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Melanoma:molecular genetics,metastasis,targeted therapies,immunotherapies,and therapeutic resistance

Genes & Diseases 2022年第6期9卷 1608-1623页

作者： William Wagstaff Rimel N.Mwamba Karina Grullon Mikhayla Armstrong Piao Zhao Bryce Hendren-Santiago Kevin H.Qin Alexander J.Li Daniel A.Hu Andrew Youssef Russell R.Reid Hue H.Luu Le Shen Tong-Chuan He Rex C.Haydon The Pritzker School of Medicine and the Medical Scientist Training ProgramThe University of Chicago Medical CenterChicagoIL 60637USA molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Orthopaedic Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Laboratory of craniofacial Suture biology.and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Surgery The University of Chicago Medical CenterChicagoIL 60637USA

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid *** some patients,early diagnosis and surgical removal of melanomas is lifesaving,while other patients typically turn to molecular targeted therapies and immunotherapies as treatment *** sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF,NRAS,and TERT genes,some of which can be therapeutically *** initially effective,many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory *** represent an alternative to molecular targeted ***,inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long *** the protocol for combination therapies develop,so will our scientific understanding of the many pathways at play in the progression of *** future direction of the field may be to find a molecule that connects all of the ***,noncoding RNAs have been shown to play important roles in melanoma development and *** noncoding RNAs may help us to understand how resistance e both primary and acquired e develops;ultimately allow us to harness the true potential of current *** review will cover the basic structure of the skin,the mutations and pathways responsible for transforming melanocytes into melanomas,the process by which melanomas metastasize,targeted therapeutics,and the potential that noncoding RNAs have as a prognostic and treatment tool.

关键词： BRAF inhibitors Checkpoint inhibitors Drug resistance Immunotherapy Melanoma Melanoma metastasis Skin cancer Targeted therapy Therapeutic resistance

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Tooth regeneration: a revolution in stomatology and evolution in regenerative medicine

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International Journal of Oral Science 2011年第3期3卷 107-116页

作者： Sibel Yildirim Susan Y. Fu Keith Kim Hong Zhou Chang Hun Lee Ang Li Sahng Gyoon Kim Shuang Wang Jeremy J. Mao Tissue Engineering and Regenerative Medicine Laboratory （TERML） Center for Craniofacial Regeneration Columbia University Medical Center New York NY 10032 USA Department of Basic Science Xi＇an Jiaotong University School of Stomatology Xi＇ an 710049 China

A tooth is a complex biological organ and consists of multiple tissues including the enamel, dentin, cementum and pulp. Tooth loss is the most common organ failure. Can a tooth be regenerated？ Can adult stem cells be orchestrated to regenerate tooth structures such as the enamel, dentin, cementum and dental pulp, or even an entire tooth？ If not, what are the therapeutically viable sources of stem cells for tooth regeneration？ Do stem cells necessarily need to be taken out of the body, and manipulated ex vivo before they are transplanted for tooth regeneration？ How can regenerated teeth be economically competitive with dental implants？ Would it be possible to make regenerated teeth affordable by a large segment of the population worldwide？ This review article explores existing and visionary approaches that address some of the above-mentioned questions. Tooth regeneration represents a revolution in stomatology as a shift in the paradigm from repair to regeneration： repair is by metal or artificial materials whereas regeneration is by biological restoration. Tooth regeneration is an extension of the concepts in the broad field of regenerative medicine to restore a tissue defect to its original form and function by biological substitutes.

关键词： stem cells bioactive cues biomaterials cell homing dental pulp tooth regeneration growth factors scaffold dental implants pulp regeneration

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Platelet-rich plasma enhances adipose-derived stem cell-mediated angiogenesis in a mouse ischemic hindlimb model

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World Journal of Stem Cells 2018年第12期10卷 212-227页

作者： Chia-Fang Chen Han-Tsung Liao Department of Plastic and Reconstructive Surgery Chang Gung Memorial Hospital craniofacial Research center Chang Gung Memorial Hospital College of Medicine Chang Gung University

