Colorectal carcinomas from Middle East. Molecular and tissue microarray analysis of genomic instability pathways.

OBJECTIVE: To evaluate the overall incidence of microsatellite instability (MSI), hereditary non polyposis colorectal cancer, and tumor supressor gene (TP53) mutations in Saudi colorectal carcinomas. METHODS: We studied the MSI pathway in Saudi colorectal cancers (CRC) from 179 unselected patients using 2 methods: MSI by polymerase chain reaction, and immunohistochemistry detection of mutL homologs 1 and mutS homologs 2 proteins. The TP53 mutations were studied by sequencing exons 5, 6, 7, and 8. RESULTS: Of the 150 colorectal carcinomas analyzed for MSI, 16% of the tumors showed high level instability (MSI-H), 19.3% had low-level instability (MSI-L) and the remaining 64% tumors were stable. Survival of the MSI-H group was better as compared to the MSI-L or microsatellite stable group (p=0.0217). In the MSI-H group, 48% were familial MSI tumors, which could be attributable to the high incidence of consanguinity in the Saudi population. The TP53 mutations were found in 24% of the cases studied. CONCLUSION: A high proportion of familial MSI cases and a lower incidence of TP53 mutations are some of the hallmarks of the Saudi colorectal carcinomas, which need to be explored further.

Increased Level of Angiopoietin Like Proteins 4 and 8 in People With Sleep Apnea.

Objective: Obstructive sleep apnea (OSA) is a sleep disorder caused by the complete or partial obstruction of the upper airways. The worldwide prevalence of OSA is increasing due to its close association with obesity epidemic and multiple health complications, such as hypertension, cardiovascular disease, and Type 2 diabetes. Angiopoietin-like protein (ANGPTL)-4 and ANGPTL8 (betatrophin) have been suggested to play a role in the development of these diseases through their role in regulating the metabolism of plasma lipid molecules. This study was designed to evaluate ANGPTL4 and 8 levels in an OSA group and a control group to clarify the effect of OSA on ANGPTL4 and 8 levels. Methods: In total, 74 subjects were enrolled in this study, including 22 age- and body mass index (BMI)-matched controls with the Apnea Hypopnea Index (AHI) score of <5 events/h and 52 subjects with an AHI score of >5 events/h. Sleep apnea was assessed using a portable sleep test. ANGPTL4 and 8 levels were measured in plasma samples using enzyme-linked immunosorbent assay. Results: Mean AHI score (2.5 ± 1.6) in the control group was significantly lower than that in the OSA group (22.9 ± 17.9; p < 0.0001). Leptin, interleukin-(IL) 6, insulin, and HOMA-IR values were higher in the OSA group than in the control group. ANGPTL8 level was higher in the OSA group (1130.0 ± 108.61 pg/mL) than in the control group (809.39 ± 108.78 pg/mL; p = 0.041). Similarly, ANGPTL4 was higher in the OSA group (179.26 ± 12.89 ng/mL) than in the control group (142.63 ±7.99 ng/mL; p = 0.018). Conclusion: Our findings demonstrate that ANGPTL4 and 8 levels were increased in subjects with OSA, suggesting that the upregulation of these lipid metabolism regulators might play a role in lipid dysregulation observed in people with OSA.

Increased Circulation and Adipose Tissue Levels of DNAJC27/RBJ in Obesity and Type 2-Diabetes.

Heat shock response is an essential cellular stress response. Dysregulation of various heat shock proteins (HSPs), within the heat shock response (HSR) pathway, play a vital role in this host-defense mechanism contributing to obesity-induced insulin resistance and type 2 diabetes (T2D). Previously, we have reported changes in the expression levels of several HSPs such as HSP40, HSP60, HSP70, and HSP90 in obese compared with lean individuals. DNAJC27 is a member of the HSP40 protein family that was previously identified as a body mass index (BMI) associated locus in genome-wide association (GWAS) studies. However, not much is known about the changes in DNAJC27 expression levels in obesity and T2D. In the present study, we aimed at understanding changes in DNAJC27 expression levels in plasma, peripheral blood mononuclear cells (PBMCs) and adipose tissue in association with obesity and T2D. A total of 277 individuals enrolled including 160 non-diabetic (96 non-obese and 64 obese) and 117 T2D (45 non-obese and 72 obese) individuals. Plasma level of DNAJC27 was significantly higher in obese individuals (6.28 ± 0.64 ng/mL) compared with non-obese individuals (4.8 ± 0.45 ng/mL) with P = 0.043. Dividing the population based on diabetes status showed that there was a significant increase in the plasma level of DNAJC27 in obese (6.90 ± 1.3 ng/mL) compared with non-obese individuals (3.81 ± 0.43 ng/mL) (P = 0.033) in the non-diabetic group. Similarly, DNAJC27 expression level was also higher in PBMCs and adipose tissue of obese individuals. DNAJC27 was found to be associated with leptin and resistin, adipokines known to be dysregulated in obesity, that stimulate inflammatory processes leading to metabolic disorders. In conclusion, our data show that DNAJC27 is elevated in obese and T2D individuals and was positively associated with obesity biomarkers such as leptin and resistin suggesting that this protein may play a role in the pathophysiology of these disorders.