Diagnostic Value of TROP2 Expression in Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) represents the most common primary malignant thyroid lesion in all age groups. As diagnosis of PTC could be challenging in some cases and borderline nuclear features could be seen in some benign mimickers, several immunohistochemical markers are proposed to be helpful for making the correct diagnosis. In this study the authors investigated the diagnostic value of transmembrane glycoprotein (TROP2) for differentiating PTC from other thyroid follicular lesions. A total of 155 total thyroidectomy specimens including 84 cases of PTC and 71 cases of non-PTC were investigated. Among non-PTC group, 45 cases were follicular neoplasms and 26 cases were Hashimoto thyroiditis. TROP2 expression was observed in 82 of 84 cases of PTC group. In contrast only 5 cases of non-PTC group, all from Hashimoto thyroiditis specimens, showed positive expression. The sensitivity, specificity, positive predictive value, and negative predictive value of TROP2 for diagnosis of PTC was 98%, 93%, 94%, and 97%, respectively. The authors concluded that high sensitivity and specificity of TROP2 as well as its uniform negative reaction in follicular adenoma and carcinoma makes it a valuable immunohistochemical marker for diagnosis of PTC.

Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAFV600E mutation as biomarkers for papillary thyroid carcinoma.

Circulating cell-free DNA (cfDNA) has been considered as a diagnostic source to track genetic and epigenetic alterations in cancer. We aimed to study mutation in addition to the methylation status in the promoter regions of RASSF1 and SLC5A8 genes in tissues and circulating free DNA samples of patients affected with papillary thyroid carcinoma (PTC) and thyroid nodules as controls. BRAFV600E mutation was studied by ARMS-scorpion real-time polymerase chain reaction method in 57 PTC and 45 thyroid nodule cases. Methylation status of RASSF1 and SLC5A8 promoter regions was analyzed by methylation-specific high-resolution melting curve analysis. BRAFV600E mutation was found in 39 (68.4%) out of 57 PTC tissue samples, while in 33 (49.1%) cases of cfDNA, this mutation was detected. The frequency of BRAFV600E mutation in cfDNA was significantly different between metastatic and nonmetastatic PTC cases (22 of 33 PTC cases vs. 5 of 34 thyroid nodule samples). Methylation levels of three promoter regions of SLC5A8 and proximal promoter region of RASSF1 was significantly different between PTC and thyroid nodule cases in both cfDNA and tissue DNA. In addition, the methylation status of these two genes in tissue DNA was reflected in methylation status observed in cfDNA. This study confirmed that BRAFV600E mutation is better for discrimination between papillary thyroid carcinoma and thyroid nodules. On the other hand, hypermethylation in the more proximal promoter regions to RASSF1 and SLC5A8 genes showed higher sensitivity and more acceptable specificity for this discrimination.

The Importance of Precision Medicine in Type 2 Diabetes Mellitus (T2DM): From Pharmacogenetic and Pharmacoepigenetic Aspects.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a worldwide disorder as the most important challenges of health-care systems. Controlling the normal glycaemia greatly profit long-term prognosis and gives explanation for early, effective, constant, and safe intervention. MATERIAL AND METHODS: Finding the main genetic and epigenetic profile of T2DM and the exact molecular targets of T2DM medications can shed light on its personalized management. The comprehensive information of T2DM was earned through the genome-wide association study (GWAS) studies. In the current review, we represent the most important candidate genes of T2DM like CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1, and HNF homeoboxes. Different genetic variations of a candidate gene can predict the efficacy of T2DM personalized strategy medication. RESULTS: SLCs and AMPK variations are considered for metformin, CYP2C9, KATP channel, CDKAL1, CDKN2A/2B and KCNQ1 for sulphonylureas, OATP1B, and KCNQ1 for repaglinide and the last but not the least ADIPOQ, PPAR-γ, SLC, CYP2C8, and SLCO1B1 for thiazolidinediones response prediction. CONCLUSION: Taken everything into consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.

Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats.

BACKGROUND/AIMS: Sepsis is a common complication of cirrhosis with a high mortality. Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction, which is known as cirrhotic cardiomyopathy and might be linked to endotoxaemia. This study was aimed to explore the hypothesis that the inflammatory response induced by administration of low dose of lipopolysaccharide (LPS) exacerbates cardiac chronotropic dysfunction in cirrhotic rats; and if so, whether this is associated with altered cardiac toll-like receptor expression. METHODS: Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. Four weeks after bile duct ligation or sham surgery, the subjects were given intraperitoneal injection of either saline or LPS (0.1 mg/kg). Five hours after LPS injection, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to ß-adrenergic stimulation was assessed using standard organ bath. The expression of toll-like receptor 4 (TLR4) was assessed the atria using immunohistochemistry as well as quantitative RT-PCR. RESULTS: LPS injection could induce a significant hypo-responsiveness to adrenergic stimulation in sham-operated rats. However, in cirrhotic rats, the chronotropic responses did not change after acute injection of LPS. Immunohistochemical study showed that TLR4 is mainly expressed in the myocardium in control atria and its expression is markedly decreased in myocardial layer following chronic bile duct ligation. CONCLUSION: Our data showed that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of LPS in rats and this might be caused by altered localization of TLR4 in myocardium.

