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Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

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Frontiers of medicine 2024年第2期18卷 357-374页

作者： Haoyu Wang Zhengyuan Wang Zheng Wang Xiaoyang Li Yuntong Li Ni Yan Lili Wu Ying Liang Jiale Wu Huaxin Song Qing Qu Jiahui Huang Chunkang Chang Kunwei Shen Xiaosong Chen Min Lu Department of General Surgery Comprehensive Breast Health CenterRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine(Shanghai)Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Shanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai200025China

p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

关键词： p53 mutation triple-negative breast cancer decitabine DNMT1 IRF7 innate immune response

Safety and feasibility of laparoscopic surgery for colorectal and gastric cancer under the Chinese multi-site practice policy:admittance standards of competence are needed

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Gastroenterology Report 2022年第1期10卷 490-497页

作者： Zhenghao Cai Haiqin Song Zhenfeng Huang Abraham Fingerhut Ximo Xu Hao Zhong Zhigang Li Yingjie Zhang Dachong Sha Dandan Bao Haibo Wang Binghua Cai Shangbo Hua Yanhui Zhang Jianguang Sun Ke Ye Jianwen Li Yong Lu Bo Feng Department of General Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R.China Shanghai Minimally Invasive Surgery Center ShanghaiP.R.China Department of General Surgery People’s Hospital of Rui’anZhejiangP.R.China Section for Surgical Research Department of SurgeryMedical University of GrazGrazAustria Department of General Surgery Wuxi Huishan District People’s HospitalJiangsuP.R.China Department of General Surgery Zhoushan HospitalZhejiangP.R.China Department of General Surgery Cixi Third People’s HospitalZhejiangP.R.China Department of General Surgery People’s Hospital of WenzhouZhejiangP.R.China Department of General Surgery Chinese PLA 107 HospitalShandongP.R.China Department of General Surgery Rudong People’s HospitalJiangsuP.R.China Department of General Surgery Kunshan Hospital of Chinese MedicineJiangsuP.R.China Department of General Surgery Jingjiang Chinese Medicine HospitalJiangsuP.R.China Department of General Surgery Haiyan People’s HospitalZhejiangP.R.China Department of General Surgery Yueqing People’s HospitalZhejiangP.R.China Department of Medical Affairs Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R.China

Background:The multi-site practice(MSP)policy has been practiced in China over 10 years.This study aimed to investigate the safety and feasibility of performing laparoscopic surgery for colorectal cancer(LSCRC)and gastric cancer(LSGC)under the Chinese MSP policy.Methods:We collected and analysed the data from 1,081 patients who underwent LSCRC or LSGC performed by one gastrointestinal surgeon in his original hospital(n=573)and his MSP institutions(n=508)between January 2017 and December 2020.Baseline demographics,intraoperative outcomes,post-operative recovery,and pathological results were compared between the original hospital and MSP institutions,as well as between MSP institutions with and without specific competence(surgical skill,operative instrument,perioperative multi-discipline team).Results:In our study,690 patients underwent LSCRC and 391 patients underwent LSGC.The prevalence of post-operative complications was comparable for LSCRC(11.5%vs 11.1%,P=0.89)or LSGC(15.2%vs 12.6%,P=0.46)between the original hospital and MSP institutions.However,patients in MSP institutions without qualified surgical assistant(s)and adequate instruments experienced longer operative time and greater intraoperative blood loss.The proportion of patients with inadequate lymph-node yield was significantly higher in MSP institutions than in the original hospital for both LSCRC(11.5%vs 21.2%,P<0.01)and LSGC(9.8%vs 20.5%,P<0.01).Conclusion:For an experienced gastrointestinal surgeon,performing LSCRC and LSGC outside his original hospital under the MSP policy is safe and feasible,but relies on the precondition that the MSP institutions are equipped with qualified surgical skills,adequate operative instruments,and complete perioperative management.

