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Induced pluripotent stem cells(iPSCs):molecular mechanisms of induction and applications

Signal Transduction and Targeted Therapy 2024年第5期9卷 2065-2090页

作者： Jonas Cerneckis Hongxia Cai Yanhong Shi Department of Neurodegenerative Diseases Beckman Research Institute of City of HopeDuarteCA 91010USA Irell&Manella Graduate School of Biological Sciences Beckman Research Institute of City of HopeDuarteCA 91010USA

The induced pluripotent stem cell(iPSC)technology has transformed in vitro research and holds great promise to advance regenerative medicine.iPSCs have the capacity for an almost unlimited expansion,are amenable to genetic engineering,and can be differentiated into most somatic cell types.iPSCs have been widely applied to model human development and diseases,perform drug screening,and develop cell therapies.In this review,we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications.We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs.We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency.Subsequently,we discuss various iPSC-based cellular models,from mono-cultures of a single cell type to complex three-dimensional organoids,and how these models can be applied to elucidate the mechanisms of human development and diseases.We use examples of neurological disorders,coronavirus disease 2019(COVID-19),and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells.We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies.Finally,we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.

关键词： mechanisms programming holds

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Recent advances and remaining challenges in lung cancer therapy

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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 death.Given 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 population.However,the overall cure and survival rates for lung cancer patients remain low,especially in metastatic cases.Among the available lung cancer treatment options,such as surgery,radiation therapy,chemotherapy,targeted therapies,and alternative therapies,immunotherapy has shown to be the most promising.The 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 patients.Substantial 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 cancer.In 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 tumorigenesis.It 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 tumorigenesis.Here,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in AML.Moreover,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 miR-126.Mechanistically,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of pre-miR-126.YTHDF2 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 AML.Overall,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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Thermomechanical Dynamics (TMD) and Bifurcation-Integration Solutions in Nonlinear Differential Equations with Time-Dependent Coefficients

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Journal of Applied Mathematics and Physics 2024年第5期12卷 1733-1743页

作者： Hiroshi Uechi Lisa Uechi Schun T. Uechi Osaka Gakuin University Suita Osaka Japan beckman Research institute University of California Los Angeles USA Nozuta Machida-City Tokyo Japan

The new independent solutions of the nonlinear differential equation with time-dependent coefficients (NDE-TC) are discussed, for the first time, by employing experimental device called a drinking bird whose simple back-and-forth motion develops into water drinking motion. The solution to a drinking bird equation of motion manifests itself the transition from thermodynamic equilibrium to nonequilibrium irreversible states. The independent solution signifying a nonequilibrium thermal state seems to be constructed as if two independent bifurcation solutions are synthesized, and so, the solution is tentatively termed as the bifurcation-integration solution. The bifurcation-integration solution expresses the transition from mechanical and thermodynamic equilibrium to a nonequilibrium irreversible state, which is explicitly shown by the nonlinear differential equation with time-dependent coefficients (NDE-TC). The analysis established a new theoretical approach to nonequilibrium irreversible states, thermomechanical dynamics (TMD). The TMD method enables one to obtain thermodynamically consistent and time-dependent progresses of thermodynamic quantities, by employing the bifurcation-integration solutions of NDE-TC. We hope that the basic properties of bifurcation-integration solutions will be studied and investigated further in mathematics, physics, chemistry and nonlinear sciences in general.

关键词： The Nonlinear Differential Equation with Time-Dependent Coefficients The Bifurcation-Integration Solution Nonequilibrium Irreversible States Thermomechanical Dynamics (TMD)

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Internal m6A and m7G RNA modifications in hematopoietic system and acute myeloid leukemia

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中华医学杂志(英文版) 2024年第9期137卷 2024 Mar 28页

作者： Zhang Xiaoxu Ma Yanni Yu Jia Su Rui Wang Xiaoshuang State Key Laboratory of Common Mechanism Research for Major Diseases State Key Laboratory for Complex Severe and Rare Diseases Institute of Basic Medical Sciences Chinese Academy of Medical Sciences / Peking Union Medical College Beijing China Department of Systems Biology Beckman Research Institute of City of Hope Monrovia CA USA The institute of Blood Transfusion Chinese Academy of Medical Sciences / Peking Union Medical College Chengdu Sichuan China Key Laboratory of RNA and Hematopoietic Regulation Chinese Academy of Medical Sciences Beijing China Department of Biochemistry and Molecular Biology Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College Beijing China

Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene expression. The past decade has witnessed tremendous progress in our understanding of the landscapes and biological functions of RNA modifications, as prompted by the emergence of potent analytical approaches. The hematopoietic system provides a lifelong supply of blood cells, and gene expression is tightly controlled during the differentiation of hematopoietic stem cells (HSCs). The dysregulation of gene expression during hematopoiesis may lead to severe disorders, including acute myeloid leukemia (AML). Emerging evidence supports the involvement of the mRNA modification system in normal hematopoiesis and AML pathogenesis, which has led to the development of small-molecule inhibitors that target N6-methyladenosine (m6A) modification machinery as treatments. Here, we summarize the latest findings and our most up-to-date information on the roles of m6A and N7-methylguanine in both physiological and pathological conditions in the hematopoietic system. Furthermore, we will discuss the therapeutic potential and limitations of cancer treatments targeting m6A.

