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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]

The glasses with the formula 49B 2 O 3 –21SiO 2 –13ZnO-(17-x) Na 2 O-xWO 3 (0 ≤ x ≤ 6 mol %), were fabricated by the melt annealing procedure. The amorphous nature of these samples was verified by X-ray diffractions. It was observed that the density of these samples increased from 3.182 to 4.619 g/cm3, while their molar volume decreased from 21.32 to 16.9 cm3/mol. Optical absorption spectra were recorded in the range of 300–2700 nm, and various optical parameters, including the direct and indirect optical band gap, were determined. The following properties have been determined: optical basicity, electronic polarizability, molar refraction, refractive index, and Urbach energy. Among the examined glasses, the BSZNW 6 glass sample obtained the highest linear and mass attenuation coefficients (LAC & MAC) and the lowest half and tenth value layer (HVL & TVL) values among the glasses were examined. Therefore, it suggests that it has the highest ability to block radiation among the tested samples. The notably significant protective properties of the BSZNW 6 sample represent a crucial conclusion. The investigated glass samples show great promise for optical and shielding applications, and advancements in these areas could have far-reaching impacts. • The glasses with the formula 49B 2 O 3 –21SiO 2 –13ZnO-(17-x) Na 2 O-xWO 3 (0 ≤ x ≤ 6 mol %), were manufactured. • The density increase from 3.182 to 4.619 g/cm3. • The highly significant protective properties of the BSZNW 6 sample are an important conclusion. • The investigated glass samples have high promise for optical and shielding applications. [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]

Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is one of the major cellular signaling pathways that plays an important role in basic intracellular functions. The PI3K/Akt/mTOR pathway regulates cell proliferation, growth, cell size, metabolism, and motility. Component genes of this pathway have been extensively studied and found to be commonly activated in human cancer. Inhibition of this pathway has been shown to lead to regression of human tumors and has been studied in preclinical setup and evaluated in many clinical trials at various levels. Some inhibitors of this pathway are approved by the Food and Drug Administration after their potency and safety have been shown in clinical trials. This review discusses the recent trends in exploiting the PI3K/Akt/mTOR pathway towards the molecular targeted therapy using small molecule inhibitors in human cancer. [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]

Most data on differentiated thyroid cancer (DTC) came from the Western world. We describe its salient characteristics and outcome from a Middle Eastern country. Patients and Methods. We studied all cases of TC seen during a 2-year period (2004-2005) seen at our institution. Results. A total of 600 consecutive cases of DTC with a median age at diagnosis of 39 years (5–85) and the female : male ratio of 459 : 141 (76.5% : 23.5%). The cases included classical papillary thyroid cancer (PTC) in 77%, follicular variant PTC in 13.3%, follicular thyroid cancer in 3.2%, and other rare subtypes 6.5%. Total or near-total thyroidectomy was performed in 93%, central and/or lateral neck dissection in 64.5% of cases, and radioactive iodine ablation in 82% of cases. Additional therapies were administered to 154 patients (25.7%). At a median follow-up period of 7.63 years (0.22–13.1), 318 patients (53.3%) were in excellent response, 147 (24.5%) having an indeterminate response, 55 (9.2%) biochemically incomplete, 33 (5.5%) structurally incomplete, and 27 (4.5%) unclassifiable. Twenty cases died secondary to DTC (disease-specific mortality 3.3%). Conclusions. In Saudi Arabia, DTC is common and occurs at young age and predominantly in females. Although remission is common, persistent disease is also common but disease-specific mortality is low. [ABSTRACT FROM AUTHOR]