关键词： health policy gastrointestinal tumors laparoscopic surgery public health quality in health care

Highly efficient tumor-targeted nanomedicine assembled from affibody-drug conjugate for colorectal cancer therapy

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Nano Research 2023年第4期16卷 5256-5264页

作者： Xiaoyuan Yang Xuelin Xia Wei Huang Xiaoxia Xia Deyue Yan School of Chemistry and Chemical Engineering Shanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory of Microbial Metabolism School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China

Affibody is a new class of small non-immunoglobulin affinity proteins that possesses high affinity at the picomole level to several tumor overexpressed receptors.Owing to the simple framework,affibody is flexible for modification with payload,but the relatively low molecular weight of this construction simultaneously results in short half-life time which hinders its application in cancer therapy.In this work,we prepared a nanomedicine self-assembled from the conjugate of affibody(ZPDGFRβ:09591,PDGFRβ:platelet-derived growth factor receptorβ)with monomethyl auristatin E(MMAE)through cathepsin B cleavable dipeptide linker for targeted colorectal cancer therapy.The nanoscale characteristics of ZPDGFRβ:09591-MMAE affibody-drug conjugate nanomedicine(ZPDGFRβ:09591-M ADCN)resulted in enhanced pharmacokinetics,improved drug accumulation,and promoted biosecurity performance than those of free drugs.As a result,ZPDGFRβ:09591-M ADCN exhibited excellent antitumor efficacy with tumor inhibition rates(TIR)over 99.0%in PDGFRβ-positive tumor models with small solid tumors(~150 mm^(3))or large established tumors(~500 mm^(3)),indicating that ZPDGFRβ:09591-MMAE ADCN is promising for the clinic application in colorectal cancer therapy.

关键词： olecular self-assembly ZPDGFRβ:09591 affibody monomethyl auristatin E(MMAE) nanodrug targeted delivery

Regulated macrophage immune microenvironment in 3D printed scaffolds for bone tumor postoperative treatment

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Bioactive Materials 2023年第1期19卷 474-485页

作者： Cuidi Li Changwei Li Zhenjiang Ma Hongfang Chen Huitong Ruan Lianfu Deng Jinwu Wang Wenguo Cui Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025PR China Shanghai Key Laboratory of Orthopedic Implant Department of Orthopedic SurgeryShanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of MedicineShanghai200011PR China

The 3D printing technique is suitable for patient-specific implant preparation for bone repair after bone tumor resection.However,improving the survival rate due to tumor recurrence remains a challenge for implants.The macrophage polarization induction to M2-type tumor-associated macrophages(TAMs)by the tumor microenvironment is a key factor of immunosuppression and tumor recurrence.In this study,a regenerative scaffold regulating the macrophage immune microenvironment and promoting bone regeneration in a dual-stage process for the postoperative treatment of bone tumors was constructed by binding a colony-stimulating factor 1 receptor(CSF-1R)inhibitor GW2580 onto in situ cosslinked hydroxybutylchitosan(HBC)/oxidized chondroitin sulfate(OCS)hydrogel layer covering a 3D printed calcium phosphate scaffold based on electrostatic interaction.The hydrogel layer on scaffold surface not only supplied abundant sulfonic acid groups for stable loading of the inhibitor,but also acted as the cover mask protecting the bone repair part from exposure to unhealthy growth factors in the microenvironment at the early treatment stage.With local prolonged release of inhibitor being realized via the functional material design,CSF-1R,the main pathway that induces polarization of TAMs,can be efficiently blocked,thus regulating the immunosuppressive microenvironment and inhibiting tumor development at a low therapeutic dose.At the later stage of treatment,calcium phosphate component of the scaffold can facilitate the repair of bone defects caused by tumor excision.In conclusion,the difunctional 3D printed bone repair scaffold regulating immune microenvironment in stages proposed a novel approach for bone tumor postoperative treatment.

