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71.
72.
Runx2 Regulates Endochondral Ossification Through Control of Chondrocyte Proliferation and Differentiation
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Haiyan Chen Farah Y Ghori‐Javed Harunur Rashid Mitra D Adhami Rosa Serra Soraya E Gutierrez Amjad Javed 《Journal of bone and mineral research》2014,29(12):2653-2665
Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 gene in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2ΔE8/ΔE8 mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C‐terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal levels of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth are disrupted in Runx2ΔE8/ΔE8 mice. Loss of Runx2 in chondrocytes also impaired osteoprotegerin‐receptor activator of NF‐κB ligand (OPG‐RANKL) signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes, Gpr132, Sfn, c‐Myb, and Cyclin A1, to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes. © 2014 American Society for Bone and Mineral Research. 相似文献
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Muhammad Amjad Awan Javeria Arshad Bushra Allah Rakha Muhammad Sajjad Ansari Muhammad Waseem Ali Fouladi-Nashta David Miller Shamim Akhter 《Andrologia》2021,53(3):e13991
This study reports the first evaluation of sperm hyaluronan binding assay (HBA) for predicting the fertility of Nili-Ravi buffalo bulls in relation to standard parameters of sperm quality. Cryopreserved semen doses of low (n = 6), medium (n = 3) and high fertility (n = 8) bulls based on their respective return rates were used. Significantly, more spermatozoa bound to hyaluronan from the most fertile bulls (57.15% ± 1.44) compared with medium (42.46% ± 1.08) and low fertility bulls (29.70% ± 0.78). A strongly positive correlation (r = .824, p < .01) was found between HBA and fertility that predicts a 67.9% variability (r2 = .679, p < .01) in fertility. HBA was also strongly positively correlated with sperm viability (r = .679, p < .01) followed by their live/dead ratio (r = .637, p < .01), uncapacitated spermatozoa (r = .631, p < .01), normal apical ridge (r = .459, p < .01), motility (r = .434, p < .01), mature spermatozoa with low residual histones (r = .364, p < .01), high plasma membrane integrity (r = .316, p < .01) and nonfragmented DNA levels (r = .236, p < .05). It was negatively correlated with spermatozoa having reacted acrosome (r = −.654, p < .01). A fertility model built using a combination of sperm HBA and either sperm livability or viability predicts, respectively, 86.1% (r2 = .861, p < .01) and 85.9% (r2 = .859, p < .01) variability in buffalo bull fertility. In conclusion, sperm HBA may prove to be a single robust predictor of Nili-Ravi buffalo bull fertility. 相似文献
74.
Maan Abdullah Albarry Jamil Amjad Hashmi Ahdab Qasem Alreheli Alia M. Albalawi Bushra Khan Khushnooda Ramzan 《Ophthalmic genetics》2019,40(6):507-513
ABSTRACTBackground: Retinitis pigmentosa (RP) is a heterogeneous group of ocular dystrophy. It is challenging to identify the underlying genetic defect in individuals with RP due to huge genetic heterogeneity. This study was designed to delineate the genetic defect(s) underlying RP in extended Saudi families and to describe the possible disease mechanism.Materials and Methods: Fundus photography and a high definition optical coherence tomography (HD-OCT) were performed in order to detect the earlier stages of macular degeneration. Genomic DNA was extracted followed by genome-wide SNP genotyping and whole exome sequencing (WES). Exome data was filtered to identify the genetic variant(s) of interest.Results: Clinical examination showed that affected individuals manifest key features of RP. The fundus exam shows pale optic disc and bone spicules at the periphery. OCT shows macular degeneration as early as at the age of 4 years. Whole genome scan by SNPs identified multiple homozygous regions. WES identified a 10 bps novel insertion mutation (c.3544_3545insAGAAAAGCTG; p.Ala1182fs) in the RP1 gene in both affected individuals of family A. Affected individual from family B showed a large insertion of 48 nucleotides in the coding part of the RP1L1 gene (c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG; p.Ala1319fs). Sanger sequencing validates the autosomal recessive inheritance of the mutations.Conclusion: The results strongly suggest that the insertion mutations in the RP1 and RP1L1 genes are responsible for the retinal phenotype in affected individuals from two families. Heterozygous individuals are asymptomatic carriers. We propose that the protective allele in other homozygous regions in heterozygous carriers contribute to the phenotypic variability in asymptomatic individuals. 相似文献
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76.
