Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis

Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 μM and 1 μM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 μM and 1 μM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 ± 0.26 versus 5.5 ± 0.1 μg/10(6 )cells, respectively; p < 0.01), lower levels of u-PA (1.04 ± 0.05 versus 3.1 ± 0.4 ng/10(6 )cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 ± 0.22 versus 23.6 ± 0.1 ng/10(6 )cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation

Heart rate and cardiovascular responses to commercial flights: relationships with physical fitness

The aim of this study was to examine the influence of physical fitness on cardiac autonomic control in passengers prior to, during and following commercial flights. Twenty-two, physically active men (36.4 +/- 6.4 years) undertook assessments of physical fitness followed by recordings of 24-h heart rate (HR), heart rate variability (HRV), and blood pressure (BP) on a Control (no flight) and Experimental (flight) day. Recordings were analyzed using a two-way analysis of variance for repeated measures with relationships between variables examined via Pearson product moment correlation coefficients. Compared to the Control day, 24-h HR was significantly greater (>7%) and HRV measures (5-39%) significantly lower on the Experimental day. During the 1-h flight, HR (24%), and BP (6%) were increased while measures of HRV (26-45%) were reduced. Absolute values of HRV during the Experimental day and relative changes in HRV measures (Control-Experimental) were significantly correlated with measures of aerobic fitness (r = 0.43 to 0.51;-0.53 to -0.52) and body composition (r = -0.63 to -0.43; 0.48-0.61). The current results demonstrated that short-term commercial flying significantly altered cardiovascular function including the reduction of parasympathetic modulations. Further, greater physical fitness and lower body fat composition were associated with greater cardiac autonomic control for passengers during flights. Enhanced physical fitness and leaner body composition may enable passengers to cope better with the cardiovascular stress and high allostatic load associated with air travel for enhanced passenger well-being

Analysis of time-profiles with in-beam PET monitoring in charged particle therapy

Background: Treatment verification with PET imaging in charged particle therapy is conventionally done by comparing measurements of spatial distributions with Monte Carlo (MC) predictions. However, decay curves can provide additional independent information about the treatment and the irradiated tissue. Most studies performed so far focus on long time intervals. Here we investigate the reliability of MC predictions of space and time (decay rate) profiles shortly after irradiation, and we show how the decay rates can give an indication about the elements of which the phantom is made up. Methods and Materials: Various phantoms were irradiated in clinical and near-clinical conditions at the Cyclotron Centre of the Bronowice proton therapy centre. PET data were acquired with a planar 16x16 cm$^2$ PET system. MC simulations of particle interactions and photon propagation in the phantoms were performed using the FLUKA code. The analysis included a comparison between experimental data and MC simulations of space and time profiles, as well as a fitting procedure to obtain the various isotope contributions in the phantoms. Results and conclusions: There was a good agreement between data and MC predictions in 1-dimensional space and decay rate distributions. The fractions of $^{11}$C, $^{15}$O and $^{10}$C that were obtained by fitting the decay rates with multiple simple exponentials generally agreed well with the MC expectations. We found a small excess of $^{10}$C in data compared to what was predicted in MC, which was clear especially in the PE phantom.Comment: 9 pages, 5 figures, 1 table. Proceedings of the 20th International Workshop on Radiation Imaging Detectors (iWorid2018), 24-28 June 2018, Sundsvall, Swede

Salting-out approach is worthy of comparison with ultracentrifugation for extracellular vesicle isolation from tumor and healthy models

The role of extracellular vesicles (EVs) has been completely re-evaluated in the recent decades, and EVs are currently considered to be among the main players in intercellular commu-nication. Beyond their functional aspects, there is strong interest in the development of faster and less expensive isolation protocols that are as reliable for post-isolation characterisations as already-established methods. Therefore, the identification of easy and accessible EV isolation techniques with a low price/performance ratio is of paramount importance. We isolated EVs from a wide spectrum of samples of biological and clinical interest by choosing two isolation techniques, based on their wide use and affordability: ultracentrifugation and salting-out. We collected EVs from human cancer and healthy cell culture media, yeast, bacteria and Drosophila culture media and human fluids (plasma, urine and saliva). The size distribution and concentration of EVs were measured by nanoparticle tracking analysis and dynamic light scattering, and protein depletion was measured by a colori-metric nanoplasmonic assay. Finally, the EVs were characterised by flow cytometry. Our results showed that the salting-out method had a good efficiency in EV separation and was more efficient in protein depletion than ultracentrifugation. Thus, salting-out may represent a good alternative to ultracentrifugation