关键词： 3D printing Drug delivery Microenvironment Macrophage polarization Bone regeneration

A hydrogel system containing molybdenum-based nanomaterials for wound healing

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Nano Research 2023年第4期16卷 5368-5375页

作者： Yongzhou Lu Chuanlong Jia Chengchen Gong Han Wang Qin Xiao Jinxiao Guo Dalong Ni Nan Xu Department of Dermatology Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200092China Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Orthopaedics Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai Jiao Tong UniversityShanghai 200233China

Wound delayed healing or non-healing has seriously affected patients’quality of life and has been a significant economic burden for public health systems worldwide.Excess reactive oxygen species(ROS)play important roles for impeding the process of wound healing.Herein,we report a hydrogel system containing low-valence-state molybdenum nanomaterials(Mo hydrogel)for wound healing by scavenging the detrimental ROS.Both in vitro and in vivo results demonstrate that the synthesized Mo hydrogel can accelerate wound healing,promote angiogenesis,and stimulate the expression of growth factors.Since the molybdenum is an essential element for the survival of all organisms,such novel Mo-hydrogel has the great potential to be clinically translated for wound healing.

关键词： antioxidants wound healing hydrogel reactive oxygen species molybdenum

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1740-1754页

作者： Xiaoqing Liu Shuang Liang Xiao Sang Lili Chang Shunli Fu Han Yang Huizhen Yang Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

关键词： Nano-engager Cold tumors Increased DNA damage Augmented immunogenic cell death Dual immune checkpoint inhibition BRD4 inhibition Differ-targeting delivery MMP-2 sensitive

Honeycomb-Like Hydrogel Microspheres for 3D Bulk Construction of Tumor Models

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Research 2022年第2期2022卷 245-258页

作者： Jiachen He Chichi Chen Liang Chen Ruoyu Cheng Jie Sun Xingzhi Liu Lin Wang Can Zhu Sihan Hu Yuan Xue Jian Lu Huiling Yang Wenguo Cui Qin Shi Department of Orthopedics The First ffliated Hospital of Soochow UrniversilyOrthopedic Institute of Soochow University899 Pinghai RoadSuzhouJiangsu 215031China national Clinical Research Center for Hematologic Diseases The First Afliated Hospital of Soochow University899 Pinghai RoadSuzhouJiangsu 215031China Department of Orthopaedis Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijjin HospitalShanghai liao Tong University School of Medicine197 Ruijini 2nd RoadSharghai 200025China School of Nanotech and Nano-Bionics Universily of Science and Techmology of China388 Ruoshui RoadSuzhouJiangsu 215123 China Department of Orthopedics Wiuxi Ninth People's Hospital Afiliated to Soochow UniversityWiuciJiangs 214026China

A two-dimensional(2D)cell culture-based model is widely applied to study tumorigenic mechanisms and drug screening.However,it cannot authentically simulate the threedimensional(3D)microenvironment of solid tumors and provide reliable and predictable data in response to in vivo,thus leading to the research ilusionis and failure of drug screening.In this study,honeycomb-like gelatin methacryloyl(GelMA)hydrogel microspheres are developed by synchronous photocrosslinking microluidic technique to construct a 3D model of osteosarcoma.The in vitro study shows that ostcosarcoma cells(K7M2)culured in 3D GelMA microspheres have stronger tumorous stemness。proliferation and migration abilitics,more osteoclastogenetic ability,and reistance to chemotherapeutic drugs(DOX)than that of cells in 2D cultures.More imporantly,the 3D-cultured K7M2 cells show more tumorigenicity in immunologically sound mice,characterized by shorter tumorigenesis time,larger tumor volumc,severe bone destruction,and higher mortality.In conclusion,honeycomb like porous microsphere scaffolds are constructed with uniform structure by micofluidic technology to massively produce tumor cells with original phenotypes.Those microspheres could recapitulate the physiology microenvironment of tumors.maintain ell-cell and cell-extracellular matrix interactions,and thus provide an efective and convenient strategy for tumor pathogenesis and drug screening research.

