Bone Marrow Mononuclear Cells Up-Regulate Toll-Like Receptor Expression and Produce Inflammatory Mediators in Response to Cigarette Smoke Extract

Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-κB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-β1 production, which was dependent on NF-κB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-α, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-κB activation, but not AKT. These results indicate that CSE profoundly inhibits the growth of erythroid and granulocyte-macrophage progenitors in the bone marrow. Further, CSE modulates NF-κB- and ERK1/2-dependent responses, suggesting that cigarette smoking may impair bone marrow hematopoiesis in vivo as well as induce inflammation, two processes that proceed malignant transformation

Research Trends in Evidence-Based Medicine: A Joinpoint Regression Analysis of More than 50 Years of Publication Data

Background Evidence-based medicine (EBM) has developed as the dominant paradigm of assessment of evidence that is used in clinical practice. Since its development, EBM has been applied to integrate the best available research into diagnosis and treatment with the purpose of improving patient care. In the EBM era, a hierarchy of evidence has been proposed, including various types of research methods, such as meta-analysis (MA), systematic review (SRV), randomized controlled trial (RCT), case report (CR), practice guideline (PGL), and so on. Although there are numerous studies examining the impact and importance of specific cases of EBM in clinical practice, there is a lack of research quantitatively measuring publication trends in the growth and development of EBM. Therefore, a bibliometric analysis was constructed to determine the scientific productivity of EBM research over decades. Methods NCBI PubMed database was used to search, retrieve and classify publications according to research method and year of publication. Joinpoint regression analysis was undertaken to analyze trends in research productivity and the prevalence of individual research methods. Findings Analysis indicates that MA and SRV, which are classified as the highest ranking of evidence in the EBM, accounted for a relatively small but auspicious number of publications. For most research methods, the annual percent change (APC) indicates a consistent increase in publication frequency. MA, SRV and RCT show the highest rate of publication growth in the past twenty years. Only controlled clinical trials (CCT) shows a non-significant reduction in publications over the past ten years. Conclusions Higher quality research methods, such as MA, SRV and RCT, are showing continuous publication growth, which suggests an acknowledgement of the value of these methods. This study provides the first quantitative assessment of research method publication trends in EBM

Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion [del(5q)]. Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of MDM2, with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that lenalidomide inhibits the haplodeficient PP2Acα phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS-14 to suppress MDM2 auto-ubiquitination; whereas PP2Acα over expression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to lenalidomide over-expressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that lenalidomide restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis

Efects of cafeine intake and exercise intensity on executive and arousal vigilance

During physical eforts and sport practice, vigilance is responsible for maintaining an optimal state of activation, guaranteeing the ability to quickly respond and detect unexpected, but critical, stimuli over time. Cafeine and physical exercise are able to modulate the activation state, afecting vigilance performance. The aim of the present work was to assess the specifc efects and modulations of cafeine intake and two physical intensities on vigilance components. Participants performed an attentional task (ANTI-Vea) to measure the executive and arousal components of vigilance, in six double-blinded counterbalanced sessions combining cafeine, placebo, or no-ingestion, with light vs. moderate cyclergometer exercise. Exercise at moderate intensity improved executive vigilance with faster overall reaction time (RT), without impairing error rates. Instead, cafeine intake generally improved arousal vigilance. In conclusion, cafeine and acute exercise seems to moderate executive and arousal vigilance in diferent ways.Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)Spanish Agencia Estatal de Investigacion, Ministerio de Economia y Competitividad PSI2017-84926-P A-SEJ-036-UGR18Juan de AndaluciaUniversidad de Granad