Purpose: Differentiated thyroid cancer (DTC) is rare in children. Previous studies have suggested that it has different clinicopathologic features and mutation profiles compared with adult DTC. However, those studies focused on a single or limited number of gene mutations. This study comprehensively investigated a large series of pediatric DTC for single point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, PTEN, and TERT. It also analyzed associations between clinicopathologic features and the BRAFV600E mutation. Patients and Methods: Eighty-nine consecutive cases seen in children and adolescents (≤18 years) during 1998-2015 were identified. Rare variants of DTC were excluded, and the study focused on 72 (91.1%) classical papillary thyroid carcinoma (PTC) and seven (8.9%) follicular variant PTC. These included 68 (86.1%) females and 11 (13.9%) males, with a median age of 15.5 years (range 8-18 years). The clinical and histopathological data were obtained from medical records. DNA was extracted from paraffin-embedded tumor tissue, and was PCR-amplified and directly sequenced. Results: Mutations detected included BRAFV600E in 19/72 (26.4%) classical PTC samples, and in none of seven follicular variant PTC. Other mutations included: 1/78 (1.3%) successfully amplified tumor samples with TERT C228T; 2/79 (2.5%) NRAS 61 (c.181C>A and c.182A>G); 1/73 (1.4%) PIK3CA exon 9 (c.1589A>G and c.1598C>T in one tumor); 1/79 (1.3%) PIK3CA exon 20 (c.2951G>A); and 1/74 (1.4%) PTEN exon 5 (c.295G>A). No mutation was found in HRAS, KRAS, NRAS12, PTEN exons 6, 7, and 8, and TERT C250T. No significant association was found between BRAFV600E mutation and sex, extrathyroidal invasion, tumor multifocality, vascular invasion, lymph node or distant metastases, and persistent/recurrent disease. Conclusions: In pediatric DTC, the prevalence of the BRAFV600E mutation is significantly less common compared with adult DTC, and there is no association between this mutation and the histopathological features and outcome of PTC. PIK3CA, PTEN, NRAS 61, and TERT C228T mutations are rare. [ABSTRACT FROM AUTHOR]

• Synthesis of glass-ceramics with a combination of specific crystalline phases. • Nepheline phase can be produced in combination with other secondary crystalline phases that allow tailoring of the chemical, physical and thermal properties of both the starting glasses and the end glass-ceramics. • The second phase combeite provides enhanced properties, such as bactericidal effects on the glass-ceramics. • The crystallized phase combeite (Na 2 Ca 2 Si 3 O 9) led to a slight decrease in CTE values with respect to their starting glass CTEs. • Increase in the crystalline nepheline phase and a decrease in combeite as a result of modifying the original Al 2 O 3 and Na 2 O content in the starting glass. Synthesis of glass-ceramics with a combination of specific crystalline phases can lead in materials with superior chemical, physical and mechanical properties. The aim of this study is to outline the potential of synthesizing a novel glass system which crystallise into two crystalline phase's nepheline-combeite and provide an end monolithic glass-ceramics via sinter crystallization route for dental applications. Four novel glass compositions based on the Na 2 O-CaO-Al 2 O 3 -SiO 2 system were synthesized using the melt-quench method. Glasses were designed to contain 6 mole % of CaO and a total of 35 mole % of Al 2 O 3 and Na 2 O. Experimental glasses were ground into fine powders and then sinter crystallized to monolithic glass-ceramics. The developed glasses and glass-ceramics were characterized using DSC, Dilatometry, X-ray diffraction, Nuclear Magnetic Resonance (MAS-NMR) and scanning electron microscopy. This study shows how the nepheline phase can be produced in combination with other secondary crystalline phases which allow tailoring of the chemical, physical and thermal properties of both the starting glasses and the end glass-ceramics, including their thermal expansions coefficients, glass transition temperatures, softening points, sintering and melting temperatures. [ABSTRACT FROM AUTHOR]