AIM To evaluate the angiogenic effect of platelet-rich plasma(PRP)-preconditioned adipose-derived stem cells(ADSCs) both in vitro and in a mouse ischemic hindlimb *** ADSCs were divided based on culture medium: 2.5% PRP, 5% PRP, 7.5% PRP, and 10% PRP. Cell proliferation rate was analyzed using the MTS assay. The gene expression of CD31, vascular endothelial growth factor, hypoxia-inducible factors, and endothelial cell nitric oxide synthase was analyzed using reverse transcription polymerase chain reaction. Cell markers and structural changes were assessed through immunofluorescence staining and the tube formation assay. Subsequently, we studied the in vivo angiogenic capabilities of ADSCs by a mouse ischemic hindlimb *** The proliferation rate of ADSCs was higher in the 2.5%, 5%, and 7.5% PRP groups. The expression of hypoxia-inducible factor, CD31, vascular endothelial growth factor, and endothelial cell nitric oxide synthase in the 5% and 7.5% PRP groups increased. The 5%, 7.5%, and 10% PRP groups showed higher abilities to promote both CD31 and vascular endothelial growth factor production and tubular structure formation in ADSCs. According to laser Doppler perfusion scan, the perfusion ratios of ischemic limb to normal limb were significantly higher in 5% PRP, 7.5% PRP, and human umbilical vein endothelial cells groups compared with the negative control and fetal bovine serum(FBS) groups(0.88 ± 0.08, 0.85 ± 0.07 and 0.81 ± 0.06 for 5%, 7.5% PRP and human umbilical vein endothelial cells compared with 0.42 ± 0.17 and 0.54 ± 0.14 for the negative control and FBS, P < 0.01).CONCLUSION PRP-preconditioned ADSCs presented endothelial cell characteristics in vitro and significantly improved neovascularization in ischemic hindlimbs. The optimal angiogenic effect occurred in 5% PRP-and 7.5% PRPpreconditioned ADSCs.

关键词： Platelet-rich plasma Adipose-derived stem cells Mesenchymal stem cell Angiogenesis Endothelial differentiation Mouse ischemic hindlimb model

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The importance of a potential phosphorylation site in enamelin on enamel formation

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International Journal of Oral Science 2017年第4期9卷 210-215页

作者： Wen-Juan Yan Pan Ma Ye Tian Jing-Ya Wang Chun-Lin Qin Jian Q Feng Xiao-Fang Wang Department of Biomedical Sciences and center for craniofacial Research and Diagnosis Texas A&M University College of DentistryDallasUSA Department of Endodontics Nanfang HospitalSouthern Medical UniversityGuangzhouChina

Enamelin （ENAM） has three putative phosphoserines （pSers） phosphorylated by a Golgi-associated secretory pathway kinase （FAM20C） based on their distinctive Ser-x-Glu （S-x-E） motifs. Fam2OC-knockout mice show severe enamel defects similar to those in the Enam-knockout mice, implying an important role of the pSers in ENAM. To determine the role of pSer5s in ENAM, we characterized ENAMRgsc514 mice, in which Sers5 cannot be phosphorylated by FAM20C due to an E57〉Gs7 mutation in the S-x-E motif, The enamel microstructure of 4-week-old mice was examined by scanning electron microscopy. The teeth of 6-day-old mice were characterized by histology and immunohistochemistry. The protein lysates of the first lower molars of 4-day-old mice were analyzed by Western immunoblotting using antibodies against ENAM, ameloblastin and amelogenin. ENAMRgsc514 heterozygotes showed a disorganized enamel microstructure, while the homozygotes had no enamel on the dentin surface. The N-terminal fragments of ENAM in the heterozygotes were detained in the ameloblasts and localized in the mineralization front of enamel matrix, while those in the WT mice were secreted out of ameloblasts and distributed evenly in the outer 1/2 of enamel matrix. Surprisingly, the 15 kDa C-terminal fragments of ameloblastin were not detected in the molar lysates of the homozygotes. These results suggest that the phosphorylation of SerSS may be an essential posttranslational modification of ENAM and is required for the interaction with other enamel matrix molecules such as ameloblastin in mediating the structural organization of enamel matrix and protein-mineral interactions during enamel formation.

