Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 ...and BCL-X(L), ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total ...of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n = 10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist ...and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid β 1–42 (sAβ1–42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAβ injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.
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•PEA-OXA reduces cognitive deficits mediated by Amyloid-β(1−42) intracerebroventricular injection.•PEA-OXA prevents impaired hippocampal synaptic plasticity and neuroinflammation associated with Amyloid-β(1−42).•PEA-OXA may act as a negative allosteric modulator of α2A adrenergic receptor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper aims to investigate the ability of ultrasonic and electronic speckle pattern interferometry to analyse the low-velocity impact internal damage mechanisms on basalt composite laminates and ...to provide information on the shape and the extent of the delamination in non-destructive way.
Basalt/epoxy composites with different thicknesses have been realised and characterised by mechanical tests to investigate both fibre-dominated (tensile and flexural behaviour) and matrix-dominated properties (interlaminar shear strength). Specimens were impacted at penetration and at increasing energy values, to explore the damage onset and propagation. The results showed that the damage was concentrated under the impactor–material contact point and that the composite with intermediate thickness had the best balance between the different kinds of impact damages: delamination and indentation. Further, a good agreement was found between the overall data obtained by the two non-destructive techniques, confirming the capability of both techniques to examine the composite impact damage.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The aim of this umbrella review of systematic reviews and meta-analyses was to address workplace violence (WPV) against healthcare workers (HCWs). Several systematic reviews exist in the literature, ...but the diversity of settings, population considered, and type of violence investigated make it difficult to gain insight and use the vast amount of available data to implement policies to tackle WPV. With this in mind, we conducted an umbrella review of systematic reviews and meta-analyses on WPV against HCWs to examine the global prevalence of the phenomena and its features.
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Scopus, and ISI Web of Science were searched for relevant systematic reviews and meta-analyses published in English up to November 2022. Data on authors, year, country, violence type, prevalence (pooled and not), setting, population, and specific considerations were extracted.
A total of 32 systematic reviews were included, 19 of which performed a meta-analysis, investigating overall, physical, and non-physical violence. Even considering the variability of the data, the COVID-19 pandemic has exacerbated the scale of the problem. From our review, we found that overall violence prevalence among HCWs was reported to be as high as 78.9%, and nurses working in psychiatric wards were the professionals most impacted.
In conclusion, this umbrella review revealed a high prevalence of WPV among HCWs, which varies between countries, population subgroups, and detection methods. Strengthening recognition of the problem could lead to appropriate local and international strategies to address it.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The research reported in this paper was aimed mainly to investigate the different NDE techniques on specimens made by a new process labeled as “pulsed infusion”, very crucial for voids content under ...critical loading conditions. The impact load, in fact, is critical for composite laminates due to their anisotropy, in particular in extreme temperature conditions due to their brittleness. An additional and very relevant aim was to collect a large number of experimental results to supply useful information for the numerical models needed to simulate the dynamic behavior of composite laminates. At the aim to investigate the response under dynamic loads of laminates fabricated by a new vacuum assisted technology labeled as “pulsed infusion”, rectangular carbon fiber composite specimens were subjected to low velocity impact tests. Experimental tests up to complete penetration and at different energy levels, were carried out by a modular falling weight tower. All the parameters related to the phenomenon, like penetration energy, maximum force and indentation depths, were used to validate existing semi-empirical and numerical models. The largely used ultra sound technique (US) was adopted to investigate the delamination together with the thermo graphic technique. The results of the measurements were compared with data obtained on the same specimens by holographic analysis (ESPI). One of the scope was to investigate the crucial internal impact damage and assess the ability of an unconventional ND system (ESPI) in giving right information about non-visual damage generated inside composite laminates subjected to dynamic loads. Moreover, some of the specimens were cut to allow the fractographic analysis. The efficiency of the above mentioned new fabrication technology was studied also comparing the results with measurements from literature on impacted autoclave cured laminates. By the comparison between the results, good agreements were found denoting the efficiency and the applicability of the new fabrication and the used NDE methods.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Mild elevations in creatine kinase-MB (CK-MB) are common after successful percutaneous coronary interventions and are associated with future adverse cardiac events. The mechanism for CK-MB release ...remains unclear. A new contrast-enhanced MRI technique allows direct visualization of myonecrosis.
