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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 treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In 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 models.Histological 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 inhibition.RNA sequencing of human and mouse tissue supported these findings.The 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 osteoclasts.The 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 lesions.These 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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Novel de novo TRPV4 mutation identified in a Chinese family with metatropic dysplasia inhibits chondrogenic differentiation

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Genes & Diseases 2024年第3期11卷 83-86页

作者： Ping Wei Weizhe Shi Tianying Nong Caixia Xian Xia Li Zhaohui Li Xin Li Jianping Wu Liyuan Shang Fulong Xu Yibo Xu Hongwen Xu Mingwei Zhu Guangzhou Institute of Pediatrics Guangzhou Women and Children's Medical CenterGuangzhou Medical UniversityGuangdong Provincial Clinical Research Center for Child HealthGuangzhouGuangdong 510623China Department of Pediatric Orthopedics Guangzhou Women and Children's Medical CenterGuangzhou Medical UniversityGuangdong Provincial Clinical Research Center for Child HealthGuangzhouGuangdong 510623China

Metatropicdysplasia(MD,MIM156530)is a rare congenital bone dysplasia primarily characterized by severe platyspondyly with long and wide vertebral bodies and dumbbell deformity of the tubular bones.MD can be caused by heterozygous mutations in the gene encoding transient receptor potential vanilloid family member 4(TRPV4).We identifieda novel de novo mutation,c.2353T>C,in the TRPV4 gene,in a Chinese family with mild MD.

关键词： TRPV4 dysplasia congenital

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History of chronic gastritis:How our perceptions have changed

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World Journal of Gastroenterology 2024年第13期30卷 1851-1858页

作者： Dmitry Bordin Maria Livzan Department of Pancreatic Biliary and Upper GI Tract DiseasesA.S.Loginov Moscow Clinical Scientific CenterMoscow 111123Russia Department of Propaedeutic of Internal Diseases and Gastroenterology Russian University of MedicineMoscow 127006Russia Department of Outpatient Therapy and Family Medicine Tver State Medical UniversityTver 170100Russia Department of Internal Medicine and Gastroenterology Omsk State Medical UniversityOmsk 644099Russia

Currently,the diagnostic strategy for chronic gastritis(CG)is aimed not just at fixing the presence of gastric mucosal inflammation,but also at gastric cancer(GC)risk stratification in a particular patient.Modern classification approach with the definition of the stage of gastritis determines the need,activities and frequency of dynamic monitoring of a patient.However,this attitude to the patient suffering from CG was far from always.The present publication is a literature review describing the key milestones in the history of CG research,from the description of the first observations of inflammation of the gastric mucosa,assessment of gastritis as a predominantly functional disease,to the advent of endoscopy of the upper digestive tract and diagnostic gastric biopsy,assessment of the role of Helicobacter pylori infection in progression of inflammatory changes to atrophy,intestinal metaplasia,dysplasia and GC.

关键词： Chronic gastritis Intestinal metaplasia dysplasia Gastric cancer Helicobacter pylori

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Excitatory somatostatin interneurons in the dentate gyrus drive a widespread seizure network in cortical dysplasia

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Signal Transduction and Targeted Therapy 2023年第6期8卷 3111-3122页

作者： Yang Zheng Cenglin Xu Jinyi Sun Wenjie Ming Sijie Dai Yuying Shao Xiaoyun Qiu Menghan Li Chunhong Shen Jinghong Xu Fan Fei Jiajia Fang Xuhong Jiang Guoqing Zheng Weiwei Hu Yi Wang Shuang Wang Meiping Ding Zhong Chen Department of Neurology Zhejiang Provincial Hospital of Chinese MedicineThe First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310060China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou310053China Institute of Pharmacology and Toxicology College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Epilepsy Center Department of NeurologySecond Affiliated Hospital Zhejiang University School of MedicineHangzhou310009China Department of Neurology Fourth Affiliated Hospital of Zhejiang University School of MedicineYiwu322000China

Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery,likely due to the widespread seizure network.Previous studies have primarily focused on the disruption of dysplastic lesions,rather than remote regions such as the hippocampus.Here,we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia.We further investigated the cellular substrates leading to the epileptic hippocampus,using multiscale tools including calcium imaging,optogenetics,immunohistochemistry and electrophysiology.For the first time,we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures.Somatostatin-positive were recruited during cortical dysplasia-related seizures.Interestingly,optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization.By contrast,parvalbumin-positive interneurons retained an inhibitory role as in controls.Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus.Taken together,our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.

关键词： somatostatin dysplasia seizure

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Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency

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International Journal of Oral Science 2022年第4期14卷 572-583页

作者： Zheng Li Muxin Yue Boon Chin Heng Yunsong Liu Ping Zhang Yongsheng Zhou Department of Prosthodontics Peking University School and Hospital of StomatologyBeijingChina National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices&Beijing Key Laboratory of Digital Stomatology 22 Zhongguancun South AvenueHaidian DistrictBeijingChina The Central Laboratory Peking University School and Hospital of StomatologyBeijingChina

As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase(PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling pathway.Collectively, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.

