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Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer

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Signal Transduction and Targeted Therapy 2024年第1期9卷 295-307页

作者： Xiaoxiao Liu Xing Zhang Zhiying Shao Xiaorong Zhong Xin Ding Liang Wu Jie Chen ping He Yan Cheng Kunrui zhu Dan Zheng jing jing Ting Luo Institute for Breast Health Medicine Cancer CenterBreast CenterWest China HospitalSichuan University610041 ChengduSichuanChina Department of Radiation Oncology Cancer CenterAffiliated Hospital of Xuzhou Medical UniversityJiangsu Center for the Collaboration and Innovation of Cancer BiotherapyCancer InstituteXuzhou Medical University221000 XuzhouChina Department of Orthopedics Trauma and Reconstructive SurgeryUniversity Hospital RWTH AachenAachen 52074Germany Cancer Institute Xuzhou Medical University221000 XuzhouJiangsuChina Division of Nephrology and Transplantation Department of Internal MedicineUniversity Medical Center Rotterdam Erasmus MCRotterdam 3015 GDThe Netherlands Institute for Breast Health Medicine Department of General SurgeryBreast CenterWest China HospitalSichuan University610041 ChengduSichuanChina Institute for Breast Health Medicine West China HospitalSichuan University610041 ChengduSichuanChina

Human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC)has been the most challenging subtype of BC,consisting of 20%of BC with an apparent correlation with poor *** that pyrotinib,a new HER2 inhibitor,has led to dramatic improvements in prognosis,the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired ***,identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing ***,we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive *** determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest,inhibit the proliferation of BT-474 and SK-BR-3 BC cells,and repress in vivo tumor growth in xenograft mice *** may be attributed to enhanced autophagy induced by endoplasmic reticulum ***,the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase(G6PD)degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16(ZBTB16)in tumorigenesis of ***,we identified that miR-16-5p was a potential upstream regulator of ZBTB16,and it showed a significant inverse correlation with *** of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive ***,these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

关键词： HER2 synergistic Together

Design of dual-functional protic porous ionic liquids for boosting selective extractive desulfurization

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Petroleum Science 2024年第4期21卷 2817-2829页

作者： Jin-Rui Zhang Jie Yin jing He Hong-Shun Ran Wei Jiang Hong-ping Li Wen-Shuai zhu Hua-Ming Li Ming Zhang School of the Environment and Safety Engineering & Institute for Energy Research Jiangsu University School of Chemistry and Chemical Engineering Jiangsu University

Porous ionic liquids have demonstrated excellent performance in the field of separation, attributed to their high specific surface area and efficient mass transfer. Herein, task-specific protic porous ionic liquids(PPILs) were prepared by employing a novel one-step coupling neutralization reaction strategy for extractive desulfurization. The single-extraction efficiency of PPILs reached 75.0% for ***, adding aromatic hydrocarbon interferents resulted in a slight decrease in the extraction efficiency of PPILs(from 45.2% to 37.3%, 37.9%, and 33.5%), indicating the excellent extraction selectivity of PPILs. The experimental measurements and density functional theory calculations reveal that the surface channels of porous structures can selectively capture dibenzothiophene by the stronger electrophilicity(Eint(HS surface channel/DBT)=-39.8 kcal mol-1), and the multiple extraction sites of ion pairs can effectively enrich and transport dibenzothiophene from the oil phase into PPILs through π...π, C-H...π and hydrogen bonds interactions. Furthermore, this straightforward synthetic strategy can be employed in preparing porous liquids, offering new possibilities for synthesizing PPILs with tailored functionalities.

关键词： Protic porous ionic liquids Extractive desulfurization Selectivity Density functional theory

Postoperative body weight change and its influencing factors in patients with gastric cancer

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World Journal of Gastrointestinal Surgery 2024年第7期16卷 2242-2254页

作者： Yan Li Li-Hua Huang Hui-Di zhu ping He Bei-Bei Li Li-jing Wen Department of Gastrointestinal Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Nursing The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

BACKGROUND The high incidence and mortality of gastric cancer(GC)pose a significant threat to human life and health,and it has become an important public health challenge in *** weight loss is a common complication after surgical treatment in patients with GC and is associated with poor prognosis and GC ***,current attention to postoperative weight change in GC patients remains insufficient,and the descriptions of postoperative weight change and its influencing factors are also *** To investigate body weight changes in patients with GC within 6 mo after gastrectomy and identify factors that influence dynamic body weight *** We conducted a prospective longitudinal study of 121 patients with GC and collected data before(T0)and 1(T1),3(T2),and 6(T3)mo after gastrectomy using a general data questionnaire,psychological distress thermometer,and body weight *** general estimation equation(GEE)was used to analyze the dynamic trends of body weight changes and factors that influence body weight changes in patients with GC within 6 mo of *** The median weight loss at T1,T2,and T3 was 7.29%(2.84%,9.40%),11.11%(7.64%,14.91%),and 14.75%(8.80%,19.84%),*** GEE results showed that preoperative body mass index(BMI),significant psychological distress,religious beliefs,and sex were risk factors for weight loss in patients with GC within 6 mo after gastrectomy(P14.685,P1).Furthermore,patients with significant psychological distress were more likely to lose weight than those without(β=2.490,P1),and religious patients were less likely to lose weight 6 mo after gastrectomy than those without religious beliefs(β=-6.844,P=0.001).Compared to female patients,male patients were more likely to experience weight loss 6 mo after gastrectomy(β=4.262,P=0.038).CONCLUSION Male patients wi

关键词： Gastric cancer Gastrectomy Weight loss Influencing factors Body mass index

Network pharmacology and subsequent experimental validation reveal the synergistic myocardial protection mechanism of Salvia miltiorrhiza *** Carthamus tinctorius L.