Background: Familial non-medullary thyroid cancer (NMTC) occurs either as part of known hereditary syndromes or as a non-syndromic isolated hereditary tumor. Although the genes underlying the syndromic type of NMTC have been identified in most syndromes, no clear underlying gene has been identified in the nonsyndromic NMTC. Recently, a c.1601G>A, p.G534E mutation in the HABP2 gene was reported to be the underlying genetic defect in a family with seven members affected by NMTC. The G534E variant has also been reported to occur in about 4.7% of cases of the Thyroid Cancer Genome Atlas (TCGA) database. Objectives: The aim of this study was to explore whether the recent finding of G534E genetic variant can be replicated in a large sample of NMTC, including 11 members of four unrelated families with familial NMTC and 509 cases of sporadic pediatric (63 cases) and adult NMTC (446 cases). Methods: All exons and exon-intron boundaries of HABP2 were screened in 11 members of four families with familial non-syndromic NMTC using DNA isolated from peripheral leucocytes, polymerase chain reaction, and direct sequencing. The G534E variant was also screened for specifically in 229 cases of sporadic NMTC using DNA isolated from peripheral leucocytes and an additional 217 cases of NMTC using DNA isolated from formalin-fixed paraffin-embedded tumor tissues. As a control cohort, 190 healthy individuals without known thyroid disease were also studied for the presence of the G534E variant using DNA isolated from peripheral leucocytes. Results: None of the familial NMTC carried HABP2 mutations. Of 509 sporadic NMTC, only one case (0.2%) harbored the G534E variant. Similarly, only one case (0.5%) of the control group harbored the G534E variant. Conclusion: In this study, HABP2 mutations were not found in familial NMTC, and the G534E variant is not the underlying genetic defect in a large sample of sporadic NMTC from the Middle East. [ABSTRACT FROM AUTHOR]

Context Age is a major prognostic factor in differentiated thyroid cancer ( DTC). It is not clear if paediatric DTC has a different histopathological profile and outcome than DTC in adult patients <45 years of age. Objective To assess whether DTC in children and adolescents differs from young age group by comparing paediatric DTC (age ≤ 20) with DTC in patients >20 to <45 years of age. Patients and methods We studied all cases of paediatric DTC seen during the period 1998-2011. We compared this group with a large sample of 213 consecutive adult patients in the age group >20 to <45 years seen during the period 1998-1999 in terms of their pathological features, extent of the disease and long-term outcome. Both groups were managed by the same team at a single institution. Results A total of 310 DTC were studied including 97 paediatric patients [median age 17 years (range, 8-20)] and 213 young adult patients [median age 33 years (range, 20·5-44·9)]. There was no difference in gender distribution, tumour subtypes, size and tumour multifocality, but there was a significantly higher rate of extrathyroidal extension [40/75 (53·3%) vs 81/213 (38·0%), P = 0·03], lymph node [57/73 (78%) vs 102/183 (55·7%), P < 0·0001] and distant metastases [16/97 (16·5%) vs 8/213 (3·8%), P < 0·0001] in the paediatric than the adult groups. Kaplan-Meier analysis showed a higher risk of persistent/recurrent disease in the paediatric group than adults (log-rank test 0·03). However, there was no mortality secondary to DTC in both groups. Conclusion Paediatric DTC is distinct from DTC in the young adults (age >20 to <45 years). It is characterized by a higher rate of extrathyroidal extension, lymph node and distant metastases and a higher risk of persistent/recurrent DTC. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the rate and significance of TERT promoter mutations that have been recently described in adult thyroid cancer (TC) but not yet in the uncommonly occurring pediatric TC. Furthermore, the role of the BRAFV600E mutation in the clinical outcome of pediatric TC is unknown. Method: The study included 55 pediatric (median age 16 years, range 9-18 years; 46 females) and 210 adult TC patients (median age 40 years, range 20-75 years; 155 females) seen during the same time period. DNA was isolated from TC tissues and subjected to direct sequencing. Genetic-clinicopathological correlations were analyzed. Results: Only one case of pediatric TC was found to harbor the C228T TERT promoter mutation (1.8%). The C250T mutation was not detected in any of the 55 pediatric TC. In contrast, there was a significantly higher rate of TERT promoter mutations in the adult patients (15.7%, 33/210) compared with the pediatric patients ( p = 0.003). In addition, persistent/recurrent TC was seen in 8/12 (66.7%) pediatric patients harboring the BRAFV600E mutation versus 14/41 (34.1%) patients harboring the wild type BRAF ( p = 0.05), and when only conventional papillary TC was examined, in 7/9 (77.8%) cases harboring BRAFV600E mutation versus 11/33 (33.3%) cases harboring wild type BRAF ( p = 0.025). Conclusions: This is the first study on TERT promoter mutations in pediatric TC, which revealed an exceedingly low prevalence, suggesting a limited role of these mutations in pediatric TC. This study also for the first time demonstrates an association of the BRAFV600E mutation with TC recurrence in pediatric patients. [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]

