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Induction of Chondrogenesis of Adipose-derived Stem Cells by Novel Recombinant TGF-β3 Fusion Protein

Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第4期33卷 536-542页

作者：郑东但洋黄朋夏天杨述华许伟华杨操刘国辉刘先哲冯勇 Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

Summary： A new type of TGF-β3 fusion protein with targeted therapy function was constructed, and its feasibility and target specificity of inducing chondrogenesis were investigated by transfecting LAP-MMP-mTGF-β3 gene into adipose-derived stem cells （ADSCs）. The recombinant pIRES- EGFP-MMP was constructed by inserting the sense and antisense DNA of encoding the amino acid of the synthetic MMP enzyme cutting site into the eukaryotic expression vector pIRES-EGFE LAP and mTGF-β3 fragments were obtained by using RT-PCR and inserted into the upstream and downstream of MMP from pIRES-EGFP-MMP respectively, and the recombinant plasmid of pIRES-EGFP- LAP-MMP-mTGF-β3 was constructed, which was transferred to ADSCs. The ADSCs were cultured and divided in three groups： experimental group （MMP group）, negative control group （no MMP） and non-transfection group. The morphological changes were observed microscopically, and the expression of proteoglycan and type II collagen （Col II） was detected by using Alcian blue staining and immuno- histochemistry staining at 7th, 14th and 21st day after culture. The recombinant plasmid of pIRES-EGFP-LAP-MMP-mTGF-β3 was correctly constructed by methods of enzyme cutting and se- quencing analysis. The mTGF-β3 fusion protein was successfully expressed after transfection, and in the presence of the MMP, active protein mTGF-β3 was generated, which significantly promoted differ- entiation of ADSCs into chondrocytes and the expression of cartilage matrix. The novel fusion protein LAP-MMP-mTGF-β3 can targetedly induce differentiation of ADSCs into chondrocytes, which would open up prospects for target therapy of cartilage damage repair in future.

关键词： adipose-derived stem cells recombinant protein gene clone TGF-β3 chondrogenesis car-tilage damage target therapy

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Therapeutic implications of colon cancer stem cells

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World Journal of Gastroenterology 2010年第31期16卷 3871-3877页

作者： Eros Fabrizi Simona di Martino Federica Pelacchi Lucia Ricci-Vitiani Department of Hematology Oncology and Mo-lecular MedicineIstituto Superiore di SanitàViale Regina Elena 299Rome 00161Italy

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

关键词： Colon cancer initiating cells Colon carcinogenesis target therapy

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c-Met targeted therapy of cholangiocarcinoma

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World Journal of Gastroenterology 2008年第19期14卷 2990-2994页

作者： Matei P Socoteanu Frank Mott Gianfranco Alpini Arthur E Frankel Scott & White Hospital and Clinics 5701 SAirport RdTemple

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

关键词： Cholangiocarcinoma c-Met Chemotherapy target therapy

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Primary and acquired resistance to first-line therapy for clear cell renal cell carcinoma

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Cancer Drug Resistance 2023年第3期6卷 517-546页

作者： Serena Astore Giulia Baciarello Linda Cerbone Fabio Calabrò Medical Oncology San Camillo Forlanini HospitalRome 00152Italy Medical Oncology IRCSSNational Cancer Institute Regina ElenaRome 00128Italy

The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients’ treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.

关键词： Renal cell carcinoma resistance tumor microenvironment checkpoint inhibitors target therapy

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Overview of Research and Development for Anticancer Drugs

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Journal of Cancer therapy 2016年第10期7卷 762-772页

作者： Junjie Xu Wenwei Mao Shanghai Jiao Tong University School of Medicine Shanghai China Lab of Microbial and Biochemical Pharmaceutical School of Pharmacy Shanghai Jiao Tong University Shanghai China Engineering Research Center of Cell and Therapeutic Antibody Ministry of Education School of Pharmacy Shanghai Jiao Tong University Shanghai China

Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 - 30 years, targeting therapy for cancers has been developed and achieved enormous clinical effectiveness by transforming some previously deadly malignancies into chronically manageable conditions, but cure problem still remains. This mini review outlined the current status of anticancer drugs development and hinted the opinions of how to further increase the accuracy and efficacy of discovery for cancer treatment.

关键词： Anticancer Drugs Research and Development target therapy Phenotype targeting Anti-Tumor Immunity

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New approaches for patients with advanced radioiodine-refractory thyroid cancer

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World Journal of Clinical Oncology 2022年第1期13卷 9-27页

作者： Fabian Pitoia Fernando Jerkovich Pierpaolo Trimboli Anabella Smulever Division of Endocrinology Hospital de Clinicas Jose de San MartinUniversity of Buenos AiresBuenos Aires 1120Argentina Clinic for Endocrinology and Diabetology Lugano Regional HospitalEnte Ospedaliero CantonaleLugano 1111Switzerland Faculty of Biomedical Sciences Universitàdella Svizzera ItalianaLugano 1111Switzerland

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially *** 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)*** this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly *** initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s *** that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life *** this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events *** review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.

