Search

Background: Regeneration of bone defects remains a challenge for maxillofacial surgeons. The objective of this study was to assess the osteogenic potential of octacalcium phosphate (OCP) and bone matrix gelatin (BMG) alone and in combination with together in artificially created mandibular bone defects. Materials and Methods: In this experimental study Forty-eight male Sprague–Dawley rats (6–8 weeks old) were randomly divided into four groups. Defects were created in the mandible of rats and filled with 10 mg of OCP, BMG, or a combination of both (1/4 ratio). Defects were left unfilled in the control group. To assess bone regeneration and determine the amount of the newly formed bone, specimens were harvested at 7, 14, 21, and 56 days postimplantation. The specimens were processed routinely and studied histologically and histomorphometrically using the light microscope and eyepiece graticule. The amount of newly formed bone was quantitatively measured using histomorphometric methods. Histomorphometric data were analyzed using SPSS software. Mean, standard deviation, mode, and medians were calculated. Tukey HSD test was used to compare the means in all groups. P < 0.05 was considered as statistically significant (i.e., 5% significant level). Results: In the experimental groups, the new bone formation was initiated from the margin of defects during the 7–14 days after implantation. By the end of study, the amount of newly formed bone increased and relatively matured, and almost all of the implanted materials were absorbed. In the control group, slight amount of new bone had been formed at the defect margins (next to the host bone) on day 56. The histomorphometric analysis revealed statistically significant differences in the amount of newly formed bone between the experimental and the control groups (P < 0.001). Conclusion: Combination of OCP/BMG may serve as an optimal biomaterial for the treatment of mandibular bone defects. [ABSTRACT FROM AUTHOR]

POLD1 encodes the catalytic subunit of DNA polymerase delta (Polδ), the major lagging strand polymerase, which also participates in DNA repair. Mutations affecting the exonuclease domain increase the risk of various cancers, while mutations that change the polymerase active site cause a progeroid syndrome called mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome. We generated a set of catalytic subunit of human telomerase (hTERT)-immortalized human fibroblasts expressing wild-type or mutant POLD1 using the retroviral LXSN vector system. In the resulting cell lines, expression of endogenous POLD1 was suppressed in favor of the recombinant POLD1. The siRNA screening of DNA damage-related genes revealed that fibroblasts expressing D316H and S605del POLD1 were more sensitive to knockdowns of ribonuclease reductase (RNR) components, RRM1 and RRM2 in the presence of hydroxyurea (HU), an RNR inhibitor. On the contrary, SAMHD1 siRNA, which increases the concentration of dNTPs, increased growth of wild type, D316H, and S605del POLD1 fibroblasts. Hypersensitivity to dNTP synthesis inhibition in POLD1 mutant lines was confirmed using gemcitabine. Our finding is consistent with the notion that reduced dNTP concentration negatively affects the cell growth of hTERT fibroblasts expressing exonuclease and polymerase mutant POLD1. [ABSTRACT FROM AUTHOR]

Background: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication. Methods: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes. Results: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non‐telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC‐rich sequences. Conclusion: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra‐familial variations of CRMCC. Novel CTC1 mutations were identified in patients referred to the international registry of Werner syndrome, presenting features of progeria and recurrent bone fractures. Increased number of DNA damage foci was detected in CTC1 mutants which were extended to whole genome. [ABSTRACT FROM AUTHOR]