BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential

Effectiveness comparison between carbon spring and hinged ankle-foot orthoses in crouch gait treatment of children with diplegic cerebral palsy: A randomized crossover trial

BACKGROUND: Children with cerebral palsy (CP) often present a loss of effectiveness of the plantarflexors/knee-extensors couple that leads to crouch gait. When treating a child with crouch gait by means of ankle foot orthoses, preserving or restoring push off power is a key issue.AIM: To compare carbon-fiber spring (Carbon Ankle Seven (R) [CAFO], Ottobock (R) HealthCare, Duderstadt, Germany) and hinged ankle-foot orthoses (HAFO) effectiveness in improving functionality and walking ability in children with diplegic CP and crouch gait.DESIGN: Randomized crossover trial.SETTING: Hospital center.POPULATION: Ten children with diplegic CP and crouch gait, 5 males and 5 females, aged 11 (4) years.METHODS: The gait of each child was evaluated by means of instrumental gait analysis with both CAFO and HAFO, in a randomized order and after a 4-week adaptation period. The primary outcome measure was the change in ankle power generation. As secondary outcome measures, knee joint kinematics, stride length, walking speed, Observational Gait Scale, and preferred orthosis were considered.RESULTS: The median of the energy produced in stance was superior with CAFO (+2.2 J/kg, IQR 4.7, P=0.006), and the energy absorbed inferior (-3.3 J/kg, IQR 4.3, P=0.011). No statistically significant difference was found for any other parameter. Preference of the children was equally distributed between the two orthoses.CONCLUSIONS: No evident superiority of CAFO with respect to HAFO was found in improving gait performance of children with CP and crouch gait. Nevertheless, the results suggest the possibility that CAFO permits an energy saving and reduction of the more compromising deficits.CLINICAL REHABILITATION IMPACT: The final choice of the participants indicates that CAFOs are preferred by older and heavier children, but the preference does not correlate with the performance of the orthoses during gait

Influence of Processing Parameters and Natural Antimicrobial on Alicyclobacillus acidoterrestris and Clostridium pasteurianum Using Response Surface Methodology

The food industry must ensure the stability of the products, and this is often achieved by exposing foods to heat treatments that are able to ensure the absence of pathogenic or spoilage microorganisms. These treatments are different in terms of temperature and duration and could lead to a loss in nutritional and sensory value. Moreover, some types of microorganisms manage to survive these treatments thanks to the sporification process. The addition of antimicrobials can become necessary, but at present, consumers are more inclined toward natural products, avoiding synthetic and chemical additives. Antimicrobials from plants could be a valuable option and, in this context, a patent concerning an antimicrobial extract from fermented plant substrate was recently tested against foodborne pathogens revealing high antimicrobial activity. The objective of this study was the creation of a model for the evaluation and subsequent prediction of the combined effect of different process and product variables, including antimicrobial addition, on the inhibition and reduction of spore germination of target microorganisms, Alicyclobacillus acidoterrestris and Clostridium pasteurianum, responsible for spoilage of tomato-based products

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

e Glasgow and Manchester Experimental Cancer Medicine Centres (ECMC), which are funded by CR-UK and the Chief Scientist’s Office (Scotland). We acknowledge the funders who have contributed to this work: MRC stratified medicine infrastructure award (A.D.W.), CR-UK C11074/A11008 (F.P., L.E.M.H., T.L.H., A.D.W.); LLR08071 (S.A.A., E.C.); LLR11017 (M.C.); SCD/04 (M.C.); LLR13035 (S.A.A., K.D., A.D.W., and A.P.); LLR14005 (M.T.S., D.V.); KKL690 (L.E.P.); KKL698 (P.B.); LLR08004 (A.D.W., A.P. and A.J.W.); MRC CiC (M.E.D.); The Howat Foundation (FACS support); Friends of Paul O’Gorman (K.D. and FACS support); ELF 67954 (S.A.A.); BSH start up fund (S.A.A.); MR/K014854/1 (K.D.)

EPR Sensing of a Cation Species by Aza-Crown Ethers Incorporating a Persistent Nitroxidic Radical Unit

New nitroxides based on aza-crown ethers were prepared and employed as selective sensors for the detection of inorganic and organic cations by EPR analysis of the corresponding host-guest complexes. The nitroxide unit behaves as a sensitive probe for a number of alkali and alkaline earth metal cations affording EPR spectra differing in the value of nitrogen hyperfine constants and in the appearance of splitted signals due to the non-zero nuclear spin of some metal cation upon complexation. Owing to the remarkable EPR spectral differences between the host and the corresponding cation complex the new macrocycles are likely to act as multitasking tools to recognize several cationic species. EPR behaviour of the larger nitroxide azacrown 1(center dot) when acting as a wheel in a radical synthetic bistable [2]rotaxane containing both secondary dialkylammonium and 1,2-bis(pyridinium) molecular stations, was also investigated. Reversible movements of the macrocycle between the two recognition sites in the rotaxane were promptly revealed by EPR, which shows significant changes either in nitrogen coupling constant values (a(N)) or in the spectral shape in the two rotaxane co-conformations

Draft genome sequence of lactobacillus helveticus Lh 23, isolated from natural whey starter

Lactobacillus helveticus is a thermophilic lactic acid bacterium that is widely employed as a starter culture for manufacturing several Swiss and Italian hard-cooked cheeses. The sequencing of L. helveticus Lh 23, which consists of 2,100,230 bp with a GC content of 36.5%, reveals industrially useful traits and interesting metabolic pathways

Exploration of Gate Trench Module for Vertical GaN devices

The aim of this work is to present the optimization of the gate trench module for use in vertical GaN devices in terms of cleaning process of the etched surface of the gate trench, thickness of gate dielectric and magnesium concentration of the p-GaN layer. The analysis was carried out by comparing the main DC parameters of devices that differ in surface cleaning process of the gate trench, gate dielectric thickness, and body layer doping. . On the basis of experimental results, we report that: (i) a good cleaning process of the etched GaN surface of the gate trench is a key factor to enhance the device performance, (ii) a gate dielectric >35-nm SiO2 results in a narrow distribution for DC characteristics, (iii) lowering the p-doping in the body layer improves the ON-resistance (RON). Gate capacitance measurements are performed to further confirm the results. Hypotheses on dielectric trapping/detrapping mechanisms under positive and negative gate bias are reported.Comment: 5 pages, 10 figures, submitted to Microelectronics Reliability (Special Issue: 31st European Symposium on Reliability of Electron Devices, Failure Physics and Analysis, ESREF 2020

CMS physics technical design report : Addendum on high density QCD with heavy ions

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