Increases in Cytosolic Calcium Ion Levels in Human Natural Killer Cells in Response to Butyltin Exposure

This study investigated whether exposures to butyltins (BTs), tributylin (TBT), and dibutyltin (DBT) were able to alter cytosolic calcium levels in human natural killer (NK) cells. Additionally, the effects of cytosolic calcium ion increases on the activation state of mitogen-activated protein kinases (MAPKs) in NK cells were also investigated. NK cells are an intital immune defense against the development of tumors or viral infections. TBT and DBT are widespread environmental contaminants, due to their various industrial applications. Both TBT and DBT have been shown to decrease the ability of NK cells to lyse tumor cells (lytic function). TBT has also been shown to activate MAPKs in NK cells. The results of this study indicated that TBT increased cytosolic calcium levels by as much as 100% after a 60-min exposure to 500 nM TBT, whereas DBT increased cytosolic calcium levels to a much smaller extent (and required higher concentrations). The results also indicated that increases in cytosolic calcium could activate MAPKs but only for a short period of time (5 min), whereas previous studies showed that activation of MAPKs by TBT last for at least 6 h. Thus, it appears that TBT-stimulated increases in cytosolic calcium might contribute to, but are not fully responsible for, TBT-induced activation of MAPKs

Dibutyltin activates MAP kinases in human natural killer cells, in vitro

Previous studies have shown that dibutyltin (DBT) interferes with the function of human natural killer (NK) cells, diminishing their capacity to destroy tumor cells, in vitro. DBT is a widespread environmental contaminant and has been found in human blood. As NK cells are our primary immune defense against tumor cells, it is important to understand the mechanism by which DBT interferes with their function. The current study examines the effects of DBT exposures on key enzymes in the signaling pathway that regulates NK responsiveness to tumor cells. These include several protein tyrosine kinases (PTKs), mitogen-activated protein kinases (MAPKs), and mitogen-activated protein kinase kinases (MAP2Ks). The results showed that in vitro exposures of NK cells to DBT had no effect on PTKs. However, exposures to DBT for as little as 10 min were able to increase the phosphorylation (activation) of the MAPKs. The DBT-induced activations of these MAPKs appear to be due to DBT-induced activations of the immediate upstream activators of the MAPKs, MAP2Ks. The results suggest that DBT-interference with the MAPK signaling pathway is a consequence of DBT exposures, which could account for DBT-induced decreases in NK function

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Effects of butyltins on cytosolic calcium ion levels, MAPKs signaling pathways and apoptotic pathways in human natural killer cells

Natural killer (NK) cells are lymphocytes that kill tumor cells, virally infected cells and antibody coated cells. Butyltins (BTs) are used in industrial, agricultural and consumer applications and contaminate the global environment. Tributyltin (TBT) has been used for wood preservation, disinfection, antifouling marine paints, and slime control in paper mills. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride (PVC) plastic products. BTs inhibit the cytotoxic function of NK cells and have been found in human blood. Exposures of NK cells to TBT caused significant decreases in cytotoxic function coupled with activation (phosphorylation) of mitogen-activated protein kinases (MAPKs). TBT also caused an increase in cytosolic Ca2+. The hypothesis being tested in the current study is that DBT causes increases in cytosolic Ca2+ and activation of MAPKS DBT caused small but significant increases in Ca2+cyt after 30 and 60 min. The increases were 20% above control for 10 μM DBT and 13% for 5 μM DBT. Ten minute exposures to DBT activated the MAPK, p38 at every concentration tested. Activation was accompanied by an activation of the enzyme that activates p38, the MAP2K, MKK3/6. Exposure to DBT for 10 min also activated p44/42 and its MAP2K, MEK1/2, at the two highest concentrations of DBT. One hour exposures to DBT activated p38 and MKK3/6 at all concentration (10, 5, 2.5, 1μM) except for the lowest DBT concentration (0.5μM), A 6 hour exposure to DBT induced significant activation of p38 and MKK3/6 at the 10 μM concentration. After a 6 h exposure to 10 μM DBT there was also a very significant activation of p44/42. Thus, the ability of DBT to activate p38 diminished with length of exposure, similar to what was seen when NK cells were exposed to TBT. The effect of TBT and DBT on the Caspase-3 activity and XIAP enzyme was also assessed in this study, no significant changes were observed when the NK cells were exposed to 300, 200, 100, 50 and 25 nM TBT and 10, 5, 2.5, 1, 0.5 μM DBT for 10 min, 60 min and 24 h

Increases in Cytosolic Calcium Ion Levels in Human Natural Killer Cells in Response to Butyltin Exposure

This study investigated whether exposures to butyltins (BTs), tributylin (TBT) and dibutyltin (DBT) were able to alter cytosolic calcium levels in human natural killer (NK) cells. Additionally, the effects of cytosolic calcium ion increases on the activation state of mitogen activated protein kinases (MAPKs) in NK cells were also investigated. NK cells are an intital immune defense against the development of tumors or viral infections. TBT and DBT are widespread environmental contaminants, due to their various industrial applications. Both TBT and DBT have been shown to decrease the ability of NK cells to lyse tumor cells (lytic function). TBT has also been shown to activate MAPKs in NK cells. The results of this study indicated that TBT increased cytosolic calcium levels by as much as 100% after a 60 min exposure to 500 nM TBT while DBT increased cytosolic calcium levels to a much smaller extent (and required higher concentrations). The results also indicated that increases in cytosolic calcium could activate MAPKs but only for a short period of time (5 min), while previous studies showed that activation of MAPKs by TBT last for at least 6 hours. Thus, it appears that TBT stimulated increases in cytosolic calcium may contribute to, but are not fully responsible for, TBT-induced activation of MAPKs