Importance: BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established.Objective: To investigate the relationship between BRAF V600E mutation and PTC-related mortality.Design, Setting, and Participants: Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011.Main Outcomes and Measures: Patient deaths specifically caused by PTC.Results: Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]).Conclusions and Relevance: In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated the relationship between BRAF V600E mutation and papillary thyroid cancer (PTC)-related mortality. BRAF V600E is a prominent oncogene in PTC. A total of 1,849 patients with a median age of 46 years are considered in the study. Findings revealed 5.3% mortality in BRAF-positive versus mutation-negative patients. Deaths per 1000 person-years in the analysis of PTC conventional variant were 11.80 versus 2.25 in BRAF-positive versus mutation-negative patients. A higher BRAF-associated mortality was observed in clinicopathological subcategories.

The impact of metastasized cervical lymph nodes (CLN) identified on central neck dissection (CND) on the recurrence/persistence of papillary thyroid cancer (PTC) and the extent of CND needed to reduce recurrence/persistence have not been firmly established. To assess the impact of CLN metastasis and BRAF mutation on the recurrence/persistence of PTC and the potential of BRAF mutation in assisting CND, we analysed data of 379 consecutive patients with PTC who underwent thyroidectomy with (nZ243) or without CND (nZ136) at a tertiary-care academic hospital during the period 2001-2010 for their clinicopathological outcomes and BRAF mutation status. Increasingly aggressive tumor characteristics were found as the extent of CND was advanced following conventional risk criteria from non-CND to limited CND to formal CND. Disease recurrence/persistence rate also sharply rose from 4.7% to 15.7% and 40.5% in these CND settings respectively (P!0.0001). CLN metastasis rate rose from 18.0 to 77.3% from limited CND to formal CND (P!0.0001). An increasing rate of BRAF mutation was also found from less to more extensive CND. A strong association of CLN metastasis and BRAF mutation with disease recurrence/persistence was revealed on Kaplan- Meier analysis and BRAF mutation strongly predicted CLN metastasis. CLN metastases found on CND are closely associated with disease recurrence/persistence of PTC, which are both strongly predicted by BRAF mutation. Current selection of PTC patients for CND is appropriate but higher extent of the procedure, once selected, is needed to reduce disease recurrence, which may be defined by combination use of preoperative BRAF mutation testing and conventional risk factors of PTC. [ABSTRACT FROM AUTHOR]

Background: Lungs and bones are the most common sites for distant metastases from papillary thyroid cancer (PTC). Metastases to the pancreas are extremely rare. Here we present a man with pancreatic metastases from PTC, report our experience with sorafenib therapy, and discuss the role of endoscopic ultrasound (EUS)-guided biopsy in its diagnosis. Patient Findings: A 56-year-old man underwent total thyroidectomy, right-modified neck dissection, and radioactive iodine (RAI) remnant ablation for PTC at age 47 years (in 2002). Between 2002 and 2007, he had three more neck surgeries, two RAI therapies, and external beam radiotherapy for persistent and subsequently metastatic PTC. In 2008, a computed tomography/positron emission tomography (CT/PET) scan showed an 18F-fluorodeoxyglucose (FDG)-avid pancreatic focus. Magnetic resonance imaging (MRI) revealed a pancreatic nodule at the same location. An EUS-guided biopsy confirmed the diagnosis of pancreatic metastasis from PTC, and molecular studies showed positive BRAFV600E mutation. He was treated with sorafenib for 6 months. Although a lung CT scan done 2 months after initiation of sorafenib suggested stability of the disease, MRI studies done at 3 and 6 months showed clear progression with an increase in the size of the lung and pancreatic metastases. Subsequently, he developed liver, bone, and omental metastases. He died in July 2011, 9 years and 8 months after the initial diagnosis of PTC and 20 months after discovery of the pancreatic metastasis. Summary: A middle-aged man with PTC developed lung metastases despite multiple surgeries and RAI therapies. Seven years after the initial diagnosis, a pancreatic metastasis was accidentally discovered. Both the metastasis and the primary thyroid tumor are positive for BRAFV600E mutation. The lung and pancreatic metastases progressed while the patient was receiving sorafenib for 6 months, and the patient died 20 months after diagnosis of pancreatic metastasis. Conclusion: PTC rarely metastasizes to the pancreas. In this patient, an FDG PET scan and EUS-guided biopsy played important roles in the diagnosis. PTC metastases to the pancreas usually occur in otherwise advanced disease. In the patient presented here, sorafenib may have slowed disease progression but the overall utility of tyrosine kinase inhibitors in pancreatic metastases from PTC is not clear. [ABSTRACT FROM AUTHOR]

