Clotrimazole Preferentially Inhibits Human Breast Cancer Cell Proliferation, Viability and Glycolysis

BACKGROUND: Clotrimazole is an azole derivative with promising anti-cancer effects. This drug interferes with the activity of glycolytic enzymes altering their cellular distribution and inhibiting their activities. The aim of the present study was to analyze the effects of clotrimazole on the growth pattern of breast cancer cells correlating with their metabolic profiles. METHODOLOGY/PRINCIPAL FINDINGS: Three cell lines derived from human breast tissue (MCF10A, MCF-7 and MDA-MB-231) that present increasingly aggressive profiles were used. Clotrimazole induces a dose-dependent decrease in glucose uptake in all three cell lines, with K(i) values of 114.3±11.7, 77.1±7.8 and 37.8±4.2 µM for MCF10A, MCF-7 and MDA-MB-231, respectively. Furthermore, the drug also decreases intracellular ATP content and inhibits the major glycolytic enzymes, hexokinase, phosphofructokinase-1 and pyruvate kinase, especially in the highly metastatic cell line, MDA-MB-231. In this last cell lineage, clotrimazole attenuates the robust migratory response, an effect that is progressively attenuated in MCF-7 and MCF10A, respectively. Moreover, clotrimazole reduces the viability of breast cancer cells, which is more pronounced on MDA-MB-231. CONCLUSIONS/SIGNIFICANCE: Clotrimazole presents deleterious effects on two human breast cancer cell lines metabolism, growth and migration, where the most aggressive cell line is more affected by the drug. Moreover, clotrimazole presents little or no effect on a non-tumor human breast cell line. These results suggest, at least for these three cell lines studied, that the more aggressive the cell is the more effective clotrimazole is

Source analysis of beta-synchronisation and cortico-muscular coherence after movement termination based on high resolution electroencephalography

We hypothesized that post-movement beta synchronization (PMBS) and cortico-muscular coherence (CMC) during movement termination relate to each other and have similar role in sensorimotor integration. We calculated the parameters and estimated the sources of these phenomena.We measured 64-channel EEG simultaneously with surface EMG of the right first dorsal interosseus muscle in 11 healthy volunteers. In Task1, subjects kept a medium-strength contraction continuously; in Task2, superimposed on this movement, they performed repetitive self-paced short contractions. In Task3 short contractions were executed alone. Time-frequency analysis of the EEG and CMC was performed with respect to the offset of brisk movements and averaged in each subject. Sources of PMBS and CMC were also calculated.High beta power in Task1, PMBS in Task2-3, and CMC in Task1-2 could be observed in the same individual frequency bands. While beta synchronization in Task1 and PMBS in Task2-3 appeared bilateral with contralateral predominance, CMC in Task1-2 was strictly a unilateral phenomenon; their main sources did not differ contralateral to the movement in the primary sensorimotor cortex in 7 of 11 subjects in Task1, and in 6 of 9 subjects in Task2. In Task2, CMC and PMBS had the same latency but their amplitudes did not correlate with each other. In Task2, weaker PMBS source was found bilaterally within the secondary sensory cortex, while the second source of CMC was detected in the premotor cortex, contralateral to the movement. In Task3, weaker sources of PMBS could be estimated in bilateral supplementary motor cortex and in the thalamus. PMBS and CMC appear simultaneously at the end of a phasic movement possibly suggesting similar antikinetic effects, but they may be separate processes with different active functions. Whereas PMBS seems to reset the supraspinal sensorimotor network, cortico-muscular coherence may represent the recalibration of cortico-motoneuronal and spinal systems

In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature

BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 x 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 x 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 x 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis

A systematic review of transanal total mesorectal excision: is this the future of rectal cancer surgery?

The surgical technique used for transanal total mesorectal excision (TaTME) was reviewed including the oncological quality of resection and the peri-operative outcome.A literature search of MEDLINE, Embase, Science Citation Index Expanded and Cochrane was performed in order to identify studies reporting on TaTME.Thirty-six studies (eight case reports, 24 case series and four comparative studies) were identified, reporting 510 patients who underwent TaTME. The mean age ranged from 43 to 80 years and the mean body mass index from 21.7 to 31.8 kg/m(2) . The mean distance of the tumour from the anal verge ranged from 4 to 9.7 cm. The mean operation time ranged from 143 to 450 min and mean operative blood loss from 22 to 225 ml. The ratio of hand-sewn coloanal to stapled anastomoses performed was 2:1. One death was reported and the peri-operative morbidity rate was 35%. The anastomotic leakage rate was 6.1% and the reoperation rate was 3.7%. The mean hospital stay ranged from 4.3 to 16.6 days. The mesorectal excision was described as complete in 88% cases, nearly complete in 6% and incomplete in 6%. The circumferential resection margin was negative in 95% of cases and the distal resection margin was negative in 99.7%.TaTME is a feasible and reproducible technique, with good quality of oncological resection. Standardization of the technique is required with formal training. Clear indications for this procedure need to be defined and its safety further assessed in future trials

A systematic review of transanal total mesorectal excision: is this the future of rectal cancer surgery?

The surgical technique used for transanal total mesorectal excision (TaTME) was reviewed including the oncological quality of resection and the peri-operative outcome.A literature search of MEDLINE, Embase, Science Citation Index Expanded and Cochrane was performed in order to identify studies reporting on TaTME.Thirty-six studies (eight case reports, 24 case series and four comparative studies) were identified, reporting 510 patients who underwent TaTME. The mean age ranged from 43 to 80 years and the mean body mass index from 21.7 to 31.8 kg/m(2) . The mean distance of the tumour from the anal verge ranged from 4 to 9.7 cm. The mean operation time ranged from 143 to 450 min and mean operative blood loss from 22 to 225 ml. The ratio of hand-sewn coloanal to stapled anastomoses performed was 2:1. One death was reported and the peri-operative morbidity rate was 35%. The anastomotic leakage rate was 6.1% and the reoperation rate was 3.7%. The mean hospital stay ranged from 4.3 to 16.6 days. The mesorectal excision was described as complete in 88% cases, nearly complete in 6% and incomplete in 6%. The circumferential resection margin was negative in 95% of cases and the distal resection margin was negative in 99.7%.TaTME is a feasible and reproducible technique, with good quality of oncological resection. Standardization of the technique is required with formal training. Clear indications for this procedure need to be defined and its safety further assessed in future trials