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Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 308-325页

作者： Adilson Fonseca Teixeira Yanhong Wang Josephine Iaria Peter ten Dijke Hong-Jian Zhu Department of Surgery(The Royal Melbourne Hospital) The University of MelbourneParkvilleVICAustralia Huagene Institute Kecheng Science and Technology ParkPukou DistrictNanjingJiangsuChina Department of Cell and Chemical Biology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands

Metastasis is the leading cause of cancer-related deaths.Transforming growth factor beta(TGF-β)signaling drives metastasis and is strongly enhanced during cancer progression.Yet,the use of on-target TGF-βsignaling inhibitors in the treatment of cancer patients remains unsuccessful,highlighting a gap in the understanding of TGF-βbiology that limits the establishment of efficient anti-metastatic therapies.Here,we show that TGF-βsignaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle(sEV)secretion.Demonstrating sEV’s unique role,TGF-βsignaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β.Further,genetic disruption of sEV secretion in highlymetastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-βsignaling to nearly-normal levels.Otherwise,TGF-βsignaling activity in non-invasive breast cancer cells is inherently low,but can be amplified by sEVs,enabling invasion and metastasis of poorly-metastatic breast cancer cells.Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers,treatment with dimethyl amiloride(DMA)decreases sEV secretion,TGF-βsignaling activity,and breast cancer progression in vivo.Targeting both the sEV trafficking and TGF-βsignaling by combining DMA and SB431542 at suboptimal doses potentiated this effect,normalizing the TGF-βsignaling in primary tumors to potently reduce circulating tumor cells,metastasis,and tumor self-seeding.Collectively,this study establishes sEVs as critical elements in TGF-βbiology,demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-βsignaling levels in breast cancer cells.

关键词： metastasis doses invasion

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Phase Ⅰ study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients

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Frontiers of Medicine 2022年第2期16卷 285-294,F0004页

作者： Lei Fan Li Wang Lei Cao Huayuan Zhu Wei Xu Jianyong Li Department of Hematology Pukou CLL CenterJiangsu Province HospitalThe First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China

Anti-CD 19 chimeric antigen receptor(CAR)T cell therapy has shown impressive efficacy in treating B-cell malignancies.A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR,a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule,for the treatment of patients with refractory diffuse large B-cell lymphoma(DLBCL).Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell(C-CAR011)treatment.The overall response rate was 20%and 50%at 4 and 12 weeks after the infusion of C-CAR011,respectively,and the disease control rate was 60%at 12 weeks after infusion.Treatment-emergent adverse events occurred in all patients.The incidence of cytokine release syndrome in all grades and grade^3 was 90%and 0,respectively,which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel.Neurotoxicity or other dose-limiting toxicides was not observed in any dose cohort of C-CAR011 therapy.Antitumor efficacy was apparent across dose cohorts.Therefore,C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL,and further large-scale clinical trials are warranted.

关键词： CAR-T cell therapy refractory diffuse large B-cell lymphoma cytokine release syndrome dose-limiting toxicity

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First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1760-1767页

作者： Xiaofeng Chen Hao Xu Xiaobing Chen Tongpeng Xu Yitong Tian Deqiang Wang Fen Guo Kangxin Wang Guangfu Jin Xiao Li Rong Wang Fengyuan Li Yongbin Ding Jie Tang Yueyu Fang Jing Zhao Liang Liu Ling Ma Lijuan Meng Zhiguo Hou Rongrong Zheng Yang Liu Ni Guan Bei Zhang Shuang Tong Shiqing Chen Xing Li Yongqian Shu Department of Oncology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Gusu School Nanjing medical UniversitySuzhouChina Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingChina Department of General surgery The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of Oncology Henan Cancer Hospital Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina Henan Engineering Research center of Precision Therapy of Gastrointestinal Cancer&Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer ZhengzhouChina Department of Oncology Digestive Disease Institute&Cancer Institute of Jiangsu UniversityAffiliated Hospital of Jiangsu UniversityZhenjiangChina Department of Oncology Suzhou Hospital of Nanjing Medical UniversitySuzhouChina Department of Oncology Nanjing PuKou People’s HospitalNanjingChina Department of Epidemiology School of Public HealthNanjing Medical UniversityNanjingChina Department of Pathology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of general surgery Jurong Branch hospital of Jiangsu Province People HospitalJurongChina Department of Medical Oncology Liyang People’s HospitalLiyangChina Department of radiology Nanjing PuKou People’s HospitalNanjingChina Jiangsu Hengrui Pharmaceuticals ShanghaiChina Department of Medical Affairs 3D Medicines Inc.ShanghaiChina Shanghai OrigiMed Co. Ltd.ShanghaiChina

Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

关键词： regimen cancer doses

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Overexpression of c-Myc-dependent heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated chronic lymphocytic leukemia cells

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Chinese Medical Journal 2022年第8期135卷 920-929页

