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Recent advances and remaining challenges in lung cancer therapy

Chinese Medical Journal 2024年第5期137卷 533-546页

作者： Tasha Barr Shoubao Ma Zhixin Li Jianhua Yu Department of Hematology and Hematopoietic Cell Transplantation City of Hope National Medical CenterLos AngelesCalifornia 91010USA Comprehensive Cancer center City of HopeLos AngelesCalifornia 91010USA Department of Immuno-Oncology Beckman Research InstituteLos AngelesCalifornia 91010USA

Lung cancer remains the most common cause of cancer *** the continued research into new drugs and combination therapies,outcomes in lung cancer have been improved,and clinical benefits have been expanded to a broader patient ***,the overall cure and survival rates for lung cancer patients remain low,especially in metastatic *** the available lung cancer treatment options,such as surgery,radiation therapy,chemotherapy,targeted therapies,and alternative therapies,immunotherapy has shown to be the most *** exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer *** progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration(FDA)-approved drugs targeting the programmed cell death ligand-1 protein(e.g.,durvalumab,atezolizumab),the programmed cell death-1 receptor(e.g.,nivolumab,pembrolizumab),and cytotoxic T-lymphocyte-associated antigen 4(e.g.,tremelimumab,ipilimumab).Cytokines,cancer vaccines,adoptive T cell therapies,and Natural killer cell mono-and combinational therapies are rapidly being studied,yet to date,there are currently none that are FDA-approved for the treatment of lung *** this review,we discuss the current lung cancer therapies with an emphasis on immunotherapy,including the challenges for future research and clinical applications.

关键词： Lung cancer Therapy Immunotherapy Combination therapy Adoptive T cell therapies

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RNA m^(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression

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Genes & Diseases 2024年第1期11卷 382-396页

作者： Zheng Zhang Keren Zhou Li Han Andrew Small Jianhuang Xue Huilin Huang Hengyou Weng Rui Su Brandon Tan Chao Shen Wei Li Zhicong Zhao Ying Qing Xi Qin Kitty Wang Keith Leung Mark Boldin Chun-Wei Chen David Ann Zhijian Qian Xiaolan Deng Jianjun Chen Zhenhua Chen Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA Irell and Manella Graduate School of Biological Sciences Beckman Research Institute of City of HopeDuarteCA 91010USA Gehr Family center for Leukemia Research City of HopeDuarteCA 91010USA Sun Yat-sen University Cancer center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060China Guangzhou Laboratory GuangzhouGuangdong 510005China Bioland Laboratory GuangzhouGuangdong 51005China Department of Liver Surgery Renji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Diabetes Complications and Metabolism Beckman Research Institute of City of HopeDuarteCA 91010USA Department of Biochemistry and Molecular Biology University of FloridaGainesvilleFL 32603USA Tongji Hospital Affiliated to Tongji University Frontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China School of Pharmacy China Medical UniversityShenyangLiaoning 110001China

As the most common internal modification of mRNA,Ne-methyladenosine(m^(6)A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including *** was reported previously that m^(6)A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m^(6)A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m^(6)A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to ***,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in ***,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature ***,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of ***2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in ***,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m^(6)A plays a role in pre-miRNA processing that contributes to tumorigenesis.

关键词： AML miR-126 N^(6)-methyladenosine Pre-miRNA maturation YTHDF2

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Okazaki fragment maturation:nucleases take centre stage

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分子细胞生物学报:英文版 2011年第1期3卷 23-30页

作者： Li Zheng Binghui Shen Department of Cancer Biology City of Hope National Medical Center and Beckman Research InstituteDuarteCA 91010USA

