Early Carotid Endarterectomy after Ischemic Stroke: The Results of a Prospective Multicenter Italian Study

ObjectivesTo evaluate safety of early carotid endarterectomy (CEA) in patients with acute brain ischemia presenting to the emergency department stroke units (EDSU).MethodsThe neurologists, neuroradiologists and vascular surgeons on duty in emergency departments enrolled 96 patients who underwent very early CEA according to a predefined protocol within two years. The protocol included evaluation of neurological status by National Institute of Health Stroke Scale (NIHSS), neuroimaging assessment, ultrasound of the carotid arteries and Transcranial Doppler. Patients with NIHSS>22 or whose neuroimaging showed brain infarct >2/3 of the middle cerebral artery territory were excluded. All eligible patients underwent CEA as soon as possible. Primary end points of the study were mortality, neurological morbidity by NIHSS and postoperative hemorrhagic conversion on neuroimaging. Statistical analysis was performed by univariate analysis.ResultsThe mean time elapsing between the onset of stroke and endarterectomy was 1.5 days (±2 days). The overall 30-day morbidity mortality rate was 7.3% (7/96). No neurological mortality occurred. On hospital discharge, three patients (3%) experienced worsening of the neurological deficit (NIHSS score 1 to 2, 1 to 3 and 9 to 10 respectively). Postoperative CT demonstrated there were no new cerebral infarcts nor hemorrhagic transformation. At hospital discharge 9/96 patients (9%) had no improvement in NHISS scores, 37 were asymptomatic and 45 showed a median decrease of 4.5 NIHSS points (range 1–18). By univariate analysis none of the considered variables influenced the clinical outcome.ConclusionOur protocol selected patients who can safely undergo very early (<1.5 days) surgery after acute brain ischemia. Large randomized multicenter prospective trials are warranted to compare very early CEA versus best medical therapy

The DarkSide experiment

DarkSide is a dark matter direct search experiment at Laboratori Nazionali del Gran Sasso (LNGS). DarkSide is based on the detection of rare nuclear recoils possibly induced by hypothetical dark matter particles, which are supposed to be neutral, massive (m>10GeV) and weakly interactive (WIMP). The dark matter detector is a two-phase time projection chamber (TPC) filled with ultra-pure liquid argon. The TPC is placed inside a muon and a neutron active vetoes to suppress the background. Using argon as active target has many advantages, the key features are the strong discriminant power between nuclear and electron recoils, the spatial reconstruction and easy scalability to multi-tons size. At the moment DarkSide-50 is filled with ultra-pure argon, extracted from underground sources, and from April 2015 it is taking data in its final configuration. When combined with the preceding search with an atmospheric argon target, it is possible to set a 90% CL upper limit on the WIMP-nucleon spin-independent cross section of 2.0×10−44 cm2 for a WIMP mass of 100GeV/c2. The next phase of the experiment, DarkSide-20k, will be the construction of a new detector with an active mass of ∼ 20 tons

Estrogens and genomic instability in human cancer cells-involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals

This article is available open access through the publisher’s website. Copyright @ 2008 The Authors.Reports of the ability of estrogenic agents such as 17β-estradiol (E2), estriol (E3) and bisphenol A (BPA) to induce micronuclei (MN) in MCF-7 breast cancer cells have prompted us to investigate whether these effects are linked to activation of the estrogen receptor (ER) α. Coadministration of tamoxifen and the pure ER antagonist ICI 182 780 to cells treated with E2 and E3 did not lead to significant reductions in micronucleus frequencies. Since these antiestrogens interfere with the transcriptional activity of the ER and block promotion of ER-dependent gene expression, it appears that this process is not involved in micronucleus formation. However, ER activation also triggers rapid signaling via the Src/Raf/extracellular signal-regulated kinase (Erk) pathway. When MCF-7 cells were exposed to E2 and BPA in combination with the specific kinase inhibitors pyrazolopyrimidine and 2′-amino-3′-methoxyflavone, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic agents. Enhanced activation of the Src/Raf/Erk cascade disturbs the localization of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Using antikinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed, indicating that such processes are relevant to the induction of MN by estrogens. Our results suggest that estrogens induce MN by causing improper chromosome segregation, possibly by interfering with kinase signaling that controls the spindle checkpoint, or by inducing centrosome amplification. Our findings may have some relevance in explaining the effects of estrogens in the later stages of breast carcinogenesis.European Commissio