Improvements in Attention and Cardiac Autonomic Modulation After a 2-Weeks Sprint Interval Training Program: A Fidelity Approach

[EN] This study aimed to: (1) investigate the influence of a 2-weeks sprint interval training (SIT) program on aerobic capacity, cardiac autonomic control, and components of attention in young healthy university students; and (2) to ascertain whether training fidelity would influence these adaptations. One hundred and nine participants were divided into an experimental (EG) and control (CG) groups. The EG performed a SIT program that consisted of 6 sessions of 4 × 30 s “all-out” efforts on a cycle ergometer, interspersed with active rests of 4 min. The criterion for fidelity was achieving >90% of estimated maximum heart rate (HR) during sprint bouts. After analyses, the EG was divided into HIGH (n = 26) and LOW (n = 46) fidelity groups. Components of attention were assessed using the Attention Network Test (ANT). Aerobic capacity (VO2max) was estimated while the sum of skinfolds was determined. Autonomic control of HR was assessed by means of HR variability (HRV) and HR complexity at rest and during ANT. Both HIGH and LOW significantly increased aerobic capacity, vagal modulation before and during ANT, and executive control, and decreased body fatness after SIT (p < 0.05). However, only participants from HIGH showed an increase in HR complexity and accuracy in ANT when compared to LOW (p < 0.05). Two weeks of SIT improved executive control, body fatness, aerobic fitness, and autonomic control in university students with better results reported in those individuals who exhibited high fidelity.AdS, AM, and SD enjoy a PROSUP-CAPES grant. DB enjoys a productivity in research grant from CNPq.CNPq (Brazil) (process number 486116/2013-1) supported this project. AdS, SD, and AM were supported by a PROSUP grant from CAPES (Brazil). SB-F is supported by a doctoral fellowship awarded by ANII (Uruguay). DB was supported by a productivity research grant from CNPq (Brazil). We would like to thank all participants for their collaboration and LEEFS’s laboratory staff (Giseli Kelly de Melo Oliveira Gomes, Alessandra Matida) for their assistance during data collection. The authors declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation

Heart Rate and Cardiovascular Responses to Commercial Flights: Relationships with Physical Fitness

[EN] The aim of this study was to examine the influence of physical fitness on cardiac autonomic control in passengers prior to, during and following commercial flights. Twenty-two, physically active men (36.4 ± 6.4 years) undertook assessments of physical fitness followed by recordings of 24-h heart rate (HR), heart rate variability (HRV), and blood pressure (BP) on a Control (no flight) and Experimental (flight) day. Recordings were analyzed using a two-way analysis of variance for repeated measures with relationships between variables examined via Pearson product-moment correlation coefficients. Compared to the Control day, 24-h HR was significantly greater (>7%) and HRV measures (5–39%) significantly lower on the Experimental day. During the 1-h flight, HR (24%), and BP (6%) were increased while measures of HRV (26–45%) were reduced. Absolute values of HRV during the Experimental day and relative changes in HRV measures (Control-Experimental) were significantly correlated with measures of aerobic fitness (r = 0.43 to 0.51; −0.53 to −0.52) and body composition (r = −0.63 to −0.43; 0.48–0.61). The current results demonstrated that short-term commercial flying significantly altered cardiovascular function including the reduction of parasympathetic modulations. Further, greater physical fitness and lower body fat composition were associated with greater cardiac autonomic control for passengers during flights. Enhanced physical fitness and leaner body composition may enable passengers to cope better with the cardiovascular stress and high allostatic load associated with air travel for enhanced passenger well-being

Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients

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Impaired fas-fas ligand interactions result in greater recurrent herpetic stromal keratitis in mice

Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK