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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair

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Bone Research 2024年第2期12卷 289-301页

作者： Heeseog Kang Amy L.Strong Yuxiao Sun Lei Guo Conan Juan Alec C.Bancroft Ji Hae Choi Chase A.Pagani Aysel A.Fernandes Michael Woodard Juhoon Lee Sowmya Ramesh Aaron W.James David Hudson Kevin N.Dalby Lin Xu Robert J.Tower Benjamin Levi Center for Organogenesis Regeneration and TraumaDepartment of SurgeryUniversity of Texas SouthwesternDallasTX 75390USA section of plastic Surgery Department of SurgeryUniversity of MichiganAnn ArborMI 48109USA Quantitative Biomedical Research Center Peter O’Donnell Jr.School of Public HealthUniversity of Texas SouthwesternDallasTX 75390USA Department of Orthopedics and Sports Medicine University of WashingtonSeattleWA 98195USA Division of Chemical Biology and Medicinal Chemistry College of PharmacyUniversity of Texas at AustinAustinTX 78712USA Department of Pathology Johns Hopkins UniversityBaltimoreMD 21218USA

While hypoxic signaling has been shown to play a role in many cellular processes,its role in metabolism-linked extracellular matrix(ECM)organization and downstream processes of cell fate after musculoskeletal injury remains to be ***(HO)is a debilitating condition where abnormal bone formation occurs within extra-skeletal *** andhypoxia-inducible factor 1α(HIF-1α)activation have been shown to promote ***,the underlying molecular mechanisms bywhich the HIF-1αpathway in mesenchymal progenitor cells(MPCs)contributes to pathologic bone formation remain to ***,we used a proven mouse injury-induced HO model to investigate the role of HIF-1αon aberrant cell ***-cell RNA sequencing(scRNA-seq)and spatial transcriptomics analyses of the HO site,we found that collagen ECM organizationis the most highly up-regulated biological process in *** mesenchymal cell-specific deletion of Hif1α(Hoxa11-CreER^(T2);Hif1a^(fl/fl))significantly mitigated HO in ***-seq analysis of these Hoxa11-CreER^(T2);Hif1a^(fl/fl)mice identified the PLOD2/LOXpathway for collagen cross-linking as downstream of the HIF-1αregulation of ***,our scRNA-seq data and mechanisticstudies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α*** a translational aspect,a pan-LOX inhibitor significantly decreased HO.A newly screened compound revealed that the inhibition of PLOD2 activity in MPCssignificantly decreased osteogenic differentiation and glycolytic *** suggests that the HIF-1α/PLOD2/LOX axis linked tometabolism regulates HO-forming MPC *** results suggest that the HIF-1α/PLOD2/LOX pathway represents a promisingstrategy to mitigate HO formation.

关键词： metabolism skeletal aberrant

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A simplified noncryogenic strategy to transport mesenchymal stem cells: Potential applications in cell therapy and regenerative medicine

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Genes & Diseases 2024年第3期11卷 26-29页

作者： Xiangyu Dong Yannian Gou Meichun Guo Jiamin Zhong Aohua Li Ailing Hao Wei Zeng Rex C.Haydon Hue H.Luu Russell R.Reid Tongchuan He Yan Xu Jiaming Fan Ministry of Education Key Laboratory of Diagnostic Medicine And Department of Clinical BiochemistryCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Institute of Sports Medicine Beijing Key Laboratory of Sports InjuriesPeking University Third HospitalBejing 100191China

With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport *** for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.