Michael S. Simon MD MPH Theresa A. Hastert PhD Ana Barac MD PhD Hailey R. Banack PhD Bette J. Caan DrPH Rowan T. Chlebowski MD PhD Randi Foraker PhD Gayane Hovsepyan BS Simin Liu MD MPH ScD Juhua Luo PhD JoAnn E. Manson MD DrPH Marian L. Neuhouser PhD RD Tochukwu M. Okwuosa DO Kathy Pan MD Lihong Qi PhD Julie J. Ruterbusch MS Aladdin H. Shadyab PhD Cynthia A. Thomson PhD RD Jean Wactawski-Wende PhD Nida Waheed MD MPH Jennifer L. Beebe-Dimmer PhD 《Cancer》2021,127(4):598-608
77.
Mark Duquette Peter M. Sadow Amjad Husain Jennifer N. Sims Zeus A. Antonello Andrew H. Fischer Chen Song Elena Castellanos-Rizaldos G. Mike Makrigiorgos Junichi Kurebayashi Vania Nose Paul Van Hummelen Roderick T. Bronson Michelle Vinco Thomas J. Giordano Dora Dias-Santagata Pier Paolo Pandolfi Carmelo Nucera 《Oncotarget》2015,6(40):42445-42467
BRAFV600E mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAFV600E inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAFV600E selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAFV600E-PTC, intrathyroidal BRAFV600E-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAFV600E-PTC orthotopic mouse. We find that metastatic BRAFV600E-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAFWT-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAFV600E-PTC cells but lesser in metastatic BRAFV600E-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment–associated pro-metastatic molecules, with no effects in BRAFWT-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAFWT/V600E-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAFV600E-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAFV600E-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAFV600E-positive PTC. 相似文献
78.
Yasin MM Nasreen G Rathore FA Malik SA 《Journal of the College of Physicians and Surgeons--Pakistan : JCPSP》2012,22(7):455-457
A 62-year-old diabetic bed ridden woman, presented to the emergency department with symptoms suggestive of peritonitis. She had been taking oral laxatives and enemas to relieve her chronic constipation for last 6 years. Hard impacted stools and pelvic tenderness were found on digital rectal examination. Her X-ray abdomen showed soft tissue shadows in the colon but there was no gas under the diaphragm on chest X-ray. Sonography found free fluid in pelvis. She was resuscitated, and her hyperglycemia was controlled by use of regular insulin as per sliding scale. Operative findings revealed free fluid in pelvis and very hard faecalomas lying free in peritoneal cavity. There was a 2 x 3 cm perforation at the anterior wall of the recto-sigmoid junction. Peritoneal toilet was carried out followed by Hartmann's procedure. Histopathology of perforation side showed no evidence of malignancy. 相似文献
79.
Membranoproliferative glomerulonephritis (MPGN) is characterized by proliferation of mesangial and endothelial cells and by thickening of the peripheral capillary walls. Type II of the MPGN is associated with complement abnormalities which are factor H deficiencies due to mutations in the complement factor H (CFH) gene. We report a 15-year-old boy diagnosed with MPGN II in whom genetic analyses of the CFH gene revealed that the patient was heterozygote for a polymorphism in exon 2 of the CFH (c.184G>A), heterozygote for a polymorphism in exon 9 of the CFH (c.1204C>T), and heterozygote for a polymorphism in exon 10 of the CFH (c.1419G>A). These data recapitulate a prototypical complement genetic profile, the presence of major risk factors for MPGN II, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation. 相似文献
80.