disintegrated slower than ticagrelor(P=0.034).Conclusions:In vitro study,clopidogrel disintegrated more slowly than ticagrelor in solutions at different pH levels.Compared with clopidogrel,the disintegration rate of ticagrelor was less affected by pH.After oral administration of clopidogrel and ticagrelor,clopidogrel disintegrated more slowly than ticagrelor.The difference of complete disintegration time between individuals of ticagrelor was smaller and the disintegration rate was faster.

Objective To provide a reference for the selection of frailty assessment tools for stroke patients by conducting a literature review of existing frailty assessment tools for stroke patients. Methods Systematic searches were conducted in PubMed, Web of Science, EMbase, SinoMed, Wanfang, VIP, and China National Knowledge Infrastructure(CNKI) databases from their inception to May 2023. The literature that met the research purpose and question were screened, and the basic information of each article, including the first author, publication year, country of publication, type of research design, name of the assessment tool, dimensions of scale, the number of items, and assessment time, was extracted. Results A total of 1, 729 articles were retrieved in this study. After multiple screenings, 22 articles (including 8 frailty assessment tools) were ultimately included. The analysis results showed that the evaluation indicators, evaluation time, and evaluation methods of the 8 frailty assessment tools were different and had their own advantages and disadvantages. Among them, the frailty index was the most commonly used frailty assessment tool for stroke patients. The selection of effective frailty assessment tools for stroke patients is essential for strengthening prestroke risk stratification and improving poststroke outcomes. Conclusion There are significant differences among different frailty assessment tools, and existing assessment tools have limitations in measuring frailty in stroke patients. Comprehensive assessments should be conducted in combination with clinicians' experience and judgment. New frailty assessment tools are needed in future research to better guide the rehabilitation treatment and management of stroke patients.

NUT carcinoma(nuclear protein in testis carcinoma)is a rare and highly invasive malignant tumor,which is most common in midline organs and lungs.The characteristic genetic change of NUT carcinoma is the rearrangement of NUT middle carcinoma family member 1(NUTM1)gene.In this article,we will review the pathogenic mechanism of its most common fusion form,bromodomaincontaining protein 4(BRD4)-NUTM1 fusion gene,and the progress in the research and development of targeting drugs.

Objective To investigate the relationship of miRNA gene polymorphisms with blood pressure(BP)responses to the sodium and potassium diet intervention.Methods In 2004,we recruited 514 participants from 124 families in seven villages of Baoji,Shaanxi Province,China.All subjects were given a three-day normal diet,followed by a seven-day low-salt diet,a seven-day high-salt diet,and finally a seven-day high-salt and potassium supplementation.A total of 19 miRNA single nucleotide polymorphisms(SNPs)were selected for analysis.Results Throughout the sodium-potassium dietary intervention,the BP of the subjects fluctuated across all phases,showing a decrease during the low-salt period and an increase during the high-salt period,followed by a reduction in BP subsequent to potassium supplementation during the high-salt diet.MiR-210-3p SNP rs 12364149 was significantly associated with systolic BP(SBP),diastolic BP(DBP)and mean arterial pressure(MAP)responses to low-salt diet.MiR-4638-3p SNP rs6601178 was significantly associated with SBP while miR-26b-3p SNP rs115254818 was significantly associated with MAP responses to low-salt intervention.In addition,miR-26b-3p SNP rs115254818 was significantly correlated with SBP,DBP and MAP responses to high-salt intervention.MiR-1307-5p SNPs rs1 1191676 and rs2292807 were associated with SBP and MAP responses to high-salt diet.MiR-4638-3p SNP rs6601178,miR-210-3p SNP rs12364149,miR-382-5p SNP rs4906032 and rs4143957 were significantly associated with SBP response to high-salt diet.In addition,miR-26b-3p SNP rs115254818 was significantly associated with SBP,DBP and MAP responses to potassium supplementation.MiR-1307-5p SNPs rs11191676,rs2292807,and miR-19a-3p SNP rs4284505 were significantly associated with SBP responses to high-salt and potassium supplementation.Conclusion miRNA gene polymorphisms are associated with BP response to sodium and potassium,suggesting that miRNA genes may be involved in the pathophysiological process of salt sensitivity and potassium sensitivity.