作者： Yixin Zou Hanning Tang Yi Miao Huayuan Zhu Li Wang Lei Fan Jianxin Fu Wei Xu Jianyong Li Yi Xia department of Hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China Key Laboratory of Hematology of Nanjing Medical University NanjingJiangsu 210029China Collaborative Innovation center for Cancer Personalized Medicine NanjingJiangsu 210029China pukou cll center NanjingJiangsu 210000China

Background: NOTCH1 mutation is an essential molecular biologic aberration in chronic lymphocytic leukemia (cll). cll patients withNOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused byNOTCH1 mutation from the perspective of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1).Methods: The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPA1 was checked by testing the proliferation and apoptosis of cll-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPA1.Results: RNA splicing was found to play a vital part inNOTCH1-mutated cll cells;hence, hnRNPA1 was selected as the focus of this study. Higher expression of hnRNPA1 validated in primaryNOTCH1-mutated cll samples could promote proliferation and inhibit apoptosis in cll. The expression of hnRNPA1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPA1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPA1 expression decreased through c-Myc inhibition.Conclusion: Overexpression of c-Myc-dependent hnRNPA1 could promote proliferation and inhibit apoptosis inNOTCH1- mutated cll cells, which might partly account for the poor prognosis of patients withNOTCH1 mutation.

关键词： Chronic lymphocytic leukemia NOTCH1 mutation c-Myc Heterogeneous nuclear ribonucleoprotein A1

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Time-limited,Combined Regimen in Chronic Lymphocytic Leukemia:A Promising Strategy to Achieve a Drug Holiday

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Current Medical Science 2021年第3期41卷 431-442页

作者： Rui JIANG Jian-yong LI Hua-yuan ZHU pukou cll center Pukou Division of Jiangsu Province HospitalNanjing 211800China Department of Hematology the First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjing 210029China Collaborative Innovation center for Cancer Personalized Medicine Nanjing 210029China

Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(cll)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in cll.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit cll in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

关键词： small molecular targeted agents Bruton's tyrosine kinase inhibitor chronic lymphocytic leukemia chemoimmunotherapy combination

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Efficacy and safety of decitabine combined with low-dose cytarabine, aclarubicin, and granulocyte colony-stimulating factor compared with standard therapy in acute myeloid leukemia patients with TP53 mutation

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Chinese Medical Journal 2021年第12期134卷 1477-1479页

作者： Si-Si Chen Qian Sun Lan Cao Wen-Zhong Wu Yue Xie Chun Qiao Jian-yong Li Si-Xuan Qian Ming Hong Department of Hematology The Affiliated Yixing Hospital of Jiangsu UniversityWuxiJiangsu 214200China Department of Hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China Key Laboratory of Hematology of Nanjing Medical University NanjingJiangsu 210029China Collaborative Innovation center for Cancer Personalized Medicine NanjingJiangsu 210029China pukou cll center Pukou division of Jiangsu Province HospitalNanjingJiangsu 211899China

Tumor suppressor gene P53(TP53)is a critical tumor suppressor gene.The mutant p53 protein enhances the activity,invasion and metastasis of tumor cells.Acute myeloid leukemia(AML)patients with TP53 mutations respond poorly to conventional chemotherapy and have poor clinical outcomes.We previously conducted a multi-center phase II clinical trial(No.ChiCTRONC-11001700)in elderly AML patients with decitabine,low-dose cytarabine,aclarubicin,and granulocyte colony-stimulating factor(G-CSF)(DCAG regimen),which showed an overall response rate(ORR)of 82.4%and a complete remission(CR)rate of 64.7%.[1]Given this satisfactory effect of DCAG regimen,the present study has been designed to compare the efficacy and safety of DCAG regimen with standard therapy in AML patients with TP53 mutations.

关键词： TP53 patients stimulating

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The role of polymorphic cytochrome P450 gene(CYP2B6)in B-chronic lymphocytic leukemia(B-cll)incidence and outcome among Egyptian patients

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Oncology Research 2024年第4期32卷 785-797页

作者： MENNA AL-ADL MAGDY MYOUSSEF AHMED EL-SEBAIE SHERIF REFAAT AFAF EL-SAID Division of Biochemistry Department of ChemistryFaculty of ScienceMansoura UniversityMansoura35511Egypt Hematology Unit Department of Clinical PathologyFaculty of MedicineMansoura UniversityMansoura35511Egypt Medical Oncology Unit Oncology Center Mansoura UniversityMansoura35511Egypt Department of Genetics Mansoura University Children’s HospitalMansoura35511Egypt

Cytochromes P450(CYPs)play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75%of the total metabolism of commercially available drugs,including chemotherapeutics.The gene expression and enzyme activity of CYPs are variable between individuals,which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics,as well as differences in the efficacy and toxicity of clinically used drugs.This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-cll in Egyptian patients,as well as the clinical outcome after receiving cyclophosphamide chemotherapy.DNA was isolated from whole blood samples of 100 de novo B-cll cases and also from 100 sex-and age-matched healthy individuals.The presence of the CYP2B6*9(G516T)polymorphism was examined by PCR-based allele specific amplification(ASA).Patients were further indicated for receiving chemotherapy,and then they were followed up.The CYP2B6*9 variant indicated a statistically significant higher risk of B-cll under different genetic models,comprising allelic(T-allele vs.G-allele,OR=4.8,pcll susceptibility among Egyptian patients.This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.