关键词： skeletal dysplasia homeostasis

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Chinese expert consensus on the diagnosis and treatment of borderline developmental dysplasia of the hip (2022 Edition)

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Chinese Medical Journal 2023年第9期136卷 1012-1014页

作者： Jia Zhang Chunbao Li Mingyang An Yidong Wu Kangkang Yu Yujie Liu The Youth Group of the Sports Medicine Branch of the Chinese Medical Association The Hip Sports Injury Working Committee of the Sports Medicine Branch of the Chinese Medical Association The Hip Preservation Group of the Rehabilitation Reconstruction Surgery Committee of the Chinese Association of Rehabilitation Medicine The Hip Preservation Group of Orthopaedic Surgeon Branch of the Chinese Medical Doctor Association Department of Sports Medicine Senior Department of OrthopedicsThe Fourth Medical Center of Chinese PLA General HospitalBeijing 100853China Medical School of Chinese PLA Beijing 100853China 不详

Developmental dysplasia of the hip(DDH)is one of the most common diseases causing hip pain in adults and is an important cause of osteoarthritis(OA).Borderline developmental dysplasia of the hip(BDDH)is a condition that falls between a normal hip and adult DDH.In BDDH,the lateral center-edge angle(LCEA)of the acetabulum is usually defined between 18°and 25°or 20°and 25°;however,this definition remains controversial.

关键词： dysplasia diagnosis diseases

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Significance of dysplasia in bile duct resection margin in patients with extrahepatic cholangiocarcinoma:A retrospective analysis

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World Journal of Clinical Cases 2022年第10期10卷 3078-3087页

作者： Jung Wan Choe Hyo Jung Kim Jae Seon Kim Department of Internal Medicine Korea University Ansan HospitalKorea University College of MedicineAnsan 15355South Korea Department ofInternal Medicine Korea University Guro HospitalKorea University College of MedicineSeoul 08308South Korea Department ofInternal Medicine Korea University Guro Hospital2

BACKGROUND Radical resection is the only indicator associated with survival in extrahepatic cholangiocarcinoma(EHCC).However,limited data are available regarding the implications of dysplasia at the resection margin following surgery.AIM To evaluate the prognostic significance of dysplasia-positive margins in patients diagnosed with EHCC.METHODS We reviewed the records of patients who had undergone surgery for EHCC with curative intent between January 2013 and July 2017.We retrospectively analyzed the clinicopathological data of 116 patients followed for longer than 3 years.The status of resection margin was used to classify patients into negative low-grade dysplasia(LGD)and high-grade dysplasia(HGD)/carcinoma in situ(CIS)categories.RESULTS Based on postoperative status,72 patients underwent resection with negative margins,19 had LGD-positive margins,and 25 showed HGD/CIS-positive margins.The mean survival rates of the patients with negative margins,LGD margins,and HGD/CIS margins were 49.1±4.5,47.3±6.0,and 20.8±4.4 mo,respectively(P70 years and HGD/CIS-positive margins were significant independent factors for survival(hazard ratio=1.90 and 2.47,respectively).CONCLUSION HGD/CIS margin in resected EHCC is associated with a poor survival.However,the LGDpositive resection margin is not a significant indicator of survival in patients with EHCC.

关键词： dysplasia Cholangiocarcinoma Survival Extrahepatic cholangiocarcinoma Low-grade dysplasia High-grade dysplasia

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Characterization of E-cadherin expression in normal mucosa,dysplasia and adenocarcinoma of gastric cardia and its influence on prognosis

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World Journal of Gastrointestinal Oncology 2022年第1期14卷 265-277页

作者： Hai-Ling Wang Xue-Ke Zhao Fu-You Zhou Xin Song Liu-Yu Li Gai-Rong Huang Qi-De Bao Ling-Ling Lei Hai-Jun Yang Li Li Rui-Hua Xu Ai-Li Li Xian-Zeng Wang Wen-Li Han Jing-Li Ren Li-Dong Wang State Key Laboratory of Esophageal Cancer Prevention&Treatment and Henan Key Laboratory for Esophageal Cancer Research The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina Department of Thoracic Surgery and Tumor Prevention Treatment Anyang Tumor HospitalAnyang 455000Henan ProvinceChina Department of Geriatrics Henan Provincial People’s HospitalZhengzhou 450003Henan ProvinceChina Department of Oncology Anyang District HospitalAnyang 455000Henan ProvinceChina Department of Pathology Anyang Tumor HospitalAnyang 455000Henan ProvinceChina Department of Pathology Linzhou Tumor HospitalLinzhou 456500Henan ProvinceChina Department of Thoracic Surgery Linzhou People's HospitalLinzhou 456500Henan ProvinceChina Department of Pathology The Second Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000Henan ProvinceChina