Summary Context Mutations of the insulin receptor gene ( INSR) can cause genetic syndromes associated with severe insulin resistance. Objectives We aimed to analyse INSR mutations in Saudi patients with severe insulin resistance. Design Ten patients with Type A insulin resistance syndrome from five unrelated Saudi families were investigated. The entire coding region of INSR was sequenced. The founder effect was assessed by microsatellite haplotype analysis. The functional effect of the mutation was investigated by in vitro functional assays. Results A novel biallelic c.433 C>T (p.R118C) mutation was detected in all patients. The c.433 C>T (p.R118C) sequence variation was not found in 100 population controls. The arginine residue at position 118 is located in the ligand-binding domain of INSR and is highly conserved across species. Microsatellite haplotype analysis of these patients indicated that p.R118C was a founder mutation created approximately 2900 years ago. The wild-type and mutant R118C INSR were cloned and expressed in CHO cells for functional analysis. Specific insulin binding to the mutant receptor was reduced by 83% as compared to wild-type (WT), although the mutant receptor was processed and expressed on the cell surface. Insulin-mediated receptor autophosphorylation was also significantly reduced in CHOR118C cells. Conclusions Biallelic c.433 C>T (p.R118C) mutation of INSR causes significant damage to insulin binding and insulin-mediated signal transduction. p.R118C is a founder mutation frequently present in the Saudi patients with severe insulin resistance. [ABSTRACT FROM AUTHOR]

Significant progress has been made to elucidate the molecular mechanisms that determine thyroid tumor development and progression. However, most investigations have mainly focused on the genetic alterations of nuclear DNA. The potential role of mitochondrial DNA (mtDNA) mutations in thyroid tumorigenesis is not well defined. In the present study, we investigated the frequency of mtDNA mutations in 24 thyroid tumor specimens (19 primary papillary thyroid carcinomas (PTC), one follicular thyroid carcinoma, and four multinodular hyperplasias) and four thyroid cancer cell lines by sequencing the entire coding regions of mitochondrial genome. Among the 19 PTC samples tested, seven (36.8%) had somatic mutations. Somatic mtDNA mutations were also detected in one of four multinodular hyperplasias examined. All the thyroid tumor cell lines carried sequence variations that change amino acid and have not been reported previously as normal sequence variants. Flow cytometry analysis of mitochondria respiratory function in the thyroid tumor cell lines revealed a severe defect in mitochondrial complex I activity. The majority of the mutations was involved in genes located in the complex I of the mitochondrial genome. The mutations were either A?G or C?T transitions, often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. These data suggest that mtDNA mutations may play an important role in the thyroid tumorigenesis. Given that mtDNA mutation is present in the benign multinodular hyperplasia, it might be involved in the early stage of tumor development.Oncogene (2005) 24, 1455-1460. doi:10.1038/sj.onc.1208292 Published online 20 December 2004 [ABSTRACT FROM AUTHOR]

