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Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

Chinese Medical Journal 2024年第3期137卷 338-349页

作者： feng xu Kun xu Lingling Fan Xintong Li Yiqiu Liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The Comprehensive Cancer Center of Nanjing Drum Tower Hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： Androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

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Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients receiving reperfusion therapy:a meta-analysis

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World Journal of Emergency Medicine 2024年第3期15卷 181-189页

作者： Zeyu Yang Huiruo Liu Dazhou Lu Shengchuan Cao feng xu Chuanbao Li Department of Emergency Medicine Qilu Hospital of Shandong UniversityJinan 250012China Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine Institute of Emergency and Critical Care Medicine of Shandong UniversityChest Pain CenterQilu Hospital of Shandong UniversityJinan 250012China Key Laboratory of Emergency and Critical Care Medicine of Shandong Province Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong ProvinceShandong Provincial Engineering Laboratory for Emergency and Critical Care MedicineQilu Hospital of Shandong UniversityJinan 250012China Shandong Key Laboratory:Magnetic Field-free Medicine&Functional Imaging(MF) Qilu Hospital of Shandong UniversityJinan 250012China National Medical Products Administration(NMPA)Key Laboratory for Clinical Research and Evaluation of Innovative Drug Qilu Hospital of Shandong UniversityJinan 250012China

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulinpotassium(GIK) therapy on clinical outcomes in acute coronary syndrome(ACS) patients receiving reperfusion therapy.METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs) that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs).RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio [RR] 0.57,95% confidence interval [95% CI]:0.35 to 0.94,P=0.03) and the risk of heart failure(RR 0.48,95% CI:0.25 to 0.95,P=0.04) and improved the left ventricular ejection fraction(LVEF)(mean difference [MD] 2.12,95% CI:0.40 to 3.92,P=0.02) at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95% CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95% CI:1.74 to 47.29,P=0.009) and hypoglycemia(RR 6.50,95% CI:1.28 to 33.01,P=0.02) but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD) activity but not glutathione peroxidase(GSH-Px) or catalase(CAT) activity.CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering eflcacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.

关键词： Acute coronary syndrome High-dose Glucose-insulin-potassium treatment Reperfusion therapy Meta-analysis

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A novel predictor of unsustained return of spontaneous circulation in cardiac arrest patients through a combination of capnography and pulse oximetry: a multicenter observational study

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World Journal of Emergency Medicine 2024年第1期15卷 16-22页

作者： Jing Yang Hanqi Tang Shihuan Shao feng xu Yangyang Fu Shengyong xu Chen Li Yan Li Yang Liu Joseph Harold Walline Huadong Zhu Yuguo Chen xuezhong Yu Jun xu Emergency Department State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100730China Emergency Department Peking University People’s HospitalBeijing 100044China Department of Emergency and Chest Pain Center Shandong Provincial Clinical Research Center for Emergency and Critical Care MedicineKey Laboratory of Emergency and Critical Care Medicine of Shandong ProvinceQilu Hospital of Shandong UniversityJinan 250012China Emergency Department Beijing Jishuitan HospitalBeijing 100035China Emergency Department Tianjin Medical University General HospitalTianjin 300052China Department of Emergency Medicine Penn State Health Milton S.Hershey Medical Center and Penn State College of MedicineHershey 17033USA

BACKGROUND:Unsustained return of spontaneous circulation(ROSC)is a critical barrier to survival in cardiac arrest patients.This study examined whether end-tidal carbon dioxide(ETCO_(2))and pulse oximetry photoplethysmogram(POP)parameters can be used to identify unsustained ROSC.METHODS:We conducted a multicenter observational prospective cohort study of consecutive patients with cardiac arrest from 2013 to 2014.Patients’general information,ETCO_(2),and POP parameters were collected and statistically analyzed.RESULTS:The included 105 ROSC episodes(from 80 cardiac arrest patients)comprised 51 sustained ROSC episodes and 54 unsustained ROSC episodes.The 24-hour survival rate was significantly higher in the sustained ROSC group than in the unsustained ROSC group(29.2%vs.9.4%,P<0.05).The logistic regression analysis showed that the difference between after and before ROSC in ETCO_(2)(ΔETCO_(2))and the difference between after and before ROCS in area under the curve of POP(ΔAUCp)were independently associated with sustained ROSC(odds ratio[OR]=0.931,95%confi dence interval[95%CI]0.881-0.984,P=0.011 and OR=0.998,95%CI 0.997-0.999,P<0.001).The area under the receiver operating characteristic curve ofΔETCO_(2),ΔAUCp,and the combination of both to predict unsustained ROSC were 0.752(95%CI 0.660-0.844),0.883(95%CI 0.818-0.948),and 0.902(95%CI 0.842-0.962),respectively.CONCLUSION:Patients with unsustained ROSC have a poor prognosis.The combination ofΔETCO_(2) andΔAUCp showed signifi cant predictive value for unsustained ROSC.

