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Science China Life Sciences 2025年第1期 249-262页

作者： Jinliang Wang Wenyong Zhou Yu Xu Jianchun Duan Qiaoxia Zhou Guoqiang Wang Leo Li Chunwei Xu Wenxian Wang Shangli Cai Zhijie Wang Jie Wang Department of Oncology The Fifth Medical Center of Chinese PLA General Hospital Department of Thoracic Surgery Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong University Burning Rock Biotech CAMS Key Laboratory of Translational Research on Lung cancer State Key Laboratory of Molecular OncologyDepartment of Medical OncologyNational Cancer Center/National Clinical Research Center for ancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College institute of Basic Medicine and cancer (IBMC) Chinese Academy of Sciences Department of Clinical Trial The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)

In non-small cell lung cancers,the non-squamous and squamous subtypes（nsqNSCLC and sqNSCLC） exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor（ICI）-based *** our inhouse training cohort（n=85）,the presence of the LRP1B deleterious mutation（LRP1B-del） was associated with longer and shorter progression-free survival（PFS） on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteractioncancer therapeutics.

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The ubiquitin ligase Siah2 is revealed as an accomplice of the androgen receptor in castration resistant prostate cancer

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Asian Journal of Andrology 2013年第4期15卷 447-448页

作者： Michael R Freeman Research Division of cancer Biology and therapeutics Departments of Surgery Medicine and BiomedicalSciences Cancer Biology Program Samuel OschinComprehensive Cancer Institute Los Angeles CA90048 USA

The androgen receptor （AR） remains the primary molecular target forprostate cancer （PCa） treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown that the AR is still functional during latestage disease in the absence of circulating hormone fol lowing castration therapy. The molecular mechanisms that operate during this ＇cas tration resistant＇ phase are still not well understood. Qi et al. have now implicated the ubiquitin ligase Siah2 as an important mediator of AR action in castration resis tant prostate cancer （CRPC）. Siah2 was found to target repressed AR chromatin complexes for degradation, resulting in activation of ARregulated genes involved in tumor cell proliferation, cell motility and lipid metabolism. The authors show a requirement for Siah2 activity for PCa cell growth under conditions of low androgen, and also that targeting Siah2 results in tumor growth suppression under castrate conditions. These findings identify a new mechanism of AR regulation in progressing disease as well as a novel enzymatic target for therapeutic intervention. The AR is a wellstudied hormone receptor that belongs to the large nuclear receptor gene superfamily. AR is activated by androgen binding （principally 5：~dihydrotestosterone, 5DHT）, which elicits changes in AR resident cytosolic complexes, translocation of the receptor to cell nuclei, formation of multiprotein transcriptional complexes onchromatin, and activation or repression of gene expression. Experiments with in vivo model systems have provided evidence that virtually all physiologic processes affected by androgens require the AR as a mediator of molecular effects at the gene level.1 AR is widely expressed beyond the reproductive systems and is believed to play important roles in several nonreproductive tissues, including muscle and brain. The fact that PCa growth is initially dependent on the pre sence of androgens in the circulation, and that prostat

关键词： ligase revealed accomplice

Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function

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Neural Regeneration Research 2025年第10期20卷 2913-2914页

作者： William J.Flerlage Mark L.Dell’Acqua Brian M.Cox Fereshteh S.Nugent Uniformed Services University of the Health Sciences Department of Pharmacology and Molecular TherapeuticsBethesdaMDUSA Department of Pharmacology University of Colorado School of MedicineAnschutz Medical CampusAuroraCOUSA

There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders(Simmons et al.,2024).Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis,synaptic function,and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds,including the family of proteins known as A-kinase anchoring proteins(AKAPs).