BACKGROUND Gastric cardia adenocarcinoma(GCA),which has been classified as type II adenocarcinoma of the esophagogastric junction in western countries,is of similar geographic distribution with esophageal squamous cell carcinoma in China,and even referred as"sister cancer"by Chinese oncologists.The molecular mechanism for GCA is largely unknown.Recent studies have shown that decreased expression of E-cadherin is associated with the invasion and metastasis of multiple cancers.However,the E-cadherin expression has not been well characterized in gastric cardia carcinogenesis and its effect on GCA prognosis.AIM To characterize E-cadherin expression in normal gastric cardia mucosa,dysplasia and GCA tissues,and its influence on prognosis for GCA.METHODS A total of 4561 patients with GCA were enrolled from our previously established GCA and esophageal cancer databases.The enrollment criteria included radical surgery for GCA,but without any radio-or chemo-therapy before operation.The GCA tissue from 4561 patients and matched adjacent normal epithelial tissue(n=208)and dysplasia lesions(n=156)were collected,and processed as tissue microarray for immunohistochemistry.The clinicopathological characteristics were retrieved from the medical records in hospital and follow-up was carried out through letter,telephone or home interview.E-cadherin protein expression was determined by two step immunohistochemistry.Kaplan–Meier and Cox regression analyses were used to correlate E-cadherin protein expression with survival of GCA patients.RESULTS Of the 4561 GCA patients,there were 3607 males with a mean age of 61.6±8.8 and 954 females with a mean age of 61.9±8.6 years,respectively.With the lesions progressed from normal gastric cardia mucosa to dysplasia and GCA,the positive immunostaining rates for E-cadherin decreased significantly from 100%to 93.0%and 84.1%,respectively(R2=0.9948).Furthermore,E-cadherin positive immunostaining rate was significantly higher in patients at early stage(0 and I)than in those at late stage(II and III)(

关键词： E-cadherin expression Immunohistochemistry Gastric cardia adenocarcinoma dysplasia Clinicopathological feature Prognosis

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Influence of SCENIC recommendations on terminology used for histopathologic diagnosis of inflammatory bowel disease-associated dysplasia

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World Journal of Gastrointestinal Oncology 2022年第8期14卷 1375-1387页

作者： Yuan Li Hanlin L Wang Department of Pathology and Laboratory Medicine David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesCA 90095United States Department of Pathology Molecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical ScienceBeijing 100730China

BACKGROUND Published in 2015,the International Consensus Recommendations on Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients(SCENIC)recommended abandoning the use of diagnostic term“dysplasia-associated lesion or mass(DALM)”for polypoid dysplastic lesions detected in patients with inflammatory bowel disease(IBD).The aim of this study was to investigate whether this recommendation had any influence on diagnostic terminologies used by pathologists in their practice.METHODS We retrospectively reviewed all pathology reports for surveillance colonoscopic biopsies from ulcerative colitis(UC)patients in our institution during 1/2012-12/2014(pre-SCENIC)and 1/2016-12/2018(post-SCENIC).These included 1203 biopsies from 901 UC patients during the pre-SCENIC period and 1273 biopsies from 977 UC patients during the post-SCENIC period.Their corresponding endoscopic findings and histopathologic diagnoses were recorded.Clinical indications for total colectomy for UC patients and corresponding histopathologic findings in colectomy specimens were also recorded and compared.RESULTS A total of 347 and 419 polyps/polypoid lesions were identified during the preSCENIC and post-SCENIC periods,among which 60 and 104 were dysplastic/adenomatous,respectively.More polypoid dysplastic lesions were simply diagnosed as“adenoma”during the post-SCENIC period in comparison with the pre-SCENIC period(97.1%vs 65.0%;Pdysplasia”was more consistently used for random biopsies during the post-SCENIC period.Furthermore,the terms“sessile serrated adenoma/polyp”(SSA/P)and“serrated epithelial change”(SEC)were more consistently used for polypoid lesions and random biopsies,respectively,during the post-SCENIC period,although these were not specifically addressed in the S

关键词： Inflammatory bowel disease Ulcerative colitis dysplasia Terminology SCENIC

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Continuing interventions in a quality improvement bundle to reduce bronchopulmonary dysplasia

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World Journal of Pediatrics 2022年第4期18卷 278-282页

作者： Yan-Ping Xu Li-Ping Shi Li-Zhong Du Division of NICU Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child Health3333 Binsheng RoadHangzhou 310052China

Bronchopulmonary dysplasia(BPD)is a chronic lung disease of premature infants that results from an imbalance between lung injury and repair in the developing lung[1],BPD is the most common respiratory morbidity with multiple factors implicated in its etiopathogenesis for preterm infants.Despite the scientific advances in the field of neonatology,the incidence of BPD has largely been unchanged due to increased survival of extremely premature infants.Definition of BPD continues to be challenging and is used differently in the literature.BPD was first defined by Northway et al.

关键词： lung dysplasia bundle

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