Surgical resection of persistent/recurrent (P/R) papillary thyroid cancer (PTC), when localized to the neck, is generally recommended; however, its impact on the course of the disease is not clear. We introduced a new technique in the form of preoperative neck ultrasonographic mapping (US-M) to improve the outcome of the surgical resection of P/R PTC. A total of 19 patients had undergone regional (central, lateral, or both) neck dissection before introducing the current technique (group 1, or G1), and 26 patients (group 2, or G2) had limited lymph node resection guided by US-M with findings accurately plotted on a standard diagram. All of the operations were performed by a single surgeon. The surgical outcomes of the two groups were compared. The resected lesions were positive for PTC in 17 patients (89.5%) in G1 and in 25 patients (96.2%) in G2. In G2, the intraoperative findings exactly matched the US-M in 23 patients (88.5%). Postoperatively, neck US became negative in 50% in G1 and in 83.3% in G2 (p= 0.02). Thyroglobulin (Tg) became undetectable in 37.5% in G1 and 52.3% in G2 (p= 0.37). Whole-body iodine scans (WBS) became negative in one of six patients (16.7%) in G1, and in three of four patients (75%) in G2, (p= 0.06). After a mean follow-up of 23.8 ± 7.1 months in G1 and 9.8 ± 4.7 months in G2, 6 patients (31.6%) in G1 and 15 patients (62.5%) in G2 were in remission (p= 0.04), whereas the disease persisted in 13 cases (68.4%) in G1 and 9 (37.5%) in G2 (p= 0.04). In conclusion, US-M improved the surgical outcome, as evidenced by the postoperative US, Tg, and WBS findings and the higher remission rate for the G2 patients than for the G1 patients. [ABSTRACT FROM AUTHOR]

Presents the case of an East Asian woman who have autoimmune thyroid disease with fluctuating thyroid function. Medical condition of the patient; Symptoms experienced by the patient; Main disorders that comprise autoimmune thyroid disease.

This article aims to propose a novel neural adaptive control approach for the fixed-time attitude tracking of space vehicle subject to constrained outputs. The proposed controller is recursively synthesized by integrating with the barrier Lyapunov function (BLF) and neural approximation under the fixed-time backstepping control framework. The whole control design procedure involves two steps. In the first step, the virtual control signal is designed by adopting the BLF to guarantee the attitude tracking errors always within the predefined output constraints. In the second step, the actual control signal is designed by augmenting the neural network (NN) to approximate the uncertain term caused by unknown dynamics and disturbances. Theoretical analysis shows that the proposed controller can ensure all error signals in the closed-loop system stabilize to the small regions about the origin in fixed time even under unknown dynamics and disturbances. The effectiveness and excellent performance of the proposed control approach are validated by simulations and comparisons. [ABSTRACT FROM AUTHOR]

Unmanned aerial vehicles are subject to complex aerodynamic or hydrodynamic forces and various uncertainties, making their dynamic modeling difficult. Hence, in these systems, it is preferred to apply control techniques whose closed-loop systems can predict the system's uncertain dynamics and provide acceptable performance. To this end, this paper exploits a new neural network-based optimal mixed H 2 / H ∞ control for a modified unmanned aerial vehicle to accomplish trajectory tracking missions. Firstly, the dynamic model of the modified unmanned aerial vehicles is presented. Then, the design procedure of the new controller is delineated. In this approach, H ∞ attenuates the effect of uncertainties and through H 2 the consumed control energy is minimized. Similar to real-world applications, it is supposed that there are control input constraints and external disturbances. The neural networks are also employed to estimate all uncertainties. The numerical simulations for two different desired paths are demonstrated. Simulation results illustrate the efficient performance of the proposed control technique in the presence of external disturbances, dynamic uncertainties, and control input constraints. [ABSTRACT FROM AUTHOR]

