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Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1665-1674页

作者： Jie Xiong Shu Cheng Xiao Gao Shan-He Yu Yu-Ting Dai Xin-Yun Huang Hui-Juan Zhong Chao-Fu Wang Hong-Mei Yi Hao Zhang Wei-Guo Cao Rong Li Wei Tang Yan Zhao peng-peng xu Li Wang Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Nuclear Medicine Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Pathology Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Otolaryngology Shanghai Rujin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Radiation Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Hematology Navy Medical Center of PLAShanghaiChina Pole de Recherches Sino-Francais en Science du Vivant et Genomique Laboratory of Molecular PathologyShanghaiChina

Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive chemotherapy.To explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase ll study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days.The complete response and overall response rate after induction treatment were 59%(95%Cl,43-79%)and 68%(95%Cl,47-84%),respectively.With a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68%(95%Cl,45-83%)and 86%(95%Cl,63-95%),respectively.The most frequently grade 3/4 adverse events were neutropenia(32%,n=7)and hypofibrinogenemia(18%,n=4),which were manageable and led to no discontinuation of treatment.Tumor proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-l correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment.In conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage NKTCL.Dysregulated lipid profle and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

关键词： killer metabolism lymphoma

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Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma

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Signal Transduction and Targeted Therapy 2023年第5期8卷 2304-2314页

作者： Rong Shen Di Fu Lei Dong Mu-Chen Zhang Qing Shi Zi-Yang Shi Shu Cheng Li Wang peng-peng xu Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Pathology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Pôle de Recherches Sino-Français en Science du Vivant et Génomique Laboratory of Molecular PathologyShanghaiChina

Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma(DLBCL).Using whole exome/genome sequencing,RNA-sequencing,and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients,we established a simplified 38-gene algorithm(termed‘LymphPlex’)based on the information on mutations of 35 genes and rearrangements of three genes(BCL2,BCL6,and MYC),identifying seven distinct genetic subtypes:TP53Mut(TP53 mutations),MCD-like(MYD88,CD79B,PIM1,MPEG1,BTG1,TBL1XR1,PRDM1,IRF4 mutations),BN2-like(BCL6 fusion,NOTCH2,CD70,DTX1,BTG2,TNFAIP3,CCND3 mutations),N1-like(NOTCH1 mutations),EZB-like(BCL2 fusion,EZH2,TNFRSF14,KMT2D,B2M,FAS,CREBBP,ARID1A,EP300,CIITA,STAT6,GNA13 mutations,with or without MYC rearrangement),and ST2-like(SGK1,TET2,SOCS1,DDX3X,ZFP36L1,DUSP2,STAT3,IRF8 mutations).Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype.TP53Mut subtype showed poor prognosis,characterized by p53 signaling dysregulation,immune deficiency,and PI3K activation.MCD-like subtype was associated with poor prognosis,activated B-cell(ABC)origin,BCL2/MYC double-expression,and NF-κB activation.BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation.N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell(GCB)-DLBCL,respectively.EZB-like-MYC+subtype was characterized by an immunosuppressive tumor microenvironment,while EZB-like-MYC-subtype by NOTCH activation.ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation.Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy.Collectively,LymphPlex provided high efficacy and feasibility,representing a step forward to the mechanism-based targeted therapy in DLBCL.

关键词： lymphoma algorithm representing

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Positron emission tomography-adapted therapy in low-risk diffuse large B-cell lymphoma:results of a randomized,phase Ⅲ,non-inferiority trial

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Cancer Communications 2023年第8期43卷 896-908页

作者： Qing Shi Yang He Hong-Mei Yi Rong-Ji Mu xu-Feng Jiang Di Fu Lei Dong Wei Qin peng-peng xu Shu Cheng Qi Song Sai-Juan Chen Li Wang Wei-Li Zhao State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiShanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Pathology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Clinical Research Institute Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Nuclear Medicine Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Radiology Ruijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Laboratory of Molecular Pathology Pole de Recherches Sino-Francis en Science du Vivant et GénomiqueShanghaiChina