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Journal of Traditional Chinese Medical Sciences 2024年第1期11卷 44-54页

作者： Linying Zhong Ling Dong jing Sun Jie Yang Zhiying Yu ping He Bo zhu Yuxin zhu Siyuan Li Wenjuan Xu School of Life Sciences Bejing University of Chinese MedicineBeijing 102488China School of Chinese Materia Medica Beijing University of Chinese MedicineBejing 102488China

Objective:To reveal the molecular mechanism underlying the compatibility of Salvia miltiorrhiza Bge(***,Dan Shen)and *** L.(***,Hong Hua)as an herb pair through network pharmacology and subsequent experimental ***:Network pharmacology was applied to construct an active ingredient-efficacy target-disease protein network to reveal the unique regulation pattern of *** and *** as herb *** docking was used to verify the binding of the components of these herbs and their potential *** H9c2 glucose hypoxia model was used to evaluate the efficacy of the components and their synergistic effects,which were evaluated using the combination *** blot was performed to detect the protein expression of these ***:Network pharmacology analysis revealed 5 pathways and 8 core targets of *** and *** in myocardial *** of the core targets were enriched in the hypoxia-inducible factor-1(HIF-1)signaling *** achieved vascular tone mainly by regulating the target genes of the HIF-1 *** an upstream gene of the HIF-1 pathway,STAT3 can be activated by the active ingredients cryptotanshinone(Ctan),salvianolic acid B(Sal.B),and myricetin(Myric).Cell experiments revealed that Myric,Sal.B,and Ctan also exhibited synergistic myocardial protective *** docking verified the strong binding of Myric,Sal.B,and Ctan to *** blot further showed that the active ingredients synergistically upregulated the protein expressionof ***:The pharmacodynamic transmission analysis revealed that the active ingredients of *** and *** can synergistically resist ischemia through various targets and *** study provides a methodological reference for interpreting traditional Chinese medicine compatibility.

关键词： S.miltiorrhiza-C.tinctorius herb pair Compatibilitymechanism Networkpharmacology Multipletargeteffect Myocardial protection

Gene cloning,protein expression,and enzymatic characterization of a double-stranded RNA degrading enzyme in Apolygus lucorum

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Insect Science 2024年第1期31卷 119-133页

作者： Jie-Yu Zhang jing Zhao Keyan zhu-Salzman Qin-Qin Ji Yi-ping Jiang Liu-Bin Xiao De-Jin Xu Guang-Chun Xu Lin-Quan Ge Yong-An Tan College of Plant Protection Yangzhou UniversityYangzhouJiangsu ProvinceChina Institute of Plant Protection Jiangsu Academy of Agricultural SciencesNanjingJiangsu ProvinceChina Department of Entomology Texas A&M UniversityCollege StationTXUSA Taizhou Customs of the People's Republic of china TaizhouJiangsu ProvinceChina

RNA interference(RNAi)is a powerful tool that post-transcriptionally silences target genes in eukaryotic ***,silencing efficacy varies greatly among different insect ***,we met with little success when attempting to knock down genes in the mirid bug Apolygus lucorum via dsRNA *** disappearance of double-stranded RNA(dsRNA)could be a potential factor that restricts RNAi ***,we found that dsRNA can be degraded in midgut fluids,and a dsRNase of ***(AldsRNase)was identified and *** alignment indicated that its 6 key amino acid residues and the Mg2+-binding site were similar to those of other insects’*** signal peptide and endonuclease non-specific domain shared high sequence identity with the brown-winged green stinkbug Plautia stali *** showed high salivary gland and midgut expression and was continuously expressed through the whole life cycle,with peaks at the 4th instar ecdysis in the whole *** purified AldsRNase protein obtained by heterologously expressed can rapidly degrade *** comparing the substrate specificity of AldsRNase,3 specific substrates(dsRNA,small interfering RNA,and dsDNA)were all degraded,and the most efficient degradation is ***,immunofluorescence revealed that AldsRNase was expressed in the cytoplasm of midgut *** cloning and functional study of AldsRNase,the enzyme activity and substrate specificity of the recombinant protein,as well as the subcellular localization of nuclease,the reason for the disappearance of dsRNA was explained,which was useful in improving RNAi efficiency in *** and related species.

