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Ion exchange of a glass-ceramic system with a specific crystalline phase can lead to materials with superior chemical, physical and mechanical properties. The aim of this study is to characterize newly synthesised nepheline glass-ceramics for dental restorative applications. Four novel experimental glasses based on the nepheline composition were ground into fine powders and then sinter-crystallized into monolithic glass-ceramics. The developed glass-ceramics were characterized before and after ion exchange in a potassium nitrate bath using X-ray diffraction, EDX-SEM, and biaxial flexural strength, hardness and solubility testing in accordance with ISO-6872. The ion exchange process of nepheline containing glass-ceramic Al20 increased the characteristic strength by more than 163 % compared to the starting value. The experimental glass-ceramics increased in strength after ion exchange compared to their as-sintered values by 139 %, 24 % and 123 %. The strength scatter decreased after ion exchange for the nepheline-containing glass-ceramics by 10 %. The characterised glass-ceramics in this work require further investigation and have the potential to be developed into layered glass powders, which can be ion exchanged after sinter-crystallization to produce dental restorations with superior mechanical and chemical properties. [ABSTRACT FROM AUTHOR]

• Electric filed-assisted ion exchange depth were found to depend on the total time of the ion exchange treatment. • Multiple steps EF-IE treatments were found to not improve the penetration depth of K+, but guarantee a continuous coverage of the treated region. • It was possible to achieve a potassium penetration depth of about 20 μm with a treatment of 300 s, and this value is close to that obtained with the conventional IE process conducted at 450 °C for 4 h. Ion exchange can be used to mechanically reinforce dental glass-ceramics to reduce the problems associated to the flaws created upon various processing steps and handling. This work introduces a novel ion exchange method to the field of dental glass-ceramic to increase the possibilities of preparing highly reliable glass-ceramic restorations. The aim of the study was to compare Electric Field-Assisted Ion Exchange with conventional method, for newly developed nepheline based dental glass-ceramic. Multicomponent glass system was synthesized using melt-quench method and then prepared into glass-ceramic specimens via powder sinter-crystallisation route. The prepared glass-ceramic specimens were tested for bi-axial flexural strength before and after ion exchange according to the dental ceramics ISO 6872:2015. Ion exchange process was carried out in molten potassium nitride and the potassium penetration depth determined by EDXS was found greater and occurring in a matter of minutes within the nepheline crystal structure during electrical field assisted ion exchange compared with several hours of conventional treatment. The newly developed nepheline glass-ceramic system and the results achieved by electrical field assisted ion exchange may renew the ion exchange concept for dental application. [ABSTRACT FROM AUTHOR]

The high Machinability of Mica glass-ceramics is due to its unique microstructure. This study investigated barium fluormica glass-ceramics, with reference to parameters, which determine the microstructure that governs Hardness and machinability and explore the validity of Baik's model for high mica Volume Fractions. Barium fluormica glasses were synthesized and casted into rods then heat-treated at 1175 °C and 1200 °C for various times. Glass-ceramics were characterized using DSC, SEM, Vickers microhardness and machinability test. "House of Cards" microstructure was successfully obtained upon heat treatment and was associated with an increase in Volume Fraction and Aspect Ratio of crystals. The Volume Fraction was almost identical for all the samples. However, crystal length and width increased with increasing holding time. Hardness and machinability forces decreased with increasing the Aspect Ratio and Effective Crystallinity. Hardness and Machinability data agreed well with Baik's data and extend the validity of Baik's model to much higher Volume Fractions. [ABSTRACT FROM AUTHOR]

Despite ethnic variation, 11 β-hydroxylase deficiency (11β-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene ( CYP11B1 ) in patients from Saudi Arabia. We studied 16 patients with 11β-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 β-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population. [ABSTRACT FROM AUTHOR]