Engineered swift equilibration of a Brownian particle

A fundamental and intrinsic property of any device or natural system is its relaxation time relax, which is the time it takes to return to equilibrium after the sudden change of a control parameter [1]. Reducing $tau$ relax , is frequently necessary, and is often obtained by a complex feedback process. To overcome the limitations of such an approach, alternative methods based on driving have been recently demonstrated [2, 3], for isolated quantum and classical systems [4--9]. Their extension to open systems in contact with a thermostat is a stumbling block for applications. Here, we design a protocol,named Engineered Swift Equilibration (ESE), that shortcuts time-consuming relaxations, and we apply it to a Brownian particle trapped in an optical potential whose properties can be controlled in time. We implement the process experimentally, showing that it allows the system to reach equilibrium times faster than the natural equilibration rate. We also estimate the increase of the dissipated energy needed to get such a time reduction. The method paves the way for applications in micro and nano devices, where the reduction of operation time represents as substantial a challenge as miniaturization [10]. The concepts of equilibrium and of transformations from an equilibrium state to another, are cornerstones of thermodynamics. A textbook illustration is provided by the expansion of a gas, starting at equilibrium and expanding to reach a new equilibrium in a larger vessel. This operation can be performed either very slowly by a piston, without dissipating energy into the environment, or alternatively quickly, letting the piston freely move to reach the new volume

INVESTIGATING THE SEISMIC RESPONSE OF URM WALLS WITH IRREGULAR OPENING LAYOUT THROUGH DIFFERENT MODELING APPROACHES

The façade and internal walls of unreinforced masonry (URM) buildings often present an irregular opening layout, due to architectural reasons or modifications to the structure, which make the expected seismic damage pattern less predictable a priori. Therefore, the discretization of the walls in structural components is not standardized, conversely to cases with a regular opening layout for which the available modeling methods are corroborated by seismic damage surveys reporting recurrent failure patterns. The structural component discretization is a relevant step for the code-conforming seismic assessment, typically based on comparing the internal forces and drifts of each component to strength criteria and drift thresholds. Therefore, the lack of well-established approaches can significantly influence the assessment. The issue is even more evident when the structural components must be identified a priori in the modeling stage, namely for equivalent frame models. The applicability of available methods for discretization of URM walls with irregular opening layout has been already investigated in literature, but a conclusive judgment requires further studies. In this context, this paper presents an overview of the preliminary results addressing the numerical modeling of this type of walls within the framework of the DPC-ReLUIS 2022-2024 project (Subtask 10.3), funded by the Italian Department of Civil Protection. The Subtask aims to propose consensus-based recommendations for researchers and practitioners which can contribute to harmonize the use of different modeling approaches. Seven research groups are involved in the research, adopting different modeling approaches and computer codes, but similar assumptions and the same analysis method (pushover) are used. The benchmark URM structure illustrated in the paper is a two-story wall from which four configurations with increasing irregularity of opening layout were derived. The results of four modeling approached are presented. Three of them reproduce the mechanical response of masonry at the material scale by means of FE models implemented in OpenSees, DIANA and Abaqus software, while the remaining approach describes the mechanical response of masonry at the macro-element scale in 3DMacro software. Results were compared in terms of capacity curves, predicted failure mechanisms and evolution of internal forces in piers. The adoption of consistent assumptions among the different approaches led to an overall agreement of predictions at both wall and pier scales, particularly in terms of damage pattern with higher concentration of damage at the ground story. Despite that, differences on the pushover curves have been highlighted. They are mainly due to some deviations of the internal forces in squat piers deriving from a complex load flow in these elements

Investigating the seismic response of URM walls with irregular opening layout through different modeling approaches

TThe façade and internal walls of unreinforced masonry (URM) buildings often present an irregular opening layout, due to architectural reasons or modifications to the structure, which make the expected seismic damage pattern less predictable a priori. Therefore, the discretization of the walls in structural components is not standardized, conversely to cases with a regular opening layout for which the available modeling methods are corroborated by seismic damage surveys reporting recurrent failure patterns. The structural component discretization is a relevant step for the code-conforming seismic assessment, typically based on comparing the internal forces and drifts of each component to strength criteria and drift thresholds. Therefore, the lack of well-established approaches can significantly influence the assessment. The issue is even more evident when the structural components must be identified a priori in the modeling stage, namely for equivalent frame models. The applicability of available methods for discretization of URM walls with irregular opening layout has been already investigated in literature, but a conclusive judgment requires further studies. In this context, this paper presents an overview of the preliminary results addressing the numerical modeling of this type of walls within the framework of the DPC-ReLUIS 2022-2024 project (Subtask 10.3), funded by the Italian Department of Civil Protection. The Subtask aims to propose consensus-based recommendations for researchers and practitioners which can contribute to harmonize the use of different modeling approaches. Seven research groups are involved in the research, adopting different modeling approaches and computer codes, but similar assumptions and the same analysis method (pushover) are used. The benchmark URM structure illustrated in the paper is a two-story wall from which four configurations with increasing irregularity of opening layout were derived. The results of four modeling approached are presented. Three of them reproduce the mechanical response of masonry at the material scale by means of FE models implemented in OpenSees, DIANA and Abaqus software, while the remaining approach describes the mechanical response of masonry at the macro-element scale in 3DMacro software. Results were compared in terms of capacity curves, predicted failure mechanisms and evolution of internal forces in piers. The adoption of consistent assumptions among the different approaches led to an overall agreement of predictions at both wall and pier scales, particularly in terms of damage pattern with higher concentration of damage at the ground story. Despite that, differences on the pushover curves have been highlighted. They are mainly due to some deviations of the internal forces in squat piers deriving from a complex load flow in these elements.DPC - Dipartimento della Protezione Civile, Presidenza del Consiglio dei Ministri(LA/P/0112/2020

Integrin-Linked Kinase Overexpression and Its Oncogenic Role in Promoting Tumorigenicity of Hepatocellular Carcinoma

Background: Integrin-linked kinase (ILK) was first discovered as an integrin β1-subunit binding protein. It localizes at the focal adhesions and is involved in cytoskeleton remodeling. ILK overexpression and its dysregulated signaling cascades have been reported in many human cancers. Aberrant expression of ILK influenced a wide range of signaling pathways and cellular functions. Although ILK has been well characterized in many malignancies, its role in hepatocellular carcinoma (HCC) is still largely unknown. Methodology/Principal Findings: Quantitative PCR analysis was used to examine ILK mRNA expression in HCC clinical samples. It was shown that ILK was overexpressed in 36.9% (21/57) of HCC tissues when compared to the corresponding non-tumorous livers. The overall ILK expression level was significantly higher in tumorous tissues (P = 0.004), with a significant stepwise increase in expression level along tumor progression from tumor stage I to IV (P = 0.045). ILK knockdown stable clones were established in two HCC cell lines, BEL7402 and HLE, and were subjected to different functional assays. Knockdown of ILK significantly suppressed HCC cell growth, motility and invasion in vitro and inhibited tumorigenicity in vivo. Western blot analysis revealed a reduced phosphorylated-Akt (pAkt) at Serine-473 expression in ILK knockdown stable clones when compared to control clones. Conclusion/Significance: This study provides evidence about the clinical relevance of ILK in hepatocarcinogenesis. ILK was found to be progressively elevated along HCC progression. Here our findings also provide the first validation about the oncogenic capacity of ILK in vivo by suppressing its expression in HCC cells. The oncogenic role of