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Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4

Genes & Diseases 2024年第4期11卷 411-425页

作者： Mengmeng Guo Pan Hu Jiayi Xie Kefu Tang Shixiu Hu Jialiang Sun Yundong He Jing Li Weiqiang Lu Huirong Liu Mingyao Liu Zhengfang Yi Shihong Peng Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghai 200241China Prenatal Diagnosis Center Department of Clinical LaboratoryChangning Maternity and Infant Health HospitalEast China Normal UniversityShanghai 200051China Key Laboratory of Acupuncture and Immunological Effects Shanghai University of Traditional Chinese MedicineShanghai 201203China fengxian hospital Affiliated to Southern Medical University Shanghai 201400China Shanghai Yuyao Biotech Co. Ltd.Shanghai 200241China

Gastric cancer is highly prevalent among digestive tract tumors.Due to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastric cancer.However,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric cancer.In our previous study,we identified a novel small molecule EP4 receptor antagonist called YY001.Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model.Furthermore,adminis-tration of YYo01 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 macro-phages.Additionally,our research revealed that YYo01 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than fluorouracil.These findings suggest that YYo01 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combination with other drugs.

关键词： EP4 Immunomodulation Synergy Tumor microenvironment YY001

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Platelet rich plasma-complexed hydrogel glue enhances skin wound healing in a diabetic rat model

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BIOCELL 2022年第5期46卷 1329-1338页

作者： YUNLONG ZHANG JINGWEI ZHANG YU ZHU BIN CAI Department of Orthopedic Surgery Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai200233China Department of Orthopedics Shanghai Fengxian District Central Hospital/Southern Medical University Affiliated Fengxian HospitalShanghai201400China

Diabetic patients often exhibit delayed or incomplete progress in the healing of acute wounds,owing to poor blood perfusion.Platelet-rich plasma(PRP)has attracted much attention as a means to improve wound healing,because it contains high growth factor concentrations.However,the burst-like release of PRP growth factors results in a short halflife of these therapeutic proteins,thus greatly limiting the therapeutic effect.In this study,we prepared PRP from human umbilical cord blood and developed an in situ photocrosslinkable PRP hydrogel glue(HNPRP)by adding a photoresponsive hyaluronic acid(HA-NB)into PRP.The HNPRP hydrogel allowed for controlled release of plateletderived growth factor-BB(PDGF-BB)and transforming growth factor-β(TGF-β)for up to 28 days.In vitro cell culture showed that HNPRP promoted migration of fibroblasts and keratinocytes as well as PRP and did not reveal the advantages of HNPRP.However,in a diabetic rat skin wound model,HNPRP treatment promoted faster wound closure.Furthermore,the HNPRP group,compared with the control,PRP and hydrogel only groups,showed significantly greater re-epithelialization and numbers of both newly formed and mature blood vessels.The HNPRP group also displayed higher collagen formation than did the control group.In conclusion,HNPRP enhances angiogenesis and skin regeneration and consequently achieves faster wound healing,thus extending its potential for clinical applications to treat diabetic skin wounds.

关键词： Platelet-rich plasma Wound healing Umbilical cord blood Hydrogel glue Angiogenesis

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Inflammatory macrophages exacerbate neutrophil-driven joint damage through ADP/P2Y_(1)signaling in rheumatoid arthritis

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Science China(Life Sciences) 2022年第5期65卷 953-968页

作者： Xiaoyu Zhang Wenxiang Zhao Yihan Zhao Zeda Zhao Zhangsheng Lv Zhen Zhang Hua Ren Qin Wang Mingyao Liu Min Qian Bing Du Juliang Qin Changning Maternity and Infant Health hospital and School of Life Sciences Shanghai Key Laboratory of Regulatory BiologyEast China Normal UniversityShanghai 200241China Department of Orthopedics The Eighth Affiliated HospitalSun Yat-sen UniversityShenzhen 510275China Joint Center for Translational Medicine Fengxian District Central HospitalShanghai 201499China