The sodium iodide symporter ( NIS ) (solute carrier family 5; SLC5A), mediates the active transport of iodine anion (I − ) into thyroid follicular cells to facilitate thyroid hormone biosynthesis. Considering its fundamental role in thyroid function, our objective in this study is to explore its potential involvement in the pathogenesis of differentiated thyroid cancer (DTC). Following a preliminary sequencing of the gene in a representative sample of the general population, five variants, (1) rs45602038, (2) rs4808708, (3) rs4808709, (4) rs7250346 and (5) rs12327843, were selected for a larger population-based association study consisting of 507 cases and 597 controls, of which only the rs45602038_TT [Odds ratio (95% confidence interval) = 1.90 (1.26–2.88); p = 0.002] was associated with disease following adjustment for other confounders using the multivariate analysis. Furthermore, a 5-mer haplotype CGAGT constructed from the five studied SNPs conferred a significant risk ( χ 2 = 10.98; p = 0.0009) for DTC. This association trickled down through shorter derivatives, with the 4-mer haplotype CGAG ( χ 2 = 13.25; p = 0.0003) displaying the most significant association and the 3-mer GAG ( χ 2 = 11.80; p = 0.0006) being equally strongly linked to the disease. Comparison of the flanking derivatives of the primary 5-mer haplotype also indicated that the 3-mer CGA ( χ 2 = 4.04; p = 0.045) constructed from SNP block 1–3 was a lot weaker than that of the AGT ( χ 2 = 6.73; p = 0.0095) constructed from the blocks 3–5 from the other end of the gene. Put together, these data implicate the three nucleotide changes at the rs4808708, rs4808709 and rs7250346 loci (blocks 2–4) as the core for this relationship. [ABSTRACT FROM AUTHOR]

Activating BRAF mutations have been reported in 40% of papillary thyroid carcinomas (PTCs). The involvement of BRAF pseudogene in thyroid tumorigenesis has not previously been studied. We investigated BRAF pseudogene expression in 68 thyroid tumors: 16 multinodular goiters, 43 classic PTCs, 6 follicular variants of PTC, and 3 anaplastic thyroid carcinomas. BRAF pseudogene function was studied by Western blots, soft agar assay, and tumorigenesis in nude mice. BRAF pseudogene expression was detected in 7 multinodular goiters, 18 classic PTC, and 1 follicular variants of PTC. There is an inverse correlation between BRAF pseudogene expression and BRAF mutation. The pseudogene transcripts were more frequently detected in tumors without BRAF mutation than those with BRAF mutation. Furthermore, BRAF pseudogene expression could activate the MAP kinase signaling pathway, transform NIH3T3 cells in vitro, and induce tumors in nude mice. These data suggest that BRAF pseudogene activation may play a role in thyroid tumor development. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the second most common cancer affecting Saudi women after breast cancer, with papillary thyroid carcinoma (PTC) accounting for 80–90% of thyroid cancers. DNA methyltransferases affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers. We sought to evaluate the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases using exome sequencing, capture sequencing, immunohistochemistry and methylation-specific polymerase chain reaction. We also performed in vitro analysis to investigate the role of DNMT3A methylation in PTC cell lines. DNMT3A pathogenic mutations were noted in 1.2% (12/1013) of PTC cases. Reduced/loss of DNMT3A expression was seen in 59.8% (579/968) of PTC cases and was significantly associated with the DNMT3A mutation (p = 0.0120). DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. The promoter region of the DNMT3A gene was methylated in 57.1% of PTC cases tested and was significantly associated with reduced DNMT3A protein expression (p = 0.0253). Treatment of the methylated PTC cell line with 5-aza-2′-deoxycytidine resulted in demethylation of the DNMT3A gene, leading to restoration of its expression. Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cells. Interestingly, silencing of DNMT3A using siRNA suppressed TRAIL-mediated apoptosis. These findings suggest that DNMT3A alterations play an important role in PTC pathogenesis and demethylation agents can be used to restore the function of DNMT3A in a subset of patients with PTC. • Papillary thyroid carcinoma (PTC) is the second most common cancer affecting Saudi women after breast cancer. • Investigated the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases. • Low DNMT3A expression was significantly associated with the DNMT3A mutation. • DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. • Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cell lines. [ABSTRACT FROM AUTHOR]

