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Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

World Journal of Hepatology 2024年第11期16卷 1219-1224页

作者： Yong-Zhi Zhuang Li-Quan Tong Xue-Ying Sun Department of Oncology The Fifth Affiliated Hospital of Harbin Medical UniversityDaqing 163316Heilongjiang ProvinceChina Department of General Surgery The Fifth Affiliated Hospital of Harbin Medical UniversityDaqing 163316Heilongjiang ProvinceChina Hepatosplenic Surgery Center The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001Heilongjiang ProvinceChina Department of Molecular Medicine and Pathology Faculty of Medical and Health SciencesThe University of AucklandAuckland 1023New Zealand

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of *** therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic ***,there has been a sustained search for novel molecular targets for *** study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and *** authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue *** results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological *** authors conclude that PSMD6 may play a promoting role in *** major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the *** studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for *** addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting *** hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

关键词： Cholangiocarcinoma 26S proteasome non-ATPase regulatory subunit 6 Molecular targeted therapies proteasome inhibitors Clustered regularly interspaced short palindromic repeat

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Therapeutics to harness the immune microenvironment in multiple myeloma

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Cancer Drug Resistance 2022年第3期5卷 647-661页

作者： James J.Ignatz-Hoover James J.Driscoll University Hospitals Seidman Cancer CenterClevelandOH 44106USA Department of Biochemistry Case Western Reserve UniversityClevelandOH 44106USA Hematopoietic and Immune Cancer Biology Program Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandOH 44106USA

Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)*** therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune *** inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma ***,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient *** current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease *** logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to *** complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging *** cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug ***,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug *** effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

关键词： Multiple myeloma drug resistance proteasome inhibitors immunomodulators immunotherapeutics adaptive resistance bone marrow microenvironment

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Overcoming drug resistance by targeting protein homeostasis in multiple myeloma

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Cancer Drug Resistance 2021年第4期4卷 1028-1046页

作者： Maria Moscvin Matthew Ho Giada Bianchi Department of Medicine Division of HematologyBrigham and Women’s HospitalBostonMA 02115USA Department of Medicine Mayo ClinicRochesterMN 240010USA

Multiple myeloma(MM)is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light *** incurable,a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades,significantly improving patient *** inhibitors,immunomodulatory drugs,and monoclonal antibodies are among the most effective anti-MM drugs,targeting not only the cancerous cells,but also the bone marrow ***,de novo resistance has been reported,and acquired resistance is inevitable for most patients over time,leading to relapsed/refractory disease and poor *** protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis,offering us the opportunity to target this intrinsic vulnerability for therapeutic *** review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.

关键词： Multiple myeloma drug resistance proteasome inhibitors immunomodulatory drugs proteostasis endoplasmic reticulum stress unfolded protein response

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Advancements in drugs restructured with nanomedicines for multiple myeloma treatment

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Science China Materials 2024年第12期67卷 3780-3795页

作者： Zhaoyun Liu Hongli Shen Hui Liu Kai Ding Jia Song Jingtian Zhang Dan Ding Rong Fu Department of Hematology Tianjin Medical University General HospitalTianjin 300052China Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control Tianjin 300052China Tianjin Institute of Hematology Tianjin 300052China State Key Laboratory of Medicinal Chemical Biology Key Laboratory of Bioactive MaterialsMinistry of Education and College of Life SciencesNankai UniversityTianjin 300071China

Multiple myeloma(MM)is an incurable malignancy of clonal plasma cells,characterized by high relapse rates and rapid development of drug *** emergence of proteasome inhibitors has dramatically improved the therapeutic effect of MM;however,side effects and drug resistance still negatively affect the survival rate of ***-medicine has become a promising field for therapeutic innovation owing to its biodegradability and ***(NPs),when combined with MM therapeutic drugs,can reduce side effects,increase treatment efficacy,and alleviate drug resistance,providing a new direction for the treatment of *** drugs with NPs presents an ideal strategy for ongoing studies aimed at more effective ***,clinical nanomedicine research has yielded new opportunities for MM *** review,guided by the development of MM therapeutic drugs,summarizes the past 20 years of research progress and breakthroughs in NP-based systems for treating MM and improving drug targeting ability.

关键词： plasma cell disease nanotechnology hematology proteasome inhibitors

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First line vs delayed transplantation in myeloma:Certainties and controversies

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World Journal of Transplantation 2016年第2期6卷 321-330页

作者： Annamaria Brioli Klinik für Innere MedizinⅡ(Abteilung Hämatologie und internistische Onkologie) Universitätsklinikum Jena07740 JenaGermany Istituto di Ematologia Seràgnoli Università degli Studi di Bologna

Since the middle of 1990 s autologous stem cell trans-plantation has been the cornerstone for the treatment of young patients with multiple myeloma(MM). In the last decade the introduction of novel agents such as immunomodulatory drugs(IMi Ds) and proteasome inhibitors(PI), has dramatically changed the therapeutic scenario of this yet incurable disease. Due to the impressive results achieved with IMi Ds and PI both in terms of response rates and in terms of progression free and overall survival, and to the toxicity linked to high dose therapy and autologous stem cell transplantation(ASCT), a burning question nowadays is whether all young patients should be offered autotransplanta-tion up front or if this should be reserved for the time of relapse. This article provides a review of the data available regarding ASCT in MM and of the current opinion of the scientific community regarding its optimal timing.

关键词： Autologous stem cell transplantation Immunomodulatory drugs proteasome inhibitors High dose therapy Multiple myeloma

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Design,synthesis and antitumor activities of naphthoquinone derivatives

Design,synthesis and antitumor activities of naphthoquinone ...

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2011年全国药物化学学术会议——药物的源头创新

作者： Kai Xu,Zhiyan Xiao Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road,Beijing 100050 China

＜正＞proteasomes play a major role in the homeostasis of cellular protein *** the approval of the first proteasome inhibitor,Bortezomib,by ***,the strategy to target the proteasome becomes a validated approach for th... 详细信息

关键词： naphthoquinone derivatives antiproliferative proteasome inhibitors

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Synthesis of protected aminoalkyl sulfinyl dilactones from α-amino acids

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Journal of Chinese Pharmaceutical Sciences 2007年第2期16卷 119-124页

作者：付刚邹晓民傅翌秋牟科马超吕扬徐萍北京大学药学院天然药物及仿生药物国家重点实验室北京100083

Aim To synthesize protected aminoalkyl sulfinyl dilactones which were useful as the synthetic intermediates or the Cterminal pharmacophores of potential peptidomimetic proteasome inhibitors. Methods Organic reactions such as reduction, oxidation, olcfmation, and dihydroxylation were used. Results A convenient synthetic procedure to afford a series of aminoalkyl *** was presented, which would be useful in the synthesis of five- or six-member sulfmyl dilactones. Conclusion Four aminoalkyl sulfmyl dilactones connecting different α-amino acids were synthesized.

关键词： proteasome inhibitors Protected aminoalkyl sulfmyl dilactone, Synthesis

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