关键词： drugs maintain shorter

Matrix stiffness regulates osteoclast fate through integrin-dependent mechanotransduction

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Bioactive Materials 2023年第9期27卷 138-153页

作者： Xiaogang Wang Luli Ji Jing Wang Changsheng Liu State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai200237PR China Key Laboratory for Ultrafine Materials of Ministry of Education East China University of Science and TechnologyShanghai200237PR China

Osteoclasts ubiquitously participate in bone homeostasis,and their aberration leads to bone diseases,such as osteoporosis.Current clinical strategies by biochemical signaling molecules often perturb innate bone metabolism owing to the uncontrolled management of osteoclasts.Thus,an alternative strategy of precise regulation for osteoclast differentiation is urgently needed.To this end,this study proposed an assumption that mechanic stimulation might be a potential strategy.Here,a hydrogel was created to imitate the physiological bone microenvironment,with stiffnesses ranging from 2.43kPa to 68.2kPa.The impact of matrix stiffness on osteoclast behaviors was thoroughly investigated.Results showed that matrix stiffness could be harnessed for directing osteoclast fate in vitro and in vivo.In particular,increased matrix stiffness inhibited the integrinβ3-responsive RhoA-ROCK2-YAP-related mechanotransduction and promoted osteoclastogenesis.Notably,preosteoclast development is facilitated by medium-stiffness hydrogel(M-gel)possessing the same stiffness as vessel ranging from 17.5 kPa to 44.6 kPa by partial suppression of mechanotransduction,which subsequently encouraged revascularization and bone regeneration in mice with bone defects.Our works provide an innovative approach for finely regulating osteoclast differentiation by selecting the optimum matrix stiffness and enable us further to develop a matrix stiffness-based strategy for bone tissue engineering.

关键词： Stiffness Mechanotransduction Osteoclast Integrin Bone repair

Spectral computed tomography-guided photothermal therapy of osteosarcoma by bismuth sulfide nanorods

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Nano Research 2023年第7期16卷 9885-9893页

作者： Yuhan Li Xiaoxue Tan Han Wang Xiuru Ji Zi Fu Kai Zhang Weijie Su Jian Zhang Dalong Ni School of medicine Shanghai UniversityNo.99 Shangda RdShanghai 200444China Shanghai University Shanghai Universal Medical Imaging Diagnostic CenterBldg 8No.406 Guilin RdShanghai 200233China Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineNo.197Ruijin 2nd RdShanghai 200025China Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s HospitalShanghai JiaoTong University School of MedicineNo.639Zhizaoju Rd.Shanghai 200011China

Osteosarcoma(OS)is the most normally primary malignant bone cancer in adolescents.Due to their analogous X-ray attenuation properties,healthy bones and malignancies with iodine enhancement cannot be distinguished by conventional computed tomography(CT).As one kind of spectral CT,dual-energy CT(DECT)offers multiple functions for material separation and cancer treatments.Herein,bismuth sulfide(Bi_(2)S_(3))nanorods(NRs)were synthesized as special contrast agents(CAs)for DECT,which have superior imaging properties than clinical iodine CAs.At the same time,the high photothermal conversion rates of Bi_(2)S_(3)NRs can be used for DECT-guided photothermal therapy(PTT)to destroy OS and inhibit tumor growth under the guidance of DECT imaging.Importantly,DECT imaging real-timely monitored that PTT could accelerate the diffusion of Bi2S3 NRs in the tumor,obtaining detailed information on the internal distribution of nanomaterials in tumors around the bone to avoid injury to normal tissues by PTT.Overall,the proposed strategy of DECT imaging-guided PTT appears enormous promise for bone disease treatment.

关键词： dual-energy computed tomography nanomedicine bismuth sulfide photothermal therapy osteosarcoma