Objective:To investigate the prevalence of enterovirus infection and its clinical characteristics in neonatal febrile cases.Methods:A total of 308 neonates in the neonatal ward of Kunming Children′s Hospital with febrile symptoms from March 2018 to February 2019 were selected for the study.Fecal specimens and some (271) cerebrospinal fluid specimens were collected from all neonates.Enterovirus was respectively detected in feces and cerebrospinal fluid by using reverse transcription-polymerase chain reaction (RT-PCR) method.The rate of enterovirus infection in febrile neonates was clarified.They were divided into enterovirus infection group ( n=91) and no enterovirus infection group ( n=217). The clinical data of the subjected neonates in the two groups were analyzed and the clinical manifestations of the neonates and their laboratory findings were compared statistically. Results:Ninety-one enteroviruses (90 enterovirus were general type, and 1 was coxsackievirus A16 type) were detected in 308 children, accounting for 29.55% of all neonates.Viral RNA was detected in only 1 case [0.37% (1/271)]of all examined cerebrospinal fluid specimens, which was significantly lower than the detection rate of 29.55% (91/308) in fecal specimens.There were no fatal cases, but there was one severe case in enterovirus infection group.Except for the severe case which was discharged automatically, all of them improved or healed and discharged from hospital.The clinical manifestations of the enterovirus infection group were non-specific statistically compared with the non-enterovirus infection group(all P>0.05), except for respiratory symptoms and skin rash(all P<0.05). The incidence of enterovirus infection was significantly seasonal[83.52%(76/91)in summer and autumn]. Conclusion:In the epidemic season of enterovirus, it is recommended to list fecal enterovirus as a routine test item to improve the accuracy and timeliness of diagnosis and treatment, and avoid the application of unnecessary antibiotics and the outbreak of enterovirus in the neonatal ward.

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and most of the patients are diagnosed at the advanced stage. Most of the treating options are comprehensive treatment, in which immunotherapy plays more and more important role. Melanoma antigen-associated gene-A (MAGE-A) family is a kind of cancer testis antigens. Except in germ cells of testis and trophoblast cells of placenta, MAGE-A family is highly expressed in cancerous tissues and participates in a variety of biological processes, such as cancer cell proliferation, differentiation and metastasis. In addition, cancer testis antigen also possesses good immunogenicity, which can induce humoral and cellular immune responses, is a good target for immunotherapy, and has good application value in the diagnosis, treatment and prognosis of GC. A variety of targeted therapeutic drugs based on MAGE-A are in phase I or II clinical trials, it has good safety and potential clinical application value. With the continuous progress of clinical trials and basic research on MAGE-A targets in GC, it is expected to provide a theoretical basis for clinical transformation and immunotherapy of MAGE-A in the future.
Male ; Humans ; Stomach Neoplasms/therapy* ; Antigens, Neoplasm/genetics* ; Melanoma ; Immunotherapy ; Prognosis

【Objective】 Corin, a transmembrane serine protease that can cleave atrial natriuretic peptide precursor (pro-ANP) into atrial natriuretic peptide with smaller bioactive molecules, participates in the pathophysiological process of hypertension and cardiac hypertrophy. The purpose of this study was to explore the relationship of Corin gene variation with blood pressure responses to sodium and potassium dietary interventions. 【Methods】 In 2004, we recruited 514 participants from 124 families in 7 villages of Baoji, Shaanxi Province, China. All the subjects received a 3-day normal diet, a 7-day low-salt diet, a 7-day high-salt diet, and finally a 7-day high-salt and potassium supplementation. Fifteen single nucleotide polymorphisms (SNPs) of Corin gene were selected for final analysis. 【Results】 SNPs rs12509275 were significantly associated with diastolic blood pressure (DBP) response to low-salt diet, while rs3749584 was associated with pulse pressure (PP) response to low-salt diet.SNP rs3749584 and rs10517195 were significantly associated with PP response to high-salt diet. In addition,rs17654278 were significantly associated with systolic blood pressure (SBP) response to high-salt and potassium supplementation, rs2271037 was significantly correlated with DBP responses to high-salt and potassium supplementation, and rs4695253, rs12509275, rs2351783, rs36090894 were significantly associated with PP response to high-salt and potassium supplementation. 【Conclusion】 Corin gene polymorphisms were associated with blood pressure response to sodium and potassium, suggesting that Corin gene may be involved in pathophysiological process of salt sensitivity and potassium sensitivity.