Rheumatoid arthritis(RA)is a chronic autoimmune disease that primarily affects the joints and is associated with excessive immune cell infiltration.However,the complex interactions between the immune cell populations in the RA synovium remain unknown.Here,we demonstrate that inflammatory macrophages in the synovium exacerbate neutrophil-driven joint damage in RA through ADP/P2Y_(1)signaling.We show that extracellular ADP(e ADP)and its receptors are obviously increased in synovial tissues of RA patients as well as collagen-induced arthritis(CIA)mice,and e ADP enhances neutrophil infiltration into joints through macrophages producing the chemokine CXCL2,aggravating disease development.Accordingly,the arthritis mouse model had more neutrophils in inflamed joints following ADP injection,whereas P2Y_(1)deficiency and pharmacologic inhibition restored arthritis severity to basal levels,suggesting a dominant role of ADP/P2Y_(1)signaling in RA pathology.Moreover,cellular activity of ADP/P2Y_(1)-mediated CXCL2 production was dependent on the G_(αq)/Ca^(2+)-NF-κB/NFAT pathway in macrophages.Overall,this study reveals a non-redundant role of e ADP as a trigger in the pathogenesis of RA through neutrophil recruitment and disrupted tissue homeostasis and function.

关键词： extracellular ADP P2Y_(1) macrophage joint inflammation rheumatoid arthritis

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Molecular biomarkers for gestational diabetes mellitus and postpartum diabetes

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Chinese Medical Journal 2022年第16期135卷 1940-1951页

作者： Wenqian Lu Cheng Hu Shanghai Diabetes Insttute Shanghai Jiao Tong University Afiliated Sixth People's HospitalShanghai 200233China The Third School of Clinical Medicine Southern Medical UniversityGuangzhouGuangdong 510630China Department of Endocrinology and Metabolism Fengxian Central Hospital Affliated to the Southern Medical UniversityShanghai 201400China

Gestational diabetes mellitus(GDM)is a growing public health problem worldwide that threatens both maternal and fetal health.Identifying individuals at high risk for GDM and diabetes after GDM is particularly useful for early intervention and prevention of disease progression.In the last decades,a number of studies have used metabolomics,genomics,and proteomic approaches to investigate associations between biomolecules and GDM progression.These studies clearly demonstrate that various biomarkers reflect pathological changes in GDM.The established markers have potential use as screening and diagnostic tools in GDM and in postpartum diabetes research.In the present review,we summarize recent studies of metabolites,single-nucleotide polymorphisms,microRNAs,and proteins associated with GDM and its transition to postpartum diabetes,with a focus on their predictive value in screeningand diagnosis.

关键词： Gestational diabetes mellitus Biomarkers Metabolomics Proteomics microRNA Single-nucleotide polymorphism

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Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus

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Journal of Molecular Cell Biology 2023年第6期15卷 40-52页

作者： Hairong Yu Haoyong Yu Rong Zhang Danfeng Peng Dandan Yan Yunjuan Gu Yuqian Bao Weiping Jia Hong Zhang Cheng Hu Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MellitusShanghai Clinical Center for DiabetesShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China Department of Endocrinology Affiliated Hospital of Nantong UniversityNantong 226001China Institute for Metabolic Disease Fengxian Central Hospital Affiliated to Southern Medical UniversityShanghai 201499China

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

关键词： molecular diagnosis monogenic diabetes mellitus monogenic obesity targeted panel whole-exome sequencing

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Successful re-challenge of PD-1 inhibitors in combination with bevacizumab and pemetrexed for multiple primary NSCLC progressing on prior PD-1 inhibitor therapy:one case report

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Drug Combination Therapy 2023年第3期5卷 9-13页

作者： Sheng-Hong Wu Mei Wang Ying Zhu Zhong-Hui He Department of Medical Oncology Fengxian District Central HospitalShanghai 201499China Department of Phase I Clinical Center Fengxian District Central HospitalShanghai 201499China.

Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumor therapies,such as chemotherapy,radiotherapy,and targeted therapy,have limited efficacy in the treatment of advanced synchronous multiple primary NSCLC.Immunotherapy is considered the standard of care for advanced or recurrent NSCLC,however,approximately 60%of patients develop primary or secondary resistance to treatment.There are no standard recommendations for overcoming immune resistance.We describe a case of simultaneous multiple primary NSCLC in a patient who received programmed death factor-1(PD-1)inhibitor monotherapy and developed brain metastases.After receiving second-line treatment with a combination of another PD-1 inhibitor,pemetrexed,and bevacizumab,the patient achieved complete remission,although they experienced grade 3 immune-related adverse reactions.Immune re-challenge is safe and feasible,and choosing a synergistic combination regimen is one of the options to overcome immune resistance.A larger sample size is needed to confirm the effectiveness and safety of this strategy in patients with NSCLC resistant to prior PD-1 inhibitors.