关键词： ameloblastin enamel enamelin FAM20C phosphorylation phosphoserine

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Epstein-Barr virus infection mechanisms

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Chinese Journal of Cancer 2014年第11期33卷 545-548页

作者： Liudmila S.Chesnokova Lindsey M.Hutt-Fletcher Department of Microbiology.and Immunology Center for Molecular Tumor Virology and Feist-Weiller Cancer CenterLouisiana State University Health Sciences CenterShreveportLA 71130USA

Epstein-Barr virus(EBV) infection occurs by distinct mechanisms across different cell types. EBV infection of B cells in vitro minimally requires 5 viral glycoproteins and 2 cellular proteins. By contrast, infection of epithelial cells requires a minimum of 3 viral glycoproteins, which are capable of interacting with one or more of 3 different cellular proteins. The full complement of proteins involved in entry into all cell types capable of being infected in vivo is unknown. This review discusses the events that occur when the virus is delivered into the cytoplasm of a cell, the players known to be involved in these events, and the ways in which these players are thought to function.

关键词：病毒感染机制蛋白质相互作用病毒糖蛋白细胞类型细胞蛋白上皮细胞 EBV

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Smyd1 is essential for myosin expression and sarcomere organization in craniofacial,extraocular,and cardiac muscles

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Journal of Genetics and Genomics 2021年第3期48卷 208-218页

作者： Shuang Jiao Rui Xu Shaojun Du Department of Biochemistry and molecular biology Institute of Marine and Environmental TechnologyUniversity of Maryland School of MedicineBaltimoreMD 21202USA Key Laboratory of Experimental Marine biology Center for Ocean Mega-ScienceInstitute of OceanologyChinese Academy of SciencesQingdao 266071China School of Life Sciences Shandong University of TechnologyZibo 255049China

Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle *** studies revealed that Smyd1,a lysine methyltransferase,plays a key role in sarcomere assembly in heart and trunk skeletal ***,Smyd1 expression and function in craniofacial muscles are not ***,we analyze the developmental expression and function of two smyd1 paralogous genes,smyd1 a and smyd1 b,in craniofacial and cardiac muscles of zebrafish *** data show that loss of smyd1a(smyd1a^(mb5))or smyd1b(smyd1b^(sa15678))has no visible effects on myogenic commitment and expression of myod and myosin heavy-chain m RNA transcripts in craniofacial ***,myosin heavy-chain protein accumulation and sarcomere organization are dramatically reduced in smyd1b^(sa15678) single mutant,and almost completely diminish in smyd1a^(mb5);smyd1b^(sa15678) double mutant,but not in smyd1a^(mb5) *** defects are also observed in cardiac muscles of smyd1b^(sa15678) *** craniofacial and cardiac muscle formation is associated with an upregulation of hsp90α1 and unc45b mRNA expression in smyd1b^(sa15678) and smyd1a^(mb5);smyd1b^(sa15678) ***,our studies indicate that Smyd1b,but not Smyd1a,plays a key role in myosin heavy-chain protein expression and sarcomere organization in craniofacial and cardiac *** of smyd1b results in muscle-specific stress response.

关键词： Smyd1 Myosin Sarcomere craniofacial muscle Cardiac muscle

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Engineered nucleus-free mesenchymal stem cells (MSCs) for the targeted delivery of therapeutics to disease site

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Genes & Diseases 2023年第2期10卷 310-312,I0001页

作者： Zander Schwartz Piao Zhao Annie Wang Guozhi Zhao Wei Zeng Yonghui Wang Hue H. Luu Rex C. Haydon Tong-Chuan He Russell R. Reid Jason Strelzow School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China Laboratory of craniofacial Suture biology.and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Specialized therapeutic delivery, or use of pharmaceuticals and other biomaterials to target specific parts of the body or diseased tissue, has long been sought as an ideal way of treating human diseases. A recent article published in Nature Biomedical Engineering revealed an innovative strategy to engineer nucleus-free human mesenchymal stem cells (MSCs) for targeted delivery of therapeutics to disease site.1 MSCs have emerged as promising vehicles of therapeutic delivery.2,3 MSCs are undifferentiated pluripotent stem cells derived from areas such as bone marrow and adipose tissue.4,5 MSCs are sought after for their chemotaxis, or ability to home towards a chemical stimulus, and capacity for modification with elements such as chemoattractant receptors and adhesion molecules.1 These properties allow for site-specific and minimally-invasive therapeutic administration and treatment.