关键词： function supporting

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Current dichotomy between traditional molecular biological and omic research in cancer biology and pharmacology

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World Journal of Clinical Oncology 2015年第6期6卷 184-188页

作者： William C Reinhold Developmental therapeutics Branch Center for Cancer ResearchNational Cancer InstituteNational Institutes of Health

There is currently a split within the cancer research community between traditional molecular biological hypothesis-driven and the more recent "omic" forms or research. While the molecular biological approach employs the tried and true single alteration-single response formulations of experimentation,the omic employs broad-based assay or sample collection approaches that generate large volumes of data. How to integrate the benefits of these two approaches in an efficient and productive fashion remains an outstanding issue. Ideally,one would merge the understandability,exactness,simplicity,and testability of the molecular biological approach,with the larger amounts of data,simultaneous consideration of multiple alterations,consideration of genes both of known interest along with the novel,cross-sample comparisons among cell lines and patient samples,and consideration of directed questions while simultaneously gaining exposure to the novel provided by the omic approach. While at the current time integration of the two disciplines remains problematic,attempts to do so are ongoing,and will be necessary for the understanding of the large cell line screens including the Developmental therapeutics Program's NCI-60,the Broad institute's cancer Cell Line Encyclopedia,and the Wellcome Trust Sanger institute's cancer Genome Project,as well as the the cancer Genome Atlas clinical samples project. Going forward there is significant benefit to be had from the integration of the molecular biological and the omic forms or research,with the desired goal being improved translational understanding and application.

关键词： Omic Molecular biology Pharmacology cancer Integration

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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Overcoming tumor antigen heterogeneity in CAR-T cell therapy for malignant mesothelioma(MM)

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Journal of cancer Metastasis and Treatment 2022年第1期8卷 302-316页

作者： Reena R.D'Souza Paraskevi Dimou Reyisa Bughda Elizabeth Hawkins Clara Leboreiro Babe Astero Klampatsa Division of cancer therapeutics The Institute of Cancer ResearchLondon SM25NGUK Division of Radiotherapy and Imaging The Institute of Cancer ResearchLondon SM25NGUK

Malignant mesothelioma(MM)is a rare,aggressive solid tumor with limited therapeutic options and poor therapeutic *** role of immunotherapy in MM is now well established and therapeutic options,such as checkpoint inhibitors,are increasingly being *** antigen receptor(CAR)-T cell therapy is successfully implemented in several hematologic cancers,but currently has inadequate effect in solid tumors,owing to several limitations,such as trafficking and infiltration,limited T cell persistence and exhaustion,the immunosuppressive TME and tumor antigen *** lack of uniform and universal expression of tumor-associated antigens(TAAs)on tumor cells,as well as TAA heterogeneity following tumor editing post-therapy,are issues of significant importance to CAR-T cell and associated antigen-targeting *** review discusses the concept of tumor antigen heterogeneity in MM,the consequences for CAR-T cell therapies and the strategies to overcome it.

关键词： Antigen heterogeneity chimeric antigen receptor(CAR)T cells mesothelioma tumor-associated antigens(TAAs) bystander effect epitope spreading tumor microenvironment

Amyloid-beta pathology-induced nanoscale synaptic disruption:the case of the GABA_B-GIRK assembly

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Neural Regeneration Research 2025年第5期20卷 1409-1410页

作者： Rafael Lujan Alejandro Martín-Belmonte Sergi Ferré Francisco Ciruela Synaptic Structure Laboratory Instituto de Biomedicina de la UCLM(IB-UCLM)Departamento de Ciencias MédicasInstituto de Investigación en Salud de Castilla-La Mancha(IDISCAM)Facultad de MedicinaUniversidad Castilla-La ManchaCampus BiosanitarioC/AlmansaAlbaceteSpain Integrative Neurobiology Section National Institute on Drug AbuseIntramural Research ProgramNational Institutes of HealthBaltimoreMDUSA Pharmacology Unit Department of Pathology and Experimental TherapeuticsSchool of Medicine and Health SciencesInstitute of NeurosciencesUniversity of BarcelonaNeuropharmacology&Pain GroupNeuroscience ProgramBellvitge Institute for Biomedical ResearchL’Hospitalet de LlobregatSpain

Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic *** has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.

