NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells.

BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. METHODS: The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990-1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). RESULTS: NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. CONCLUSIONS: In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.

Ivabradine Attenuates the Microcirculatory Derangements Evoked by Experimental Sepsis.

BACKGROUND: Experimental data suggest that ivabradine, an inhibitor of the pacemaker current in sinoatrial node, exerts beneficial effects on endothelial cell function, but it is unclear if this drug could prevent microcirculatory dysfunction in septic subjects, improving tissue perfusion and reducing organ failure. Therefore, this study was designed to characterize the microcirculatory effects of ivabradine on a murine model of abdominal sepsis using intravital videomicroscopy. METHODS: Twenty-eight golden Syrian hamsters were allocated in four groups: sham-operated animals, nontreated septic animals, septic animals treated with saline, and septic animals treated with ivabradine (2.0 mg/kg intravenous bolus + 0.5 mg · kg · h). The primary endpoint was the effect of ivabradine on the microcirculation of skinfold chamber preparations, assessed by changes in microvascular reactivity and rheologic variables, and the secondary endpoint was its effects on organ function, evaluated by differences in arterial blood pressure, motor activity score, arterial blood gases, and hematologic and biochemical parameters among groups. RESULTS: Compared with septic animals treated with saline, those treated with ivabradine had greater functional capillary density (90 ± 4% of baseline values vs. 71 ± 16%; P < 0.001), erythrocyte velocity in capillaries (87 ± 11% of baseline values vs. 62 ± 14%; P < 0.001), and arteriolar diameter (99 ± 4% of baseline values vs. 91 ± 7%; P = 0.041) at the end of the experiment. Besides that, ivabradine-treated animals had less renal, hepatic, and neurologic dysfunction. CONCLUSIONS: Ivabradine was effective in reducing microvascular derangements evoked by experimental sepsis, which was accompanied by less organ dysfunction. These results suggest that ivabradine yields beneficial effects on the microcirculation of septic animals.