关键词： transport methods simplified

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz Jeffrey Hong Lily Song William Wagstaff Rex C.Haydon Hue H.Luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He Lewis L.Shi Chicago Medical School Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA Laboratory of Craniofacial Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and *** Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical *** of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling *** crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ ***-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic *** complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic ***,both stimulatory and inhibitory treatments come with potential risks that need to be *** review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt *** thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+*** description involved each of its components and their involvement in other cellular ***,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

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The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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Genes & Diseases 2024年第3期11卷 155-187页

作者： Michael Yu Kevin Qin Jiaming Fan Guozhi Zhao Piao Zhao Wei Zeng Connie Chen Annie Wang Yonghui Wang jiamin Zhong Yi Zhu William Wagstaff Rex C.Haydon Hue H.Luu Sherwin Ho Michael J.Lee Jason Strelzow Russell R.Reid Tong-Chuan He School of Medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopedic Surgery The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China Department of Orthopaedic Surgery Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China

The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across *** proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling *** behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling *** signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various *** includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem *** signaling has also been implicated in tumor cells that exhibit stem cell-like *** signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone *** surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including *** of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and ***,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt *** with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

关键词： β-Catenin Cancer Canonical Wnt Disease Non-canonical Wnt Stem cells Targeted therapy Wnt signaling

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Supraclavicular lymph node transplant:a focus on technique

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plastic and Aesthetic Research 2022年第1期9卷 77-83页

作者： Maureen Beederman David W.Chang section of plastic and Reconstructive Surgery Department of SurgeryThe University of Chicago MedicineChicagoIL 60637USA

Physiologic surgical options,including vascularized lymph node transplant and lymphovenous bypass are becoming increasingly popular interventions for the treatment of lymphedema of both the upper and lower *** different lymph node donor sites have been described,including submental,lateral thoracic,superficial groin,supraclavicular,and various intraabdominal *** paper describes a step-by-step approach to the harvest of vascularized lymph nodes from the supraclavicular area,which is the preferred donor site for most patients with both upper and lower extremity lymphedema.

关键词： Lymphedema surgery lymph node transplant microsurgery

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Designing an evidence-based free-flap pathway in head and neck reconstruction

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2022年第2期8卷 126-132页

作者： Michelle Mark Michael Eggerstedt Matthew J.Urban Samer Al-Khudari Ryan Smith Peter Revenaugh Department of Otorhinolaryngology-Head and Neck Surgery Section of Facial Plastic and Reconstructive SurgeryRush University Medical CenterChicagoIllinoisUSA

Background:The use of autologous free-tissue transfer is an increasingly utilized tool in the ladder of reconstructive options to preserve and restore function in patients with head and neck *** article focuses on the evidence surrounding perioperative care that optimizes surgical outcomes and describes one tertiary center's approach to standardized free-flap *** Sources:This article examines English literature from PubMed and offers expert opinion on perioperative free-flap care for head and neck ***:Free-flap reconstruction for head and neck cancer is a process that,while individualized for each patient,is best supported by a comprehensive and standardized care *** optimization begins in the preoperative phase and a thoughtful approach to intraprofessional communication and evidence-based practice is rewarded with improved outcomes.

关键词： facial plastics and reconstruction free-flap tissue transfer head and neck oncology

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Effect of psychological nursing intervention combined with acupressure on postoperative recovery of women after cesarean section

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World Journal of Clinical Cases 2024年第21期12卷 4527-4535页

作者： Xing-Ying Liu Xiao-Bo Chen You-Liang Wen Xiao-Ping Guo Xiao-Bin Zhou Department of Rehabilitation Medicine Second Affiliated Hospital of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Rehabilitation Therapy Teaching and Research Office Rehabilitation College of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Dermatology and plastic Surgery Department First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina

BACKGROUND Psychological intervention nursing(PIN)has been considered to have a curative effect on cesarean section(CS)post-operative ***,the therapeutic mechanisms remain *** To explore the effects of PIN combined with acupressure massage on CS postoperative *** A retrospective study was conducted on 150 pregnant women admitted to an obstetrics department between January 2020 and January *** control group(CG)received acupressure therapy(n=73),and the intervention group(IG)received acupressure therapy and PIN therapy(n=77).Postoperative recovery time was assessed by anal-exhausting,defecation,bed activity,breastfeeding,and hospital stay *** effects,including infection,bleeding,limb numbness,intrauterine hematoma,urinary retention,and venous thromboembolism,were *** pain visual analogue scale(VAS)was used to evaluate the degree of *** and depression status were qualitatively assessed using the selfrating anxiety scale(SAS),self-rating depression scale(SDS),and Edinburgh postpartum depression scale(EPDS).The Pittsburgh sleep quality index(PSQI)was used to compare sleep quality between the *** The baseline data and SAS,SDS,EPDS,and PSQI scores did not significantly differ before CS(P>0.05)and neither did complication rates between the two groups after CS(P>0.05).However,anal-exhausting,defecation,waking up,breastfeeding,and hospitalization times were significantly shorter for participants in the IG than those for participants in the CG(P<0.05).The VAS,SAS,SDS,EPDS,and PSQI scores of the IG were significantly lower than those of the CG(P<0.05).CONCLUSION PIN,combined with acupressure massage,effectively promotes maternal recovery,reduces post-CS pain,and improves post-operative negative emotions and sleeping quality.