关键词： targeted delivery sought

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Fibroblast growth factor(FGF)signaling in development and skeletal diseases

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Genes & Diseases 2014年第2期1卷 199-213页

作者： Chad M.Teven Evan M.Farina Jane Rivas Russell R.Reid The Laboratory of craniofacial biology Section of Plastic&Reconstructive SurgeryDepartment of SurgeryThe University of Chicago Medical Center5841 South Maryland AvenueMC 6035ChicagoIL 60637USA The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA

Fibroblast growth factors(FGF)and their receptors serve many functions in both the developing and adult *** contain 18 FGF ligands and four FGF receptors(FGFR).FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation,differentiation,and migration,morphogenesis,and ***-FGFR signaling is also critical to the developing axial and craniofacial *** particular,the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture *** the adult,FGFs and FGFRs are crucial for tissue *** signaling generally follows one of three transduction pathways:RAS/MAP kinase,PI3/AKT,or *** pathway likely regulates specific cellular *** expression of FGF and improper activation of FGFRs are associated with various pathologic conditions,unregulated cell growth,and ***,aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and *** biology.and mechanisms of the FGF family have been the subject of significant research over the past 30 ***,work has focused on the therapeutic targeting and potential of FGF ligands and their associated *** majority of FGF-related therapy is aimed at age-related *** understanding of FGF signaling and biology.may reveal additional therapeutic roles,both in utero and *** review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.

关键词： Craniosynostosis FGF signaling Fibroblast growth factor Fibroblast growth factor receptor Genetics Pathogenesis Signal transduction Skeletal development

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3-D bioprinting technologies in tissue engineering and regenerative medicine:Current and future trends

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Genes & Diseases 2017年第4期4卷 185-195页

作者： Elliot S.Bishop Sami Mostafa Mikhail Pakvasa Hue H.Luu Michael J.Lee Jennifer Moriatis Wolf Guillermo A.Ameer Tong-Chuan He Russell R.Reid Laboratory of craniofacial biology.and Development Section of Plastic and Reconstructive SurgeryDepartment of SurgeryThe University of Chicago MedicineChicagoIL 60637USA molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA Biomedical Engineering Department Northwestern UniversityEvanstonIL 60208USA Department of Surgery Feinberg School of MedicineNorthwestern UniversityChicagoIL 60616USA

Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living *** as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth factors with the goal of creating bioidentical tissue for a variety of *** successes have demonstrated distinct advantages over conventional tissue engineering *** surprisingly,there are current challenges to address before 3D bioprinting becomes clinically *** we provide an overview of 3D bioprinting technology and discuss key advances,clinical applications,and current *** 3D bioprinting is a relatively novel tissue engineering strategy,it holds great potential to play a key role in personalized medicine.

关键词： Additive manufacturing Bioprinting CAD/CAM 3D printing Tissue engineering

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A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

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Bone Research 2020年第2期8卷 157-168页

作者： Tobias Schwerd Freia Krause Stephen R.F.Twigg Dominik Aschenbrenner Yin-Huai Chen Uwe Borgmeyer Miryam Müller Santiago Manrique Neele Schumacher Steven A.Wall Jonathan Jung Timo Damm Claus-Christian Glüer Jürgen Scheller Stefan Rose-John E.Yvonne Jones Arian Laurence Andrew O.M.Wilkie Dirk Schmidt-Arras Holm H.Uhlig Translational Gastroenterology Unit John Radcliffe HospitalUniversity of OxfordOxfordUK Department of Pediatrics Dr von Hauner Children’s HospitalLMU MunichMunichGermany Christian-Albrechts-University Kiel Institute of BiochemistryKielGermany Clinical Genetics Group MRC Weatherall Institute of Molecular MedicineUniversity of OxfordJohn Radcliffe HospitalOxfordUK center for molecular Neurobiology.Hamburg(ZMNH) University Medical Center Hamburg-EppendorfHamburgGermany Division of Structural biology Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK craniofacial Unit Department of Plastic and Reconstructive SurgeryOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK Section Biomedical Imaging Department of Radiology and NeuroradiologyUniversity Medical Center Schleswig-HolsteinKielGermany Institute of Biochemistry and molecular biology.Ⅱ Medical FacultyHeinrich-Heine-UniversityDüsseldorfGermany Department of Paediatrics University of OxfordOxfordUK NIHR Oxford Biomedical Research Centre OxfordUK The Beatson Institute for Cancer Research GlasgowUK School of Medicine University of GlasgowGlasgowUK

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

关键词： IL11 cytokine facial

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