Context Apart from 21 Hydroxylase deficiency, other subtypes of congenital adrenal hyperplasia (CAH) are rare. We studied the clinical features and molecular genetics of a relatively large series of patients with CYP17A1, HSD3β2 and StAR deficiencies. Patients and methods We studied 21 patients including 7 patients with CYP17A1, 10 patients with HSD3β2 and 4 patients with StAR deficiencies. For mutation detection, we isolated DNA from peripheral leucocytes, amplified genes of interest using polymerase chain reaction and directly sequenced the amplicons using Dideoxy Chain Termination method. Results Regardless of their karyotype, patients with CYP17A1 deficiency presented with normally looking external female genitalia and were raised as females. Hypertension and hypokalemia were prominent features in 4 of 7 patients. Two missense (p.R416H, p.R239Q) and 2 non-sense (p.Y329X, p.Y329X) mutations were found in these 7 cases. In 3 unrelated families with 10 affected siblings with HSD3β2 mutations, two non-sense mutations were found (p.Q334X, p.R335X). 46XY patients with HSD3β2 deficiency presented with ambiguous genitalia while 46XX patients presented with normal female external genitalia. Adrenal crisis was common in patients with both karyotypes. In the 4 patients with StAR deficiency, both genetic male and female patients presented with normally looking female external genitalia and adrenal crisis. One previously reported missense mutation (p.R182H) was found in 3 unrelated patients and a novel non-sense mutation (p.Q264X) in the fourth patient. Conclusions These cases of rare subtypes of CAH illustrate the heterogeneous phenotypic and genetic features of these subtypes and add unique novel mutations to the previously known ones. [ABSTRACT FROM AUTHOR]

[Display omitted] Glioma is the most common intracranial tumor with poor treatment outcomes and has high morbidity and mortality. Various studies on genomic analyses of glioma found a variety of deregulated genes with somatic mutations including TERT , TP53 , IDH1 , ATRX , TTN , etc. The genetic alterations in the key genes have been demonstrated to play a crucial role in gliomagenesis by modulating important signaling pathways that alter the fundamental intracellular functions such as DNA damage and repair, cell proliferation, metabolism, growth, wound healing, motility, etc. The SPRK1, MMP2, MMP9, AKT, mTOR , etc., genes, and noncoding RNAs (miRNAs, lncRNAs, circRNAs, etc.) were shown mostly to be implicated in the metastases of glioma. Despite advances in the current treatment strategies, a low-grade glioma is a uniformly fatal disease with overall median survival of ∼ 5–7 years while the patients bearing high-grade tumors display poorer median survival of ∼ 9–10 months mainly due to aggressive metastasis and therapeutic resistance. This review discusses the spectrum of deregulated genes, molecular and cellular mechanisms of metastasis, recurrence, and its management, the plausible causes for the development of therapy resistance, current treatment options, and the recent trends in malignant gliomas. Understanding the pathogenic mechanisms and advances in molecular genetics would aid in the novel diagnosis, prognosis, and translation of pathogenesis-based treatment opportunities which could pave the way for precision medicine in glioma. [ABSTRACT FROM AUTHOR]

• Consanguinity rates are high in Saudi Arabia and disorders of sex development (DSD) are common. • This study characterized the molecular genetics of 77 patients from 47 families (44 families are consanguineous) with different DSDs • SRD5A2 and CYP11B1 deficiencies were the most common causes of DSDs • The splice site mutation (c.282-2A>G) was the most common in SRD5A2 • CYP11B1 mutations were mostly novel mutations • Known and novel mutations were found in CYP17A1 , HSD3B2, StAR, NR0B1, HSD17B3, LHCGR and AR. Consanguinity increases the risk of hereditary diseases including disorders of sex development (DSD). There are minimal data on DSD in the highly consanguineous population of Saudi Arabia. This study reports the molecular genetics of a series of patients with different types of DSD. We enrolled 77 patients from 47 families with DSD. DNA was isolated from peripheral leucocytes. Genes of interest were amplified by polymerase chain reaction and subsequently sequenced. Overall, 77 patients from 47 families (44 of them are consanguineous) had a total of 29 mutations; 16 of them were described before and 13 were novel mutations. The most common condition was 5-α reductase (SRD5A2) deficiency (25 patients from 18 families) and the most common mutation was a splice site mutation in intron 1 (c.282-2A>G). The next most common condition was 11-β hydroxylase (CYP11B1) deficiency where 19 patients from 10 families had 8 mutations (7 of them are novel). Other mutations affected CYP17A1 with 2 novel and 2 known mutations in 7 patients; HSD3B2 with 2 known mutations in 11 patients of 4 families; StAR with 1 novel and 1 known mutations in 4 patients; NR0B1 with 1 novel mutation in 2 siblings; HSD17B3 with 1 known mutation in 3 siblings; LHCGR with 1 novel mutation in 2 siblings; and AR with 1 novel and 3 known mutations in 4 unrelated patients. In the highly consanguineous and homogeneous population of Saudi Arabia, SRD5A2 and CYP11B1 deficiencies are common causes of DSDs. Other DSDs occur less frequently but often with novel mutations. [ABSTRACT FROM AUTHOR]