关键词： Alzheimer pathology

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The role of MT1-MMP in the progression and metastasis of osteosarcoma

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Journal of cancer Metastasis and Treatment 2022年第1期8卷 564-578页

作者： Hannah L.M.Spencer Steven D.Shnyder Paul M.Loadman Robert A.Falconer institute of cancer therapeutics Faculty of Life SciencesUniversity of BradfordBradford BD71DPUK

The dysregulation of Membrane-type 1 matrix metalloproteinase(MT1-MMP)has been extensively studied in numerous cancer types,and plays key roles in angiogenesis,cancer progression,and ***1-MMP is a predictor of poor prognosis in osteosarcoma(OS),yet the molecular mechanisms of disease progression are *** review provides a summary of the literature relating to the gene and protein expression of MT1-MMP(MMP-14)in OS clinical samples,evaluates the expression in cell lines and experimental models,and analyses its potential role in the progression and metastasis of *** addition,the therapeutic potential of MT1-MMP as a drug target has been *** to the biological complexity of MMPs,inhibition has proven to be ***,exploiting the expression and proteolytic capacity of MT1-MMP could open new avenues in the search for novel,safer and selective drugs for use in OS.

关键词： Matrix metalloproteinase membrane-type osteosarcoma MT1-MMP

A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma

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Nano Research 2017年第3期10卷 834-855页

作者： Yang Liu Guoyun Wan Hua Guo Yuanyuan Liu Ping Zhou Hemei wang Dan Wang Sipei Zhang Yinsong Wang Ning Zhang cancer institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Tianjin 300060 China Research Center of Basic Medical Science & School of Pharmacy Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics) Tianjin Medical University Tianjin 300070 China

Hepatocellular carcinoma （HCC） is one of the most common and deadly malignancies worldwide. To date, the survival of patients with HCC has not improved because of the insensitivity of HCC to conventional treatments. Sonodynamic therapy （SDT） is a promising new approach that shows remarkable potential in the treatment of HCC. Here, we designed a simple, biocompatible, and multifunctional nanosystem that combines SDT and chemotherapy to treat HCC. This nanosystem, called HPDF nanoparticles, had a core-shell structure in which hematoporphyrin （HP） was complexed with doxorubicin （DOX） to form the hydrophobic core and the surface was coated with Pluronic F68 to form the hydrophilic shell. In HCC cells, HPDF nanoparticles in combination with ultrasonic irradiation （1.0 MHz, 1.5 W/cm2, 30 s） exhibited potent cytotoxicity, resulting from the synergistic effects of a large amount of reactive oxygen species generated from HP and DOX-induced DNA damage. Notabl~ HPDF nanoparticles in combination with ultrasonic irradiation significantly reversed drug resistance in Nanog-positive cancer stem cells （CSCs） in HCC. In nude mice bearing HCC tumors, HPDF nanoparticles efficiently accumulated in the tumors and reached the maximum levels within 6-8 h, post intravenous injection. HPDF nanoparticles, in combination with ultrasonic irradiation （1.0 MHz, 3 W/cm2, 5 min）, suppressed tumor growth, angiogenesis, and collagen deposition, considerably. In summary, our results show that HPDF nanoparticles can effectively combine SDT and chemotherapy to inhibit HCC growth and progression through multiple mechanisms in both cellular and animal models.

关键词： nanoparticle sonodynamic therapy chemotherapy combination treatment hepatocellular carcinoma

Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1318-1331页

作者： Pedro Casado Ana Rio-Machin Juho JMiettinen Findlay Bewicke-Copley Kevin Rouault-Pierre Szilvia Krizsan Alun Parsons Vinothini Rajeeve Farideh Miraki-Moud David CTaussig Csaba Bödör John Gribben Caroline Heckman Jude Fitzgibbon Pedro R.Cutillas Cell Signalling and Proteomics Group Centre for Genomics and Computational BiologyBarts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK Centre for Genomics and Computational Biology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK institute for Molecular Medicine Finland-FIMM HiLIFE-Helsinki Institute of Life ScienceiCAN Digital Precision Cancer Medicine FlagshipUniversity of HelsinkiHelsinkiFinland Centre for Haemato-Oncology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK HCEMM-SU Molecular Oncohematology Research Group 1st Department of Pathology and Experimental Cancer ResearchSemmelweis University BudapestBudapestHungary cancer Research UK cancer therapeutics Unit Division of Cancer TherapeuticsThe Institute of Cancer ResearchSuttonUK a The Alan Turing institute The British Library2QR96 Euston RdLondon NW12DBUK

Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse *** these patients,targeted therapies have not yet made a significant clinical *** understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic *** data were complemented with transcriptomics analysis for 39 *** integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and *** presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged *** was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other ***-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to *** expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to *** summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged *** data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.

关键词： metabolism signature biologically