Background:The current standard of care for non-bulky diffuse large B-cell lymphoma(DLBCL)patients with an International Prognostic Index(IPI)of 0 is four cycles of rituximab plus cyclophosphamide,doxorubicin,vincristine and prednisone(R-CHOP)but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear.This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography(PET-CT,Deauville 1-3),irrespective of age and other IPI risk factors(IPI 0-1).Methods:This was an open-label,randomized,phaseⅢ,non-inferiority trial.Patients aged 14-75 years with newly diagnosed low-risk DLBCL,according to IPI,achieving PET-CT confirmed complete response(CR)after four cycles of R-CHOPwere randomized(1:1)between four cycles of rituximab(4R-CHOP+4R arm)or two cycles of R-CHOP plus two cycles of rituximab(6R-CHOP+2R arm).The primary endpoint was 2-year progression-free survival(PFS),conducted in the intention-to-treat population.Safety was assessed in patients with at least one cycle of assigned treatment.The non-inferiority margin was-8%.Results:A total of 287 patients were included in the intention-to-treat analysis,the median follow-up was 47.3 months,and the 2-year PFS rate was 95%(95%confidence interval[CI],92%to 99%)and 94%(95%CI,91%to 98%)for the 4R-CHOP+4R and 6R-CHOP+2R arm.The absolute difference in 2-year PFS between the two arms was 1%(95%CI,-5%to 7%),supporting the non-inferiority of 4R-CHOP+4R.Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm(16.7%versus 76.9%),with decreased risk of febrile neutropenia(0.0%versus 8.4%)and infection(2.1%versus 14.0%).Conclusions:For newly diagnosed low-risk DLBCL patients,interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might

关键词： diffuse large B-cell lymphoma low-risk positron emission tomography randomized phaseⅢtrial

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Modified Gant procedure for treatment of internal rectal prolapse in elderly women

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World Journal of Clinical Cases 2021年第29期9卷 8702-8709页

作者： peng-peng xu Yong-Hong Su Yan Zhang Tong Lu Department of Anorectal Shandong Provincial Hospital(Group)Huaiyin People’s HospitalJinan 250021Shandong ProvinceChina Department of Anorectal Central Hospital Affiliated to Shandong First Medical UniversityJinan 250013Shandong ProvinceChina Department of Anorectal Shanghe People’HospitalShanghe 251600Shandong ProvinceChina

BACKGROUND Although rectal prolapse is not a life-threatening condition,it can cause defecation disorders,anal incontinence,sensory abnormalities,and other problems that can seriously affect quality of life.AIM To study the efficacy of the modified Gant procedure for elderly women with internal rectal prolapse.METHODS Sixty-three elderly female patients with internal rectal prolapse underwent the modified Gant procedure.The preoperative and postoperative anal symptoms,Patient Assessment of Constipation Quality of Life(PAC-QOL),Wexner incontinence score,incontinence quality of life score,and complications(massive hemorrhage,infection,anorectal stenosis,and anorectal fistula)were compared.RESULTS The improvement rates of postoperative symptoms were defecation disorders(84.5%),anal distention(69.6%),defecation sensation(81.4%),frequent defecation(88.7%),and anal incontinence(42.9%)(P<0.05).All dimensions and total scores of the PAC-QOL after the procedure were lower than those before the operation(P<0.05).The postoperative anal incontinence score and Wexner score were significantly lower than those before the procedure(P<0.05).The quality of life and total scores of postoperative anal incontinence were significantly higher than those before the procedure(P<0.05).There were no serious complications and no deaths.CONCLUSION The modified Gant procedure has significant advantages in the treatment of elderly women with internal rectal prolapse.

关键词： Modified Gant procedure Intrarectal prolapse Rectal Prolapse Elderly women

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Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1297-1310页

作者： Rui Sun Pei-Pei Zhang Xiang-Qin Weng Xiao-Dong Gao Chuan-Xin Huang Li Wang Xiao-Xia Hu peng-peng xu Lin Cheng Lu Jiang Di Fu Bin Qu Yan Zhao Yan Feng Hong-Jing Dou Zhong Zheng Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University of MedicineShanghaiChina State Key Laboratory of Metal Matrix Composites School of Materials Science and EngineeringNational Research Center for Translational Medicine at ShanghaiShanghai Jiao Tong UniversityShanghaiChina Department of Immunobiology and Microbiology Shanghai Institute of ImmunologyShanghai Jiao Tong University School of MedicineShanghaiChina Department of Laboratory Medicine Shanghai RuiJin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina State Key Laboratory of Microbial Metabolism School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina

MicroRNAs(miRNAs)are involved in lymphoma progression by regulating the tumor microenvironment.Serum miR130b is overexpressed in diffuse large B-cell lymphoma(DLBCL),inducing Th17 cell alterations.To further illustrate its biological significance and therapeutic rationale,miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients.The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo.Therapeutic targeting miR130b was also evaluated,including OX40 agonistic antibody and lipid nanoparticles(LNPs)-miR130b antagomir.The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17,indicating lymphoma relapse and inferior survival of DLBCL patients.MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity.As mechanism of action,miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis,recruiting Th17 cells via OX40/OX40L interaction,thereby promoting immunosuppressive function of Th17 cells.In co-culture systems of B-lymphoma cells with immune cells,miR130b inhibited lymphoma cell autophagy,which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir.In murine xenograft model established with subcutaneous injection of A20 cells,both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth.In conclusion,as an oncogenic biomarker of DLBCL,miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells,attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody.Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.

关键词： lymphoma miR130b inhibited

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Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5325-5337页

作者： Ying Fang Mu-Chen Zhang Yang He Chen Li Hai Fang peng-peng xu Shu Cheng Yan Zhao Yan Feng Qian Liu Li Wang Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Network and Information Center Shanghai Jiao Tong UniversityShanghaiChina State Key Laboratory of Microbial Metabolism School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina

TP53 mutation(TP53^(mut))occurs in 10–20%of diffuse large B-cell lymphoma(DLBCL)cases and serves as an unfavorable biomarker of DLBCL progression.It confers resistance to immunochemotherapy,high-dose chemotherapy,autologous stem cell transplantation,and anti-CD19 chimeric antigen receptor T-cell therapy.Therapeutic targeting of TP53^(mut) remains a significant challenge in DLBCL treatment.Here we assessed TP53^(mut) in 667 patients with newly diagnosed DLBCL,including 576 patients treated with immunochemotherapy rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)and 91 patients with decitabine plus R-CHOP(DR-CHOP,NCT02951728 and NCT04025593).TP53^(mut) independently predicted an inferior prognosis in R-CHOP-treated DLBCL,although this could be mitigated by DR-CHOP treatment.In TP53^(mut) patients,multiple viral regulation pathways were repressed,resulting in the inhibition of immune modulation,as revealed by gene set enrichment analysis.TP53^(mut) DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation(H3K9me3),contributing to repression of endogenous retroviruses(ERVs)and immunosuppressive tumor microenvironment.In TP53^(mut) DLBCL cell lines,decitabine down-regulated SUV39H1,inhibited H3K9me3 occupancy on ERVs,and triggered ERV expression,thereby unleashing interferons program and CD4^(+)T/CD8^(+)T cell activation.Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression.In TP53^(mut) patient-derived xenograft models and TP53^(mut) patients,the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis.Collectively,our findings highlight an ERV regulatory circuitry in TP53^(mut) DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53^(mut)-driven cancers.

关键词： TP53 endogenous chemotherapy

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CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumorassociated macrophage polarization via FBXW7-N0TCHCCL2/ CSF1 axis

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Signal Transduction and Targeted Therapy 2021年第2期6卷 482-495页

作者： Yao-Hui Huang Kun Cai peng-peng xu Li Wang Chuan-Xin Huang Ying Fang Shu Cheng Xiao Jian Sun Feng Liu Jin-Yan Huang Meng-Meng Ji Wei-Li Zhao Shanghai Istitute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRulin Hospital Afliated to Shanghai Jiao Tong University School of MedicineShanghaiChina School of Life Sciences and Biotechnology.Shanghai Jiao Tong Universiy ShanghalChina Department of Immunobiology and Microbiology Shanghai Istitute of ImmunologyShanghai Jiao Tong University School of MedicineShanghaiChina Pole de Recherches Sino Francais en Science du Vivant et Genomique Laboratory of Molecular PathologyShanghalChina

Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma(DL BCL).However,the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined.The core set of genes relating to histone methylation(KMT2D,KMT2C,EZH2),histone acetylation(CREBBP,EP300),DNA methylation(TET2),and chromatin remodeling(ARID1A)were detected in the training cohort of 316 patients by whole-genome/exome sequencing(WGS/WES)and in the validation cohort of 303 patients with newly diagnosed DL BCL by targeted sequencing.Their correlation with peripheral blood immune cells and clinical outcomes were assessed.Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo.Among all 619 DLBCL patients,somatic mutations in KMT2D(19.5%)were most frequently observed,followed by mutations in ARID1A(8.7%),CREBBP(8.4%),KMT2C(8.2%),TET2(7.8%),EP300(6.8%),and EZH2(2.9%).Among them,CREBBP/EP300 mutations were signifcantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios,as well as inferior progression-free and overall survival.In B-lymphoma cells,the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation,downregulated FBXW7 expression,activated the NOTCH pathway,and downstream CCL2/CSF1 expression,resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation.In B-lymphoma murine models,xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation,higher M2 macrophage recruitment,and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis.Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.

关键词： FBXW7 P300 macrophage

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Bio-inspired inorganic-protein coating on Mg-based biomaterials for bioengineering applications

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Science China Materials 2024年第5期67卷 1678-1680页

作者： xuwen peng Haolan xu Department of Chemistry Engineering Tsinghua UniversityBeijing100084China Department of Chemical and Materials Engineering University of AlbertaEdmontonAlbertaT6G 1H9Canada Future Industries Institute UniSA STEMUniversity of South AustraliaMawson Lakes CampusAdelaideSouth Australia5095Australia

Developing smart and advanced functional materials inspired by the unparalleled complexity and efficiency of biological tissues has received much attention across various fields.Magnesium alloys,particularly pure magnesium,have emerged as notable candidates in orthopedics and dentistry due to their exceptional biocompatibility,degradability,and ability to promote bone regeneration[1].However,the highly reactive chemical nature of magnesium and its rapid degradation upon exposure to water.

关键词： coating alloys magnesium

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CFD-DEM study on the synergistic effect of coke consumption and particle dynamics in the blast furnace raceway

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Particuology 2024年第6期89卷 270-278页

作者： peng xu peng Han Zhijun He Xizhong An Kang Sun Lihua Gao Key Laboratory of Green Low-Carbon and Intelligent Metallurgy School of Materials and MetallurgyUniversity of Science and Technology LiaoningAnshan 114000China Key Laboratory for Ecological Metallurgy of Multimetallic Mineral of Ministry of Education School of MetallurgyNortheastern UniversityShenyang110819China

In this study,the gas-solid flow process in the blast furnace raceway is numerically simulated using coupled computational fluid dynamics and the discrete element method(CFD-DEM).The coke reaction kinetics data are imported into the DEM model to reproduce the consumption process of each coke particle.The effects of inlet gas velocity and angle on the morphology of the raceway,coke consumption rate,coke bed temperature,and particle size distribution in the blast process are systematically investigated and analyzed.The results show that the consumption of coke particles promotes the formation of raceways during the blast process.At the same time,a coke mixture layer is produced at the edge of the raceway.The higher the inlet gas velocity,the thicker the coke mixture layer in the middle and upper parts of the raceway region,and the larger the proportion of small particles in the coke mixture layer.The effect of the inlet gas angle on the raceway region is less than the inlet gas velocity.However,with the increase in the inlet gas angle,the high-temperature region of the coke bed extends downward gradually,which is conducive to activating the hearth.

关键词： Blast furnace Raceway Multiphase flow CFD-DEM Modeling

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Improved spatio-temporal alignment measurement method for hull deformation

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Journal of Systems Engineering and Electronics 2024年第2期35卷 485-494页

作者： xu Dongsheng YU Yuanjin ZHANG Xiaoli peng Xiafu School of Automation Beijing Institute of TechnologyBeijing 100081China School of Aerospace Engineering Xiamen UniversityXiamen 361005China

In this paper,an improved spatio-temporal alignment measurement method is presented to address the inertial matching measurement of hull deformation under the coexistence of time delay and large misalignment angle.Large misalignment angle and time delay often occur simultaneously and bring great challenges to the accurate measurement of hull deformation in space and time.The proposed method utilizes coarse alignment with large misalignment angle and time delay estimation of inertial measurement unit modeling to establish a brand-new spatiotemporal aligned hull deformation measurement model.In addition,two-step loop control is designed to ensure the accurate description of dynamic deformation angle and static deformation angle by the time-space alignment method of hull deformation.The experiments illustrate that the proposed method can effectively measure the hull deformation angle when time delay and large misalignment angle coexist.

关键词： inertial measurement spatio-temporal alignment hull deformation

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