关键词： Advanced differentiated thyroid cancer Radioactive iodine refractory thyroid cancer Multikinase inhibitors Systemic therapy target therapy

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Milk fat globule epithelial growth factorⅧ(MFG-E8)sustains survival of cancer cells by prompting tumor angiogenesis and suppressing host immunities

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Oncology and Translational Medicine 2017年第1期3卷 31-37页

作者： Keke Nie Shichao Liu Ling Zhang Zhongfa Zhang Xiao Zou Youxin Ji Oncology Department Qingdao Cancer HospitalQingdao 266042China Oncology Department Qingdao Central HospitalThe 2nd Affiliated Hospital of Qingdao UniversityQingdao 266042China

Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.

关键词： milk fat globule epithelial growth factor Ⅷ(MFG-E8) carcinoma target therapy angiogenesis apoptosis

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New Molecular targets in Metastatic Prostate Cancer

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Journal of Cancer therapy 2016年第6期7卷 388-401页

作者： Francesco Pantano Giulia Ribelli Michele Iuliani Marco Fioramonti Mark Leakos Alice Zoccoli Daniele Santini Giovanni Muto Giuseppe Tonini Medical Oncology Campus Bio-Medico University of Rome Rome Italy Translational Oncology Laboratory Campus Bio-Medico University of Rome Rome Italy Department of Urology Campus Bio-Medico University of Rome Rome Italy

Prostate cancer (PCa) is the second leading cause of cancer death in men. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). Over the past decade, increased understanding of the mechanisms that drive resistance to castration has led to the development of next-generation androgen receptor targeting agents such as abiraterone acetate and enzalutamide. Moreover in the last few years, results from large Phase III trials led to the approval of an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T) that showed improvements in terms of overall survival. In the field of metastatic CRPC, other novel therapeutics have recently been proven to extend survival via distinct mechanisms of action such as the new and more potent classes of androgen inhibitors, ortonel, ARN-509 and galeterone, the endothelin A receptor antagonist zibotentan, the Src inhibitor dasatinib, the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor ipilimumab. This review aims to revisit the evolution of androgen receptor targeting therapeutics and to discuss other important alternative biologic pathways that have given rise to new agents in metastatic prostate cancer.

关键词： Prostate Cancer target therapy

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Essential procedures of single-cell RNA sequencing in multiple myeloma and its translational value

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Blood Science 2023年第4期5卷 221-236页

作者： Jun Du Xiao-Ran Gu Xiao-Xiao Yu Yang-Jia Cao Jian Hou Department of Hematology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China School of Medicine Shanghai Jiao Tong UniversityShanghai 200025China Department of Hematology First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShanxi 710000China

Multiple myeloma(MM)is a malignant neoplasm characterized by clonal proliferation of abnormal plasma *** many countries,it ranks as the second most prevalent malignant neoplasm of the hematopoietic *** treatment methods for MM have been continuously improved and the survival of patients has been dramatically prolonged,MM remains an incurable disease with a high probability of *** such,there are still many challenges to be *** promising approach is singlecell RNA sequencing(scRNA-seq),which can elucidate the transcriptome heterogeneity of individual cells and reveal previously unknown cell types or states in complex *** this review,we outlined the experimental workflow of scRNA-seq in MM,listed some commonly used scRNA-seq platforms and analytical *** addition,with the advent of scRNA-seq,many studies have made new progress in the key molecular mechanisms during MM clonal evolution,cell interactions and molecular regulation in the microenvironment,and drug resistance mechanisms in target *** summarized the main findings and sequencing platforms for applying scRNA-seq to MM research and proposed broad directions for targeted therapies based on these findings.

关键词： Evolution Microenvironment Multiple myeloma scRNA-seq target therapy

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Docetaxel as salvage chemotherapy in patients with advanced non-small cell lung cancer after failure of cytotoxic agents and gefitinib treatment

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The Chinese-German Journal of Clinical Oncology 2008年第9期7卷 495-499页

作者： Yilong Wu Jinji Yang Yujuan Huang Qin Zhou Yisheng Huang Chongrui Xu Cancer Center and Lung Cancer Research Institute Guangdong Provincial People＇s Hospital Guangzhou 510080 China

Objective： We conducted a prospective phase II trial of single-agent salvage chemotherapy with docetaxel in patients with advanced non-small cell lung cancer （NSCLC） after failure of chemotherapy and gefitinib to assess the efficacy and toxicity of docetaxel in this setting. Methods： Patients with histologically confirmed NSCLC who were failure of chemotherapy and gefitinib were given docetaxel 75 mg/m^2 intravenously for 30 rain every 3 weeks until the toxicity was unacceptable or disease progressed. The response evaluation criteria in solid tumors （RECIST） guidelines were used for the evaluation of an- titumor activity. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Results： In total, 31 patients were enrolled in this phase II trial between February 2004 and December 2006, and 84 cycles （average 2.7 cycles） were given. We observed 4 partial responses （PRs） and 10 stable disease （SD） states in 31 eligible patients. The objective response rate was 12.9%, and the disease control rate was 45.2%. The median survival time （MST） was 10 months （95% CI, 5.05-15.08 months）. The 1-year survival rate was 40.6%. The most common toxicities were neutropenia, anemia, and peripheral neuropathy that occurred as follows： 45% of the patients experienced grade 3 or 4 neutropenia, 29% experienced grade 3 anemia, and 25.8% had grade 3 peripheral neuropathy. No patient terminated docetaxel chemotherapy due to toxicity. Conclusion： Docetaxel is beneficial as salvage chemotherapy in patients with advanced NSCLC after failure of cytotoxic agents and gefitinib.

关键词： non-small cell lung cancer (NSCLC) chemotherapy target therapy gefitinib docetaxel

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