Proper control is necessary for ensuring that UAVs successfully navigate their surroundings and accomplish their intended tasks. Undoubtedly, a perfect control technique can significantly improve the performance and reliability of UAVs in a wide range of applications. Motivated by this, in the current paper, a new data-driven-based fractional-order control technique is proposed to address this issue and enable UAVs to track desired trajectories despite the presence of external disturbances and uncertainties. The control approach combines a deep neural network with a robust fractional-order controller to estimate uncertainties and minimize the impact of unknown disturbances. The design procedure for the controller is outlined in the paper. To evaluate the proposed technique, numerical simulations are performed for two different desired paths. The results show that the control method performs well in the presence of dynamic uncertainties and control input constraints, making it a promising approach for enabling UAVs to track desired trajectories in challenging environments. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) of the head and neck is one of the six most common cancers in the world. OSCC remains the most common cause of cancer deaths in Asian countries. Conventional treatments for OSCC have not improved the overall 5 years survival and therefore alternative therapeutic targets are often sought. Ras is one of the most frequently deregulated oncogenes in oral cancer. Direct targeting the ras has proven unrealistic and hence, exploring and understanding alternative pathways and/or molecules which regulate ras and its signaling that could pave the way for novel molecular targets and therapy for oral cancer. Recently, microRNAs (miRNAs) have been reported to regulate ras oncogenes in human cancers. In this article, we address the microRNA-mediated regulation of the ras oncogenes in oral cancer. We describe extensively the tumor suppressive and oncogenic roles of miRNAs in regulation of ras oncogenes in OSCC. We also discuss the role of miRNA-mediated ras regulation in therapeutic determination of oral cancer. Complete understanding of the miRNA regulation of ras oncogenes in oral cancer may facilitate to plan better strategies for diagnosis, molecular therapeutic targeting and the overall prognosis of this common and deadly cancer. J. Cell. Physiol. 231: 1424-1431, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC. Methods: We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA. Results: BRAF V600E was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRASQ61R in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRASS65N was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF V600E and KRAS, or BRAF V600E and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01). Conclusions: Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRASS65N can constitutively activate the MAPK pathway. [ABSTRACT FROM AUTHOR]

Objective 1α, 25( OH)2D3 (calcitriol), the active form of vitamin D, has been shown to exert antiproliferative effects in many cancers. Overexpression of CYP24A1, the primary vitamin D-inactivating enzyme, is also observed in a variety of human cancers, thus potentially neutralizing the antitumour effect of 1α, 25( OH)2D3. This study investigates the expression of CYP24A1 and the effect of BRAF V600E on its expression in thyroid cancer. Methods We investigated 60 papillary thyroid carcinoma ( PTC) specimens for CYP24A1 expression and its association with BRAF mutation and disease progression. CYP24A1 expression was measured by real-time RT- PCR, and BRAF V600E mutation was detected by PCR- DNA sequencing analysis. The interaction between BRAF V600E and CYP24A1 expression was determined by Western blot analysis and real-time RT- PCR. Results CYP24A1 expression was increased in PTC as compared to benign multinodular goitre. The expression was further increased in stage III and IV tumours. There is a strong correlation between CYP24A1 overexpression and BRAF V600E mutation ( P < 0·01). In thyroid cancer cell lines expressing BRAF V600E, CYP24A1 expression was significantly higher when compared to those without BRAF V600E expression. BRAF V600E transgene expression in CAL62 cell line can induce CYP24A1 expression. Furthermore, BRAF V600E inhibitor PLX4720 can significantly down-regulate CYP24A1 expression and enhance the antiproliferative effects of calcitriol in thyroid cancer cell lines. Conclusion CYP24A1 overexpression is a poor prognostic indicator for PTC and may reflect BRAF V600E mutation and MARK activation. The crosstalk between vitamin D and MAPK signalling pathways results in resistance to calcitriol-mediated antitumour effects, and the resistance can be reversed by BRAF V600E inhibitor PLX4720. [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]