关键词： N6-methyladenosine N7-methylguanine Hematopoiesis Acute myeloid leukemia Therapeutic target RNA modifications

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Sirtuins are not conserved longevity genes

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Life Metabolism 2022年第2期1卷 122-133页

作者： Charles Brenner Department of Diabetes&Cancer Metabolism Beckman Research Institute of City of HopeDuarteCA 91010 USA

It is central to biology that sequence conservation suggests functional conservation.Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity.Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells,this is not a selected trait:SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved.Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals,overexpression of SIR2 homologs was tested in invertebrates for longevity.Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation,a global pursuit of longevity phenotypes was driven by a mixture of framing bias,confirmation bias,and hype.Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes.Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort,we review the data and suggest rejection of the notions that sirtuins(i)have any specific connection to lifespan in animals and(ii)are primary mediators of the beneficial effects of NAD repletion.

关键词： sirtuins longevity model organism publication bias resveratrol nicotinamide adenine dinucleotide

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Topoisomerase I in Human Disease Pathogenesis and Treatments

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Genomics, Proteomics & Bioinformatics 2016年第3期14卷 166-171页

作者： Min Li Yilun Liu Department of Cancer Genetics and Epigenetics Beckman Research Institute

Mammalian topoisomerase 1（TOP1） is an essential enzyme for normal development.TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth.Unfortunately,this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis,a precursor for tumorigenesis.It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth.In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability,the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells.In addition,cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity.The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders.Clearly,the impact of TOP1 on human health is multifold.In this review,we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.

关键词： Topoisomerase 1 Cancer Autism Scleroderma DNA replication Transcription

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Advances in Doppler OCT

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Chinese Optics Letters 2013年第1期11卷 44-54页

作者： Gangjun Liu Zhongping Chen beckman Laser institute University of California Department of Biomedical Engineering University of California

We review the principle and some recent applications of Doppler optical coherence tomography （OCT）. The advances of the phase-resolved Doppler OCT method are described. Functional OCT algorithms which are based on an extension of the phase-resolved scheme are also introduced. Recent applications of Doppler OCT for quantification of flow, imaging of microvasculature and vocal fold vibration, and optical coherence elastography are briefly discussed.

关键词： Advances in Doppler OCT

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Bioinspired nanotransducers for neuromodulation

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Nano Research 2024年第2期17卷 618-632页

作者： Fan Yang Xiang Wu Sa Cai Guosong Hong Department of Materials Science and Engineering Stanford UniversityStanfordCA 94305USA Wu Tsai Neurosciences institute Stanford UniversityStanfordCA 94305USA School of Science Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China

The field of neuromodulation has experienced significant advancements in the past decade,owing to breakthroughs in disciplines such as materials science,genetics,bioengineering,photonics,and beyond.The convergence of these fields has resulted in the development of nanotransducers,devices that harness the synergies of these diverse disciplines.These nanotransducers,essential for neuromodulation,often draw inspiration from energy conversion processes found in nature for their unique modalities.In this review,we will delve into the latest advancements in wireless neuromodulation facilitated by optical,magnetic,and mechanical nanotransducers.We will examine their working principles,properties,advantages,and limitations in comparison to current methods for deep brain neuromodulation,highlighting the impact of natural systems on their design and functionality.Additionally,we will underscore potential future directions,emphasizing how continued progress in materials science,neuroscience,and bioengineering might expand the horizons of what is achievable with nanotransducer-enabled neuromodulation.

关键词： bioinspired synthesis neuromodulation mechanoluminescence focused ultrasound nanotransducers sono-optogenetics

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Epigenetic changes of DNA repair genes in cancer

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分子细胞生物学报:英文版 2011年第1期3卷 51-58页

作者： Christoph Lahtz Gerd P.Pfeifer Department of Cancer Biology Beckman Research InstituteCity of HopeDuarteCA 91010USA

‘Every Hour Hurts,The Last One Kills’.That is an old saying about getting old.Every day,thousands of DNA damaging events take place in each cell of our body,but efficient DNA repair systems have evolved to prevent that.However,our DNA repair system and that of most other organisms are not as perfect as that of Deinococcus radiodurans,for example,which is able to repair massive amounts of DNA damage at one time.In many instances,accumulation of DNA damage has been linked to cancer,and genetic deficiencies in specific DNA repair genes are associated with tumor-prone phenotypes.In addition to mutations,which can be either inherited or somatically acquired,epigenetic silencing of DNA repair genes may promote tumorigenesis.This review will summarize current knowledge of the epigenetic inactivation of different DNA repair components in human cancer.

关键词： DNA methylation DNA repair epigenetics

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