Completion of lagging strand DNA synthesis requires processing of up to 50 million Okazaki fragments per cell cycle in mammalian *** in yeast,the Okazaki fragment maturation happens approximately a million times during a single round of DNA ***,efficient processing of Okazaki fragments is vital for DNA replication and cell *** this process,primase-synthesized RNA/DNA primers are removed,and Okazaki fragments are joined into an intact lagging strand *** processing of RNA/DNA primers requires a group of structure-specific nucleases typified by flap endonuclease 1(FEN1).Here,we sum-marize the distinct roles of these nucleases in different pathways for removal of RNA/DNA *** findings reveal that Okazaki fragment maturation is highly *** dynamic interactions of polymerase d,FEN1 and DNA ligase I with prolif-erating cell nuclear antigen allow these enzymes to act sequentially during Okazaki fragment *** protein–protein interactions may be regulated by post-translational *** also discuss studies using mutant mouse models that suggest two distinct cancer etiological mechanisms arising from defects in different steps of Okazaki fragment *** that affect the efficiency of RNA primer removal may result in accumulation of unligated nicks and DNA double-strand *** DNA strand breaks can cause varying forms of chromosome aberrations,contributing to development of cancer that associates with aneuploidy and gross chromosomal *** the other hand,mutations that impair editing out of polymerase a incorporation errors result in cancer displaying a strong mutator phenotype.

关键词： Okazaki fragment maturation FEN1 DNA2 PCNA RPA cancer

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Genomic instability as a major mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in cancer

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Protein & Cell 2022年第2期13卷 82-89页

作者： Bing Liu Daniela Duenas Li Zheng Karen Reckamp Binghui Shen Department of Cancer Genetics and Epigenetics Beckman Research Institute of City of Hope1500 East Duarte RoadDuarteCA 91010USA Division of Medical Oncology Cedars-Sinai Medical Center8700 Beverly BlvdWest HollywoodCA 90048USA

The mutation-mediated overexpression of epidermal growth factor receptor tyrosine kinase(EGFR TK)and its activation play an important role in the cellular proliferation and epithelial tumorigenesis.A series of inhibitors targeting the intracellular tyrosine kinase(TK)domain of EGFR have been developed and applied to clinical *** these inhibitors safely and effectively restrain tumor cell proliferation and prolong survival in some patients,acquired resistance ultimately *** mutations contribute to druginduced cancer-cell resistance.

关键词： cancer resistance clinical

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Epitranscriptomics in myeloid malignancies

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Blood Science 2022年第3期4卷 133-135页

作者： Li Han Jianjun Chen Rui Su Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA Department of Pharmacology School of PharmacyChina Medical UniversityShenyangChina City of Hope Comprehensive Cancer center City of HopeDuarteCA Gehr Family center for Leukemia Research City of HopeDuarteCA

In eukaryotes,gene expression is highly orchestrated not only by genomic promoters and enhancers but also by covalent mod-ifications added to either chromatin or ***,“epigenetics”refers to the chemical modifications that govern heritable changes in gene expression independent of the DNA sequence;“epitranscriptomics”indicates the covalent decora-tions in RNA,which plays a central role in posttranscriptional gene *** date,>170 RNA chemical modifications have been *** of these modifications were originally identified in highly abundant noncoding RNA species,such as ribosomal RNAs(rRNAs),transfer RNAs(tRNAs),and small nuclear RNA(snRNAs).

关键词： myeloid cor ics

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NEK2,a promising target in TP53 mutant cancer

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Blood Science 2022年第2期4卷 97-98页

作者： Martina Cusan Lili Wang Department of Systems Biology Beckman Research Institute and NCI City of Hope Comprehensive Cancer CenterDuarteCAUSA

In human cancers,aberration of tumor suppressors and oncogenes cooperate to contribute to tumor initiation and progression.1,2 TP53,one of the best-known tumor suppressors,appears to have diverse roles through working... 详细信息

关键词： TP53 suppressor tumor

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Sodium iodate induced retinal degeneration: new insights from an old model

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Neural Regeneration Research 2014年第23期9卷 2044-2045页

作者： Ram Kannan David R.Hinton Arnold and Mabel beckman Macular Research center Doheny Eye Institute Departments of Pathology and Ophthalmology Keck School of Medicine of the University of Southern California