Fourteen patients without prior infarction underwent cine and contrast-enhanced MRI after successful coronary stenting; 9 patients had procedure-related CK-MB elevation, and 5 did not (negative controls). The mean age of all patients was 61 years, 36% had diabetes, 43% had multivessel coronary artery disease, and all had a normal ejection fraction. Twelve patients (86%) received an intravenous glycoprotein IIb/IIIa inhibitor; none underwent atherectomy, and all had final TIMI 3 flow. Of the 9 patients with CK-MB elevation, 5 had a minor side branch occlusion during stenting, 2 had transient ECG changes, and none developed Q-waves. The median CK-MB was 21 ng/mL (range, 12 to 93 ng/mL), which is 2.3x the upper limit of normal. Contrast-enhanced MRI demonstrated discrete regions of hyperenhancement within the target vessel perfusion territory in all 9 patients. Only one developed a new wall motion abnormality. The median estimated mass of myonecrosis was 2.0 g (range, 0.7 to 12.2 g), or 1.5% of left ventricular mass (range, 0.4% to 6.0%). Hyperenhancement persisted in 5 of the 6 who underwent a repeat MRI at 3 to 12 months. No control patient had hyperenhancement.
Contrast-enhanced MRI provides an anatomical correlate to biochemical evidence of procedure-related myocardial injury, despite the lack of ECG changes or wall motion abnormalities. Mild elevation of CK-MB after percutaneous coronary intervention is the result of discrete microinfarction.
To improve the impact behaviour of composite laminates and to reduce the problem of the complex damages after dynamic loads, a two-component commercial epoxy resin was modified with a commercial ...nitrile liquid rubber modified DGEBA epoxy prepolymer that, prior the cure, has been mechanically dispersed at two concentration levels (20%w/w; 30%w/w). Experimental characterization of both neat and modified resins was performed to investigate the effect of the rubber addition on the resin properties, i.e. glass transition temperature, modulus and dynamic mechanical characteristics. Further, the rubber domain distribution in the epoxy resin was analyzed by scanning electron microscopy (SEM). The hybrid rubber modified resins did not show high viscosity allowing to manufacture E-glass fiber reinforced composites by vacuum infusion process.
The laminates were characterized by tensile mechanical tests that evidenced an overall enhancement of maximum stress and deformation for the hybrid composites. In particular, results demonstrated an improvement of 10% for the shear failure stress and of 110% for the shear failure strain. Further, impact tests were carried out at penetration, to evaluate the improvement of the impact resistance over the conventional epoxy resin system, and at increasing energy levels, 5 J, 10 J and 20 J, to investigate the damage start and propagation. A higher indentation has been observed for the modified composite samples related with a lower delamination extension.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The effect of stacking sequence on the impact damage mechanisms and the matrix-fiber dependent properties, such as flexural and interlaminar strength, of epoxy hybrid basalt/flax composites has been ...experimentally investigated. The basalt and flax fabrics have been appropriately selected with approximately the same areal weight and stacked in the same number in three different symmetrical analysed configurations to manufacture composites with comparable conditions regarding fibre content by weight. No influence of fibre sequence was observed for the flexural modulus, whereas some differences were exhibited by the flexural and the interlaminar shear strength depending on the resin content. The impact tests were carried out at penetration and different energy levels. After impact, indentation measurements have been performed by a confocal microscope to get information on the damage propagation and characteristics that resulted affected by the hybridisation type and by the impact energy. The results evidenced the relevance of the stacking sequence in the composite design to meet specific requirements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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