关键词： B-cll Xenobiotics Cytochromes P450 CYP2B6

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Development and Application of a High-Volume Recycled Powder Solidifying Material for Waterworks Sludge

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Journal of Renewable Materials 2022年第4期10卷 939-953页

作者： Xiang Deng Sudong Hua Fan Xia Yanfang Zhang Dapeng Guo Xinxing Zhu Defei Zhu College of Materials Science and Engineering Nanjing Tech UniversityNanjing211816China China Construction Installation Group Nanjing Construction Co. Ltd.Nanjing210023China Nanjing pukou Urban and Rural Construction Group Co. Ltd.Nanjing211800China

Recycled powder(RP)is produced as a by-product during the process of recycling construction and demolition(C&D)wastes,presenting a low additional value.Using RP-based solidifying material can not only improve its utilization efficiency,but also reduce the cost of commercial solidifying materials.To date,this is the best solidifying material utilized to dispose the original waterworks sludge(OWS)with high moisture contents(60%),and the product could be used to fabricate non-fired bricks.This has become a new environment-friendly technology of“using waste to treat waste”.In this paper,the influence of different particle sizes and dosages of RP on the prepared solidifying material was studied.Besides,unconfined compression strength(UCS),volume stability,chemical composition,and heat of hydration,pore structure of the solidifying material were characterized.Then,non-fired bricks were prepared by using the solidifying material,recycled aggregate,and original waterworks sludge.The UCS and softing coefficient(SC)of the non-fired bricks were evaluated.As a result,the 28-day UCS of the solidifying material with optimal(M30)was 35.40 MPa,which could reach 84.37%of Portland cement(PC).The addition of RP increased the volume stability of the solidifying material.The addition of a large amount of RP reduced the heat flux and cumulative heat release of the solidifying material,while its porosity increased.The UCS of non-fired brick(NF20)in 28 days was 15.19 MPa and the SC after 28 days was 78.35%.In conclusion,the preparation of solidifying material using RP could be a promising approach and has a great potential in disposal of original waterworks sludge.

关键词： Recycled powder solidifying material original waterworks sludge non-fired brick unconfined compressive strength

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Recent Advances in HIV-Associated Neurocognitive Disorders

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Journal of Biosciences and Medicines 2023年第9期11卷 150-157页

作者： Qianqian Tang Hao Wu Maogong Tang Jiangsu Provincial People’s Hospital pukou Branch Nanjing China Infection center of Beijing You’an Hospital Beijing China Huai’an Economic and Technological Development Zone Hospital Huai’an China

HIV-associated neurocognitive disorders (HAND) are chronic complications of HIV infection in the central nervous system. Clinical presentations include asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD). In the era of combination antiretroviral therapy (cART), the prevalence of HAD has significantly decreased, but the rates of ANI and MND have increased, impairing patients’ daily functioning, medical adherence, employment, driving abilities, risk of HIV transmission, overall quality of life, and posing challenges to society, economy, families, and public health. This article reviews the latest research findings regarding the pathogenesis, clinical diagnosis and treatment, neuroimaging, and neuropsychological assessment of HAND, aiming to provide insights into the prevention and management of HAND.

关键词： HIV-Associated Neurocognitive Disorders (HAND) Pathogenesis Clinical Diagnosis and Treatment Neuroimaging Neuropsychological Assessment

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The Wnt-dependent and Wnt-independent functions of BCL9 in development,tumorigenesis,and immunity:Implications in therapeutic opportunities

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Genes & Diseases 2024年第2期11卷 701-710页

作者： Minjie Wu Heng Dong Chao Xu Mengqing Sun Haojin Gao Fangtian Bu Jianxiang Chen College of Pharmacy and Department of Hepatology Institute of Hepatology and Metabolic DiseasesThe Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiang 311121China Laboratory of Cancer Genomics Division of Cellular and Molecular ResearchNational Cancer CentreSingapore 169610Singapore Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhouZhejiang 311121China

B-cell cll/lymphoma 9(BCL9)is considered a key developmental regulator and a well-established oncogenic driver in multiple cancer types,mainly through potentiating the Wnt/β-catenin signaling.However,increasing evidences indicate that BCL9 also plays multiple Wnt-independent roles.Herein,we summarized the updates of the canonical and non-canonical functions of BCL9 in cellular,physiological,or pathological processes.Moreover,we also concluded that the targeted inhibitors disrupt the interaction ofβ-catenin with BCL9 reported recently.

关键词： BCL9 Development Immunity Multifaceted functions Therapeutic target Tumorigenesis

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