关键词： Apolygus lucorum cloning dsRNase enzymatic activity protein expression

Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency

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Journal of Integrative Medicine 2024年第1期22卷 72-82页

作者： jing-shun Meng Yun He Heng-bin Yang Li-ping Zhou Si-yuan Wang Xi-lin Feng Omar Yahya Al-shargi Xiao-min Yu Li-qing zhu Chang-quan Ling Shanghai university of Traditional Chinese Medicine Shanghai 201203China Oncology Department of Traditional Chinese Medicine Changhai HospitalNaval Medical UniversityShanghai 200433China Faculty of Traditional Chinese Medicine Naval Medical UniversityShanghai 200043China State Key laboratory of Genetic Engineering and Engineering Research Center of Gene technology(Ministry of Education) School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China Yantai Fuheng Biological technology Co. Ltd.YantaiShandong Province 264006China. Department of Clinical laboratory the First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

Objective Melittin and its derivatives have been characterized to establish effective gene delivery *** capability of facilitating endosomal release enhances the nanoparticles-based gene ***,little investigation has been conducted to explore its potential application in the context of viral *** Various melittin-derived peptides were inserted into the loop VIII of the capsid proteins of recombinant adeno-associated virus *** vectors carrying either gfp or fluc genes were subjected to qPCR assays and transduction assays of HEK293T cells to investigate the efficiency of vector production and gene *** addition,the ability of a specific p5RHH-rAAV vector to deliver genes was examined through in vitro transduction of different cultured cells and in vivo tail vein administration to C57BL/6 ***,the intricate details of the vector-mediated transduction mechanisms were revealed by specific pharmacological inhibitors of every stage of the rAAV2 intracellular life *** A total of 76 melittin-related peptides were compiled from existing *** them,cMA2,Melt13,p5RHH and aAR3 were found to significantly enhance the gene delivery efficiency of rAAV2 *** p5RHH-rAAV2 vectors efficiently transduced not only rAAV-potent cell lines but also cell lines previously considered resistant to ***,bafilomycin A1,a vacuolar endosome acidification inhibitor,completely inhibited the transgene expression mediated by the p5RHH-rAAV2 *** importantly,p5RHH-rAAV8 vectors also demonstrated increased hepatic transduction in vivo in C57BL/6 *** The incorporation of melittin analogues into the rAAV capsids results in a significant improvement in rAAV-mediated transgene *** further modifications remain an area of interest,our studies have substantially broadened the pharmacological prospects of melittin in the context of viral vector-mediated gene delivery.

关键词： Melittin Recombinant adeno-associated virus Capsid engineering Transduction efficiency

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Checking for normality in linear mixed models

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Science china mathematics 2012年第4期55卷 787-804页

作者： WU ping 1,,zhu lixing 2,3 & FANG Yun 4 1 School of Finance and Statistics,East china Normal university,Shanghai 2002.1.china 2 School of Statistics and mathematics,Yunnan university of Finance and Economics,Yunnan 6502.1.china 3 The Department of mathematics,Hong Kong Baptist university,Hong Kong 999077,china 4 mathematics and Science College,Shanghai Normal university,Shanghai 200234,china School of Finance and Statistics East China Normal University Shanghai China School of Statistics and mathematics Yunnan University of Finance and Economics Yunnan China The Department of mathematics Hong Kong Baptist University Hong Kong China mathematics and Science College Shanghai Normal University Shanghai China

Linear mixed models are popularly used to fit continuous longitudinal data, and the random effects are commonly assumed to have normal distribution. However, this assumption needs to be tested so that further analysis can be proceeded well. In this paper, we consider the Baringhaus-Henze-Epps-Pulley （BHEP） tests, which are based on an empirical characteristic function. Differing from their case, we consider the normality checking for the random effects which are unobservable and the test should be based on their predictors. The test is consistent against global alternatives, and is sensitive to the local alternatives converging to the null at a certain rate arbitrarily close to 1/V~ where n is sample size. ^-hlrthermore, to overcome the problem that the limiting null distribution of the test is not tractable, we suggest a new method： use a conditional Monte Carlo test （CMCT） to approximate the null distribution, and then to simulate p-values. The test is compared with existing methods, the power is examined, and several examples are applied to illustrate the usefulness of our test in the analysis of longitudinal data.

关键词： linear mixed models estimated best linear unbiased predictors BHEP tests conditional MonteCarlo test

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Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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Cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang ping zhu Liang Chen Department of Cell Biology of National Translational Science Center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key laboratory of New Targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers

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World Journal of Gastroenterology 2024年第12期30卷 1751-1763页

作者： Ting Yang Kang Chao Xia zhu Xue-Ding Wang Sumyuet Chan Yan-ping Guan jing Mao Pan Li Shao-Xing Guan Wen Xie Xiang Gao Min Huang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006Guangdong ProvinceChina Institute of Clinical Pharmacology Sun Yat-sen UniversityGuangzhou 510006Guangdong ProvinceChina Department of Gastroenterology The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655Guangdong ProvinceChina Department of Pharmacy The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080Guangdong ProvinceChina Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261United States

BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of *** optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia *** To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite *** leucopenia was defined as a leukocyte count10^(9)/L over two *** Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate *** patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.

关键词： Thiopurine-induced late leucopenia DNA-thioguanine 6-thioguanine nucleotide Proactive therapeutic drug monitoring Crohn’s disease