Background: BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). Previous studies on DTC have well documented high rates of the BRAF (V600E) mutation in patients of mixed ages. Previous studies either included a mix of pediatric and adult patients or pediatric patients only. However, the prevalence of hotspot and non-hotspot BRAF mutations and its significance in pure adult DTCs is not yet well determined. In this study we determine the frequency of this classical BRAF mutation and other rare BRAF mutations in pure adult DTCs.Methods: A total of 204 adult DTC samples (Age >18 years) were analyzed for mutations in exon 15 of the BRAF gene by performing polymerase chain reaction (PCR) amplification of tumor genomic DNAs and direct sequencing of amplicons using Sanger sequencing. Obtained results were correlated to clinical and pathological characteristics of DTCs. Statistical analyses were performed using SPSS (The Statistical Package for Social Sciences) version 20 software.Results: Overall, BRAF mutations were identified in 48.5 % (99/204) of adult DTCs. Three rare non-hotspot mutations (T599I, T599dup and K601E) were detected in four tumor samples (2 %). One (K601E) of these non-hotspot mutations occurred in conventional papillary thyroid cancer (CPTC) and other three (T599I, T599dup and K601E) were found in follicular variant PTC. We found significant association between BRAF (V600E) mutation and age (P < 0.0001), extrathyroidal invasion (P = 0.017), lymph node metastasis (P = 0.038) and TNM stage III/IV (P = 0.001).Conclusions: Our study is the first to report BRAF mutations in a pure adult sample of DTCs of Saudi Arabian ethnicity. Our results show a high rate and a strong prognostic role of the classical BRAF (V600E) mutation and also suggest a common occurrence of non-hot spot mutations in adult DTC from this highly inbred population. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group.We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (R45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAFV600E mutation and persistent/recurrent disease at 6-12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAFV600E mutation, and disease persistence/recurrence than the WT TERT. [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]

In this paper, a neural adaptive fault-tolerant control scheme is proposed for the integrated attitude and position control of spacecraft proximity operations in the presence of unknown parameters, disturbances, and actuator faults. The proposed controller is made up of a relative attitude control law and a relative position control law. Both the relative attitude control law and relative position control law are designed by adopting the neural networks (NNs) to approximate the upper bound of the lumped unknowns. Benefiting from the indirect neural approximation, the proposed controller does not need any model information for feedback. In addition, only two adaptive parameters are required for the indirect neural approximation, and the online calculation burden of the proposed controller is therefore significantly reduced. Lyapunov analysis shows that the overall closed-loop system is ultimately uniformly bounded. The proposed controller can ensure the relative attitude, angular velocity, position, and velocity stabilize into the small neighborhoods around the origin. Lastly, the effectiveness and superior performance of the proposed control scheme are confirmed by a simulated example. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and matrix metalloproteinase 8 (MMP8) gene mutations have been frequently reported in human cancers; however, to the best of our knowledge, they have not been specifically examined in differentiated thyroid cancers (DTCs). Therefore, the present study aimed to determine the somatic mutational frequencies of these genes in DTCs. Mutational analysis of the ALK (exons 23, 24 and 25), IDH1 (exon 4), IDH2 (exon 4), and MMP8 (all exons 1-10) was performed in 126, 271, 271 and 50 DTCs, respectively. All the indicated exons were PCR-amplified and the PCR products were directly sequenced by Sanger sequencing. The present study identified a high frequency (86%; 43/50) of MMP8 single nucleotide polymorphism (SNP) and also found some rare SNPs of this gene (S3C, T32I, L310P and K460T) in DTCs but no somatic mutation in ALK, IDH1, IDH2 and MMP8. Analyses of 414 DTCs from The Cancer Genome Atlas revealed rare ALK (1%) and MMP8 (0.24%) mutations and none in IDH1 and IDH2. Conversely, analyses of 117 aggressive thyroid cancers [84, poorly differentiated thyroid cancer (PDTC); 33, anaplastic thyroid cancer (ATC)] from the Memorial Sloan Kettering Cancer Center cohort revealed ALK mutations in 3% of ATCs and fusions in 3.6% of PDTCs. IDH1 mutation was identified in 1.25% of PDTCs but not in ATC. IDH2 mutation was identified in 3% of ATCs but not in PDTC. The present study demonstrated that these genes are less frequently mutated in DTCs, but common in ATCs and PDTCs. It suggests that these genes serve a role in a small portion of DTCs and a more important role in ATCs and PDTCs and may serve as potential therapeutic targets in these subsets. [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]