关键词： Psychological intervention nursing Acupressure massage Cesarean section Negative emotions Sleep quality

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Regenerative peripheral nerve interfaces(RPNIs):current status and future direction

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plastic and Aesthetic Research 2022年第1期9卷 96-104页

作者： Katherine L.Burke Theodore A.Kung Rachel C.Hooper Stephen W.P.Kemp Paul S.Cederna Department of Surgery Section of Plastic SurgeryUniversity of MichiganAnn ArborMI 48109-0340USA Department of Biomedical Engineering University of MichiganAnn ArborMI 48109-0340USA

Despite significant advancements in neuroprosthetic control strategies,current peripheral nerve interfacing techniques are limited in their ability to facilitate accurate and reliable long-term *** regenerative peripheral nerve interface(RPNI)is a biologically stable bioamplifier of efferent motor action potentials with demonstrated long-term *** innovative,straightforward,and reproducible surgical technique has shown enormous potential in improving prosthetic control for individuals with upper limb *** RPNI consists of an autologous free muscle graft secured around the end of a transected peripheral nerve or individual fascicles within a residual *** construct facilitates EMG signal transduction from the residual peripheral nerve to a neuroprosthetic device using indwelling bipolar electrodes on the muscle *** review article focuses on the development of the RPNI and its use for intuitive and enhanced prosthetic control and sensory *** addition,this article also highlights the use of RPNIs for the prevention and treatment of postamputation pain.

关键词： Prosthetic control amputation RPNI regenerative peripheral nerve interface neuroma sensory feedback

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Bone without borders-Monetite-based calcium phosphate guides bone formation beyond the skeletal envelope

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Bioactive Materials 2023年第1期19卷 103-114页

作者： Furqan A.Shah Martina Jolic Chiara Micheletti Omar Omar Birgitta Norlindh Lena Emanuelsson Håkan Engqvist Thomas Engstrand Anders Palmquist Peter Thomsen Department of Biomaterials Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden Department of Materials Science and Engineering McMaster UniversityHamiltonOntarioCanada Department of Engineering Sciences Applied Materials Science SectionUppsala UniversityUppsalaSweden Department of Reconstructive plastic Surgery Karolinska University HospitalStockholmSweden

Calcium phosphates(CaP)represent an important class of osteoconductive and osteoinductive *** proof-of-concept,we show how a multi-component CaP formulation(monetite,beta-tricalcium phosphate,and calcium pyrophosphate)guides osteogenesis beyond the physiological *** a sheep model,hollow dome-shaped constructs were placed directly over the occipital *** 12 months,large amounts of bone(~75%)occupy the hollow space with strong evidence of ongoing *** of both compact bone(osteonal/osteon-like arrangements)and spongy bone(trabeculae separated by marrow cavities)reveal insights into function/need-driven microstructural *** within the CaP also contain both woven bone and vascularised lamellar *** actively contribute to CaP degradation/*** the constituent phases,only calcium pyrophosphate persists within osseous(cutting cones)and non-osseous(macrophages)*** a translational perspective,this multi-component CaP opens up exciting new avenues for osteotomy-free and minimally-invasive repair of large bone defects and augmentation of the dental alveolar ridge.

关键词： Bone Calcium phosphate Monetite Calcium pyrophosphate Electron microscopy Raman spectroscopy

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