Studies on the selective retinal degeneration induced by sodium iodate （NaIO3） date back to 1941; Sorsby （1941） described the effect of intravenously injected NaIO3 solution on the rabbit retina. Since then, NaIO3-induced retinal degeneration has been described in different mammalian species including sheep, rabbit, rat and mouse with varying doses and routes of administration. At the present time,

关键词： IO new insights from an old model RPE

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Progress in nanoparticles characterization:Sizing and zeta potential measurement

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Particuology 2008年第2期6卷 112-115页

作者： Renliang Xu Particle Characterization Beckman Coulter Inc. Miami Florida USA

Characterization of various nanoparticles is on the center stage in nanotechnology development. The subjects for nanoparticles characterization are focused on particle size and particle surface charge determinations. This article summarizes the latest development in particle size analysis using dynamic light scattering and surface charge determination using electrophoretic light scattering for nano-or even sub-nanoparticles in concentrated suspensions.

关键词： Nanoparticles Light scattering Zeta potential Suspension Sizing

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Wnt signaling in disease and in development

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Cell Research 2005年第1期15卷 28-32页

作者： Roel NUSSE USA. ABSCTACT School of Medicine Howard Hughes Medical Institute beckman center Stanford University Department of Developmental Biology

The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.

关键词： cell signaling Wnt proteins adult tissue maintenance human disease.

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Effect of Xinfeng capsule on pulmonary function in a adjuvant arthritis rat model

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Journal of Traditional Chinese Medicine 2014年第1期34卷 76-85页

作者： Lei Wan Jian Liu Chuanbing Huang Yuan Wang Li Zheng Department of Rheumatism Immunity the First Affiliated HospitalAnhui University of Chinese Medicine Department of Cancer Biology City of Hope National Medical Center and Beckman Research Institute

OBjECTIVE:To observe the relationship between reduced pulmonary function and regulatory T cells(Tregs)and helper T cells(Th)1/Th2 drift in a rat model of adjuvant arthritis(AA),and to study the impact of Xinfeng capsule(XFC)on pulmonary function and investigate the mechanism of ***:Forty rats were randomly divided into normal control group(NC),model control group(MC),Tripterygium glycosides tablet group(TPT),and XFC group,with 10 in *** for the NCgroup,AA was induced in all rats by intracutaneous injection of 0.1 mL Freund's complete adjuvant in the right *** the 19th day after modeling,the NC and MC groups were given physiological saline(0.9%),while the TPT and XFC groups were given TPT(10 mg/kg)and XFC(2.4 g/kg),once daily,*** days after administration,changes in paw swelling,arthritis index(AI),pulmonary function,levels of serumγ-interferon(IFN-γ)and interleukin(IL)-4,Tregs in peripheral blood,and IFN-γ,IL-4,Forkhead box transcription factor 3(FoxP3)in lung tissue were observed by enzyme-linked immunosorbent assay,flow cytometry,polymerase chain reaction,and western ***:Compared with the NC group,paw swelling,AI,IFN-γ,and Th1/Th2 were increased,and pulmonary function parameters,IL-4,FoxP3 were decreased significantly in the MC group(P<0.05 or P<0.01).Pulmonary function parameters,Treg,IL-4,FoxP3(and mRNA)were higher,and paw swelling,AI,and IFN-γ(and mRNA)were lower in the XFC group than those in the MC *** XFC group was also much better than theTPT group in improving pulmonary function,FoxP3 mRNA,IFN-γ,IL-4,Th1/Th2,and IL-10(P<0.05 or P<0.01).CONCLUSION:Xinfeng capsule can improve pulmonary function by regulating the levels of Tregs,inhibiting the activation of Th1 to Th2 cells,inducing drift,maintaining cell immune suppression,correcting the imbalance of Th1/Th2,and reducing inflammatory mediators.

关键词：佐剂性关节炎大鼠模型肺功能胶囊新风调节性T细胞 IFN-γ IL-4

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