The Transcultural Diabetes Nutrition Algorithm: A Middle Eastern Version.

Diabetes prevalence is on the rise in the Middle East. In countries of the Gulf region-Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates-prevalence rates are among the highest in the world. Further, Egypt now ranks as one of the top 10 countries in the world for high number of people with diabetes. Medical nutrition therapy is key to optimal management of diabetes. Patient adherence to nutritional guidance depends on advice that is tailored to regional foods and cultural practices. In 2012, international experts created a transcultural Diabetes Nutrition Algorithm (tDNA) for broad applicability. The objective of this current project was to adapt the algorithm and supportive materials to the Middle East region. A Task Force of regional and global experts in the fields of diabetes, obesity, and metabolic disorders met to achieve consensus on Middle East-specific adaptations to the tDNA. Recommendations, position statements, figures, and tables are presented here, representing conclusions of the tDNA-Middle Eastern (tDNA-ME) Task Force. Educational materials can be used to help healthcare professionals optimize nutritional care for patients with type 2 diabetes. The tDNA-ME version provides evidence-based guidance on how to meet patients' nutritional needs while following customs of people living in the Middle Eastern region.

Prognostic significance of DNMT3A alterations in Middle Eastern papillary thyroid carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Downregulation of SKP2 in Papillary Thyroid Cancer Acts Synergistically With TRAIL on Inducing Apoptosis via ROS.

Context and Objective: S-phase kinase protein 2 (SKP2) is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However, its role in papillary thyroid cancer (PTC) has not been fully elucidated. Experimental Design: SKP2 expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of >1000 PTC samples. In vitro and in vivo studies were performed using proteasome inhibitor bortezomib and proapoptopic death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) either alone or in combination on PTC cell lines. Results: SKP2 was overexpressed in 45.5% of PTC cases and was significantly associated with extrathyroidal extension (P = 0.0451), distant metastasis (P = 0.0435), and tall cell variant (P = 0.0271). SKP2 overexpression was also directly associated with X-linked inhibitor of apoptosis protein overexpression (P < 0.0001) and Bcl-xL overexpression (P = 0.0005) and inversely associated with death receptor 5 (P < 0.0001). The cotreatment of bortezomib and TRAIL synergistically induced apoptosis via mitochondrial apoptotic pathway in PTC cell lines. Furthermore, bortezomib and TRAIL synergistically induced reactive oxygen species (ROS) generation and caused death receptor 5 upregulation through activation of the extracellular signal-regulated kinase-C/EBP homologous protein signaling cascade. Finally, bortezomib treatment augmented the TRAIL-mediated anticancer effect on PTC xenograft tumor growth in nude mice. Conclusion: These data suggest that SKP2 is a potential therapeutic target in PTC and that a combination of bortezomib and TRAIL might be a viable therapeutic option for the treatment of patients with aggressive PTC.

Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in Middle Eastern papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.

Expanding the spectrum of germline variants in cancer.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.

Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

The Evolving Role of Short-Term Professional Continuous Glucose Monitoring on Glycemic Control and Hypoglycemia Among Saudi Patients with Type 1 Diabetes: A Prospective Study.

INTRODUCTION: The aim of this study was to find out the evolving role of professional continuous glucose monitoring (PCGM) on hemoglobin A1c (HbA1c) and the frequency of hypoglycemia. METHODS: This was a 3-month, prospective study conducted among patients (aged 15-24 years) with type 1 diabetes mellitus who attended a diabetes clinic [Diabetes Treatment Center, Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia] due to recurrent unexplained hypoglycemia unawareness episodes between July 2014 and December 2014. The respondents were purposively and conveniently selected and they were asked to wear the PCGM device (iPro(®)2; Medtronic MiniMed, Inc., Northridge, CA, USA) for 5 days. The PCGM results were collected by the diabetic educator and reviewed by the treating physician on the same day as removal of the device. Clinical and demographic data were also collected. RESULTS: Overall, 56 patients were included in the study. The mean (±SD) age of the study cohort was 18.1 ± 1.82 years and 27 (48.2%) patients were male. Compared with baseline, non-significant but positive differences were observed in HbA1c levels in both male and female patients and in those who were older (aged 20-24 years). Similar results were observed in the frequency of hypoglycemia and a significant change was observed for female patients (P < 0.05). Compared with baseline, a significant positive difference was observed in patients' overall frequency of hypoglycemia by the end of the study (P < 0.001). CONCLUSIONS: Professional continuous glucose monitoring is a valuable tool for detecting episodes of hypoglycemia and may help to decrease HbA1c levels and reduce the frequency of hypoglycemia.