关键词： NSCLC brain metastases PD-1 inhibitor bevacizumab pemetrexed side effect

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Pulmonary thromboembolism after distal ulna and radius fractures surgery: A case report and a literature review

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World Journal of Clinical Cases 2021年第1期9卷 197-203页

作者： Bo Lv Feng Xue Yu-Chun Shen Fang-Bao Hu Ming-Mang Pan Department of Orthopaedics Shanghai Fengxian District Central HospitalShanghai Jiao Tong University Affiliated Sixth People’s Hospital South CampusShanghai 201499China Intensive Care Unit Shanghai Fengxian District Central HospitalShanghai Jiao Tong University Affiliated Sixth People’s Hospital South CampusShanghai 201499China

BACKGROUND Pulmonary thromboembolism(PTE)is a serious postoperative complication that can occur after a fracture.Generally,PTE is caused by the falling off of lower extremity deep vein thrombosis(LEDVT)after lower limb fracture surgery.LEDVT and PTE after upper extremity fracture surgery are very rare.PTE is one of the most common clinical causes of sudden death.Venous thromboembolism includes PTE and DVT.We experienced one case of LEDVT and PTE after distal ulna and radius fracture surgery.The purpose of our report is to raise awareness for orthopedic surgeons that PTE can occur after distal ulna and radius fracture surgery,and patients with high risk factors should be considered for prevention and treatment of thrombosis in a timely manner.CASE SUMMARY We report a 51-year-old Chinese male who had severe fractures of the left distal ulna,radius and little finger after a motorcycle accident.The patient underwent external fixation,open reduction and internal fixation.On the third post-operative day,computed tomographic pulmonary angiography showed PTE.Doppler ultrasonography showed thrombus formation in the bilateral posterior tibial veins.After a period of anticoagulation therapy,on the 25th d after the PTE,computed tomographic pulmonary angiography showed that thrombus in both sides of the pulmonary artery disappeared.Furthermore,about 4 mo after the PTE,thrombosis in the deep veins of the lower limbs disappeared.About 1 year after the surgery,X-rays showed good fracture healing,and the function of the wrist joint recovered well.CONCLUSION Though rare,PTE can occur after distal ulna and radius fracture surgery and patients with high risk factors should be considered for prevention and treatment of thrombosis in a timely manner.

关键词： Distal ulna and radius fracture Pulmonary thromboembolism Deep venous thrombosis External fixation Open reduction and internal fixation Case report

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Ocular surface microbiota in patients with varying degrees of dry eye severity

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International Journal of Ophthalmology(English edition) 2023年第12期16卷 1986-1995页

作者： Xin-Rong Zou Pei Zhang Yuan Zhou Yao Yin Department of Ophthalmology Fengcheng HospitalFengxian DistrictShanghai 201411China Fengcheng Branch Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 201411China Department of Ophthalmology Huashan Hospital of Fudan UniversityShanghai 200040China Department of Ophthalmology Gonghui HospitalJing’an DistrictShanghai 200436China

AIM:To elucidate the profiles of commensal bacteria on the ocular surfaces of patients with varying severity of dry eye(DE).METHODS:The single-center,prospective,case-control,observational study categorized all participants into three distinct groups:1)control group(n=61),2)mild DE group(n=56),and 3)moderate-to-severe DE group(n=82).Schirmer’s tear secretion strips were used,and the bacterial microbiota was analyzed using 16S ribosomal ribonucleic acid gene sequencing.RESULTS:The three groups had significant differences in alpha diversity:the control group had the highest richness(Chao1,Faith’s phylogenetic diversity),the mild DE group showed the highest diversity(Shannon,Simpson),and the moderate-to-severe DE group had the lowest of the above-mentioned indices.DE severity was positively correlated with a reduction in beta diversity of the microbial community,with the moderate-to-severe DE group exhibiting the lowest beta diversity.Linear discriminant analysis effect size presented distinct dominant taxa that significantly differed between each.Furthermore,the exacerbation of DE corresponded with the enrichment of certain pathogenic bacteria,as determined by random forest analysis.CONCLUSION:As DE severity worsens,microbial community diversity tends to decrease.DE development corresponds with changes in microbial constituents,primarily characterized by reduced microbial diversity and a more homogenous species composition.