关键词： Return of spontaneous circulation Pulse oximetry photoplethysmogram End-tidal carbon dioxide Cardiac arrest Cardiopulmonary resuscitation

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Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression

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Science China(Life Sciences) 2024年第4期67卷 698-710页

作者： Runtian Wang Gaigai Li Fangyan Gao feng xu Xintong Li Jian Zhang Jinbo Li Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China State Key Laboratory of Analytical Chemistry for Life Sciences Jiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023China Department of Medical Oncology Fudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai 200032China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing 211166China

Triple-negative breast cancer(TNBC)is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets.c-Myc is hyperactivated in the majority of TNBC tissues,however,it has been considered an“undruggable”target due to its disordered structure.Herein,we developed an ultrasound-responsive spherical nucleic acid(SNA)against c-Myc and PD-L1 in TNBC.It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA(si RNA)shell and a hydrophobic core made of a peptide nucleic acid(PNA)-based antisense oligonucleotide(ASO)and a sonosensitizer.We accomplished significant enrichment in the tumor by enhanced permeability and retention(EPR)effect,the controllable release of effective elements by ultrasound activation,and the combination of targeted therapy,immunotherapy and physiotherapy.Our study demonstrated significant anti-tumoral effects in vitro and in vivo.Mass cytometry showed an invigorated tumor microenvironment(TME)characterized by a significant alteration in the composition of tumor-associated macrophages(TAM)and decreased proportion of PD-1-positive(PD-1+)T effector cells after appropriate treatment of the ultrasound-responsive SNA(USNA).Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population.Our finding offers a novel therapeutic strategy against the“undruggable”c-Myc,develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.

关键词： triple-negative breast cancer c-Myc spherical nucleic acid self-assembly

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Chromosome-level assembly of triploid genome of Sichuan pepper(Zanthoxylum armatum)

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Horticultural Plant Journal 2024年第2期10卷 437-449页

作者： Lizhi Song Yue Huang Hao Zuo Ning Tang Zhengguo Li Wenbiao Jiao feng xu Qiang xu Zexiong Chen National Key Laboratory for Germplasm Innovation and Utilization for Fruit and Vegetable Horticultural Crops Huazhong Agricultural UniversityWuhanHubei 430070China Chongqing Key Laboratory of Economic Plant Biotechnology Chongqing University of Arts and SciencesChongqing 402160China School of Life Sciences Chongqing UniversityChongqing 400030China College of Horticulture and Gardening Yangtze UniversityJingzhouHubei 434025China College of Informatics Huazhong Agricultural UniversityWuhanHubei 430070China

As an important spice species in Rutaceae, the Sichuan pepper (Zanthoxylum armatum) can provide pungent and numbing taste, as well as aroma in its mature fruit. Here we assembled a chromosome-level genome of green prickly ash which was widely cultivated in a major production area including Chongqing and Sichuan province, China. We generated 712 Gb (~112×) PacBio long reads and 511 Gb (~82×) Hi-C data, and yielded an assembly of 99 pseudochromosomes with total size of 5.32 Gb and contig N50 of 796 kb. The genomic analyses and cytogenetic experiments both indicated that the cultivarZhuye Huajiao’ was a triploid. We identified a Zanthoxylum-specific whole genome duplication event emerging about 24.8 million years ago (Mya). We also detected a transposition burst event (0.3-0.4 Mya) responsible for the large genome size of Z. armatum. Metabolomic analysis of the Zanthoxylum fruits during development stages revealed profiles of39 volatile aroma compounds and 528 secondary metabolites, from which six types of sanshools were identified. Based on metabolomic and transcriptomic network analysis, we screened candidate genes encoding long chain acyl-CoA synthetase, fatty acid desaturase,branched-chain amino acid aminotransferase involved in sanshool biosynthesis and three genes encoding terpene synthase during fruit development. The multi-omics data provide insights into the evolution of Zanthoxylum and molecular basis of numbing and aroma flavor of Sichuan pepper.

关键词： Zanthoxylum armatum Genome Sanshool Terpenoid

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