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101.
Steven D Rhodes Xiaohua Wu Yongzheng He Shi Chen Hao Yang Karl W Staser Jiapeng Wang Ping Zhang Chang Jiang Hiroki Yokota Ruizhi Dong Xianghong Peng Xianlin Yang Sreemala Murthy Mohamad Azhar Khalid S Mohammad Mingjiang Xu Theresa A Guise Feng‐Chun Yang 《Journal of bone and mineral research》2013,28(12):2476-2489
Dysregulated transforming growth factor beta (TGF‐β) signaling is associated with a spectrum of osseous defects as seen in Loeys‐Dietz syndrome, Marfan syndrome, and Camurati‐Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGF‐β1 signaling pivotally underpins osseous defects in Nf1flox/?;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF‐β1 levels are fivefold to sixfold increased both in Nf1flox/?;Col2.3Cre mice and in a cohort of NF1 patients. Nf1‐deficient osteoblasts, the principal source of TGF‐β1 in bone, overexpress TGF‐β1 in a gene dosage–dependent fashion. Moreover, Nf1‐deficient osteoblasts and osteoclasts are hyperresponsive to TGF‐β1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21‐Ras–dependent hyperactivation of the canonical TGF‐β1–Smad pathway. Reexpression of the human, full‐length neurofibromin guanosine triphosphatase (GTPase)‐activating protein (GAP)‐related domain (NF1 GRD) in primary Nf1‐deficient osteoblast progenitors, attenuated TGF‐β1 expression levels and reduced Smad phosphorylation in response to TGF‐β1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF‐β receptor 1 (TβRI) kinase inhibitor, SD‐208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1flox/?;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF‐β1 signaling in the pathogenesis of NF1‐associated osteoporosis and pseudarthrosis, thus implicating the TGF‐β signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies. © 2013 American Society for Bone and Mineral Research. 相似文献
102.
Jameela Abdulaziz Kari Sherif El-Desoky Youssef Farag Hisham Mosli Abdul-Malik Altyieb Ahmad Al Sayad Othman Radawi Hosam Ghabra Faten Basnawi Ohood Bahrawi Ajay Singh Hassan Farsi 《Pediatric nephrology (Berlin, Germany)》2013,28(6):927-931
Background
Posterior urethral valves (PUV) are a common cause of end-stage renal failure in childhood. Our aim was to describe a cohort of patients with PUV and to investigate the predictors of renal impairment.Methods
We performed a retrospective chart review of children with PUV who were followed at King Abdulaziz University hospital between 2002 and 2011.Results
The cohort comprised 68 boys. There was a significant difference in the duration of follow-up (p?=?0.024), nadir serum creatinine (p?<?0.001), and last known serum creatinine level (p?=?0.001) between the patients with and without renal impairment. The duration of follow-up appeared to be a significant predictor for serum creatinine doubling (p?=?0.003; odds ratio, 1.8). There was no difference in the age of presentation, age at the time of the study, and first or last serum creatinine between children who initially had vesicostomy and children who had ablation.Conclusions
Ablation of PUV or vesicostomy did not influence kidney function in our study cohort. Children with a normal nadir serum creatinine who presented early had a better outcome. 相似文献103.
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109.
Meyer Alexa R. Carducci Michael A. Denmeade Samuel R. Markowski Mark C. Pomper Martin G. Pierorazio Philip M. Allaf Mohamad E. Rowe Steven P. Gorin Michael A. 《Annals of nuclear medicine》2019,33(8):617-623
Annals of Nuclear Medicine - Complete surgical resection of metastatic sites has been shown to prolong survival in select patients with oligometastatic RCC. This treatment strategy is dependent... 相似文献
110.
Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two‐center experience 下载免费PDF全文