Expression of matrix metalloproteinase-2, but not caspase-3, facilitates distinction between benign and malignant thyroid follicular neoplasms.

PURPOSE: Definite diagnosis of follicular thyroid carcinoma (FTC) is based on the presence of capsular or vascular invasion. To date, no reliable and practical method has been introduced to discriminate this malignant neoplasm from follicular thyroid adenoma (FTA) in fine needle aspiration biopsy material. Matrix metalloproteinase-2 (MMP-2), by degrading extracellular matrix, and caspase-3, by induction of apoptosis, have been shown to play important roles in carcinogenesis and aggressive behavior in many tumor types. The aim of this study was to examine expression of MMP-2 and caspase-3 in thyroid follicular neoplasms and to determine their usefulness for differential diagnosis. METHOD: Sixty FTAs and 41 FTCs were analysed immunohistochemically for MMP-2 and caspase-3. RESULT: MMP-2 was positive in 4 FTCs (9.8%), but in none of FTAs, with statistical significance (p=0.025). Caspase-3 was positive in 30 (50%) of FTAs and in 27 (65.9%) of FTCs. CONCLUSION: Our results show MMP-2 expression only in FTCs and suggest that this protein may be a useful marker to confirm diagnosis of FTC versus FTA with 100% specificity and 100% predictive value of a positive test. We failed to show any differential diagnostic value for caspase-3 in thyroid follicular neoplasms.

Opioid receptor antagonist promotes angiogenesis in bile duct ligated rats.

BACKGROUND AND AIM: Angiogenesis, formation of new capillaries from existing vasculature, plays a pivotal role in different pathological states such as many chronic inflammatory diseases including the chronic liver diseases. There is increasing evidence demonstrating accumulation of endogenous opioids and their role in the pathophysiology and manifestations of cholestasis, the main feature of a number of chronic progressive liver diseases. Hence, we investigated the significance of endogenous opioids in angiogenesis in an experimental model of cholestasis. METHODS: Cholestasis was induced in male Sprague-Dawley rats by bile duct ligation and resection. Naltrexone, an opioid antagonist (20 mg/kg/day) was administered to cholestatic animals for 22 +/- 1 days. The serial sections from liver tissue were stained with von Willebrand Factor antibody and micro-vessel density was assessed by calculating mean micro-vessel number in three hot spots high power microscopic fields. RESULTS: Naltrexone treatment in bile duct ligated rats led to a marked increase in the micro-vessel number (6.34 +/- 0.21 vs 5.61 +/- 0.22) (P < 0.05), which had already increased during cholestasis. CONCLUSION: In order to clarify the impacts of opioid system blockade in cirrhosis, our findings demonstrate the promoting role of opioid antagonist in angiogenesis in a rat model of cholestasis.

Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis.

BACKGROUND: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play a role in the pathophysiology and manifestation of cholestasis. Evidence of centrally mediated induction of liver injury by exogenous opioid agonist administration, prompts the question of whether opioid receptor blockade by naltrexone can affect cholestasis-induced liver injury. METHODS: Cholestasis was induced by BDL and cholestatic and sham-operated rats received either naltrexone or saline for 7 consecutive days. On the 7th day, liver samples were collected for determining matrix metalloproteinase-2 (MMP-2) activity, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content and blood samples were obtained for measuring plasma nitrite/nitrate and liver enzyme activities. RESULTS: Naltrexone-treated BDL animals had a significant reduction in plasma enzyme activity and nitrite/nitrate level. Liver SAM : SAH ratio and SAM level improved by naltrexone treatment in cholestatic animals compared to saline-treated BDL ones. Naltrexone treatment in BDL rats led to a decrease in the level of liver MMP-2 activity, which had already increased during cholestasis. CONCLUSION: Opioid receptor blockade improved the degree of liver injury in cholestasis, as assessed by plasma enzyme and liver MMP-2 activities. The beneficial effect of naltrexone may be due to its ability to increase liver SAM level and restore the SAM : SAH ratio.