关键词： dry eye microbiota ocular surface tear film break up time

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Glucagon-like peptide-1 protects against cardiac microvascular endothelial cells injured by high glucose

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Asian Pacific Journal of Tropical Medicine 2015年第1期8卷 73-78页

作者： Guang-Hao Ge Hong-Jie Dou Shuan-Suo Yang Jiang-Wei Ma Wen-Bo Cheng Zeng-Yong Qiao Yue-Mei Hou Wei-Yi Fang Department of Cardiology Fengxian District Central Hospital Department of Cardiology Shanghai Jiaotong University Affiliated Sixth People's Hospital South campus Department of Intensive Care Unit Fengxian District Central Hospital Department of Intensive Care Unit Department of CardiologyShanghai Jiaotong University Affiliated Sixth People's Hospital South campus Department of Cardiology Shanghai Jiaotong University Affiliated Chest Hospital

Objective:To investigate the protective effect of glucagon-like peptid-1(GLP-l) against cardiac microvascular endothelial cell(GTFCs) injured by high glucose.Methods:CMECs were isolated and cultured.Superoxide assay kit and dihydroethidine(DHE) staining were used to assess oxidative stress.TENEL staining and caspase 3 expression were used to assess the apoptosis of CMECs.H89 was used to inhibit eAMP/PKA pathway:fasudil was used to inhibit Rho/ROCK pathway.The protein expressions of Rho.ROCK uere examined by Western blol analysis.lesults:High glucose increased the production of ROS.the activity of NADPH.the apoptosis rate and the expression level of Rho/ROCK in CMECs.while GLP- 1 decreased high glucose-induced ROS production.the NADPH activity and the apoptosis rate and the expression level of Rho/ROCK in CMECs,the difference were statistically significant(P<0.05).Conclusions:GLP-1 could protect the cardiac microvessels against oxidative stress and apoptosis.The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-dependent manner,resulting in a subsequent decrease in the expression of NADPH oxidase.

关键词： Glucagon-like peptid-1 Cardiac microvascular endothelial cell ROS Rho/ROCK

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Development and validation of a nomogram to predict failure of 14-day negative nucleic acid conversion in adults with non-severe COVID-19 during the Omicron surge: a retrospective multicenter study

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Infectious Diseases of Poverty 2023年第1期12卷 36-46页

作者： Honglian Gui Zhenglan Zhang Bin Chen Yaoxing Chen Yue Wang Zhuo Long Chuanwu Zhu Yinling Wang Zhujun Cao Qing Xie Department of Infectious Diseases Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Infectious Diseases Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiChina Department of Hepatology Wuwei People’s HospitalGansuChina Department of Infectious Diseases The Affiliated Infectious Diseases Hospital of Soochow UniversitySuzhouChina Department of Endocrine and Metabolic Diseases Fengcheng Hospital of Fengxian DistrictShanghaiChina

Background With the variability in emerging data,guidance on the isolation duration for patients with coronavirus disease 2019(COVID-19)due to the Omicron variant is controversial.This study aimed to determine the predictors of prolonged viral RNA shedding in patients with non-severe COVID-19 and construct a nomogram to predict patients at risk of 14-day PCR conversion failure.Methods Adult patients with non-severe COVID-19 were enrolled from three hospitals of eastern China in Spring 2022.Viral shedding time(VST)was defined as either the day of the first positive test or the day of symptom onset,whichever was earlier,to the date of the first of two consecutively negative PCR tests.Patients from one hospital(Cohort I,n=2033)were randomly grouped into training and internal validation sets.Predictors of 14-day PCR conversion failure were identified and a nomogram was developed by multivariable logistic regression using the training dataset.Two hospitals(Cohort II,n=1596)were used as an external validation set to measure the performance of this nomogram.Results Of the 2033 patients from Cohort I,the median VST was 13.0(interquartile range:10.0-16.0)days;716(35.2%)lasted>14 days.In the training set,increased age[per 10 years,odds ratio(OR)=1.29,95%confidence interval(CI):1.15-1.45,P14 days,whereas full or boosted vaccination(OR=0.63,95%CI:0.42-0.95,P=0.028)and antiviral therapy(OR=0.56,95%CI:0.31-0.96,P=0.040)were protective factors.These predictors were used to develop a nomogram to predict VST>14 days,with an area under the ROC curve(AUC)of 0.73 in the training set(AUC,0.74 in internal validation set;0.76 in external validation set).Conclusions Older age,increasing comorbidities,incomplete vaccinations,and lack of antiviral therapy are risk factors for persistent infection with Omicron variant for>14 days.A nomogram based on these predictors could be used as a prediction tool to guide treatment and isola

关键词： Nomogram Viral shedding time Prediction Omicron variant COVID-19

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