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

Study on lipid fractions of Streptococcus thermophilus by TLC, GC and GC/MS techniques

In this research the lipid fraction of two strains of Streptococcus thermophilus was studied. Lipids were extracted by applying Folch method and fractioned by thin layer chromatography (TLC). Fatty acid composition was determined both before TLC, on the total fat extracted, and after TLC on diacylglycerol and apolar fractions. Gas chromatographic analysis was performed by using both flame ionization (FID) and mass spectrometer (MS) detector. The main difference between the two strains was the presence of short and medium chain fatty acids in food-born S. thermophilus. Moreover one of the most important bacterial fatty acids, C19 cyclopropane, was detected only in diacylglycerols, which, as reported in literature, are formed transiently as intermediates in the biosynthesis of glycerophospholipids

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.)

The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche

The capture of tumour-derived extracellular vesicles (TEVs) by cells in the tumour microenvironment (TME) contributes to metastasis and notably to the formation of the pre-metastatic niche (PMN). However, due to the challenges associated with modelling release of small EVs in vivo, the kinetics of PMN formation in response to endogenously released TEVs have not been examined. Here, we have studied the endogenous release of TEVs in mice orthotopically implanted with metastatic human melanoma (MEL) and neuroblastoma (NB) cells releasing GFP-tagged EVs (GFTEVs) and their capture by host cells to demonstrate the active contribution of TEVs to metastasis. Human GFTEVs captured by mouse macrophages in vitro resulted in transfer of GFP vesicles and the human exosomal miR-1246. Mice orthotopically implanted with MEL or NB cells showed the presence of TEVs in the blood between 5 and 28 days after implantation. Moreover, kinetic analysis of TEV capture by resident cells relative to the arrival and outgrowth of TEV-producing tumour cells in metastatic organs demonstrated that the capture of TEVs by lung and liver cells precedes the homing of metastatic tumour cells, consistent with the critical roles of TEVs in PMN formation. Importantly, TEV capture at future sites of metastasis was associated with the transfer of miR-1246 to lung macrophages, liver macrophages, and stellate cells. This is the first demonstration that the capture of endogenously released TEVs is organotropic as demonstrated by the presence of TEV-capturing cells only in metastatic organs and their absence in non-metastatic organs. The capture of TEVs in the PMN induced dynamic changes in inflammatory gene expression which evolved to a pro-tumorigenic reaction as the niche progressed to the metastatic state. Thus, our work describes a novel approach to TEV tracking in vivo that provides additional insights into their role in the earliest stages of metastatic progression.The authors would like to thank Mrs. J. Rosenberg for her help in the formatting of the manuscript, and the personnel of the Core Facilities of the Saban Research Institute at Children's Hospital Los Angeles (Flow Cytometry, Extracellular Vesicle, Cell Imaging, and Animal Imaging Cores) for their expertise and assistance. This work was supported by National Institutes of Health/National Cancer Institute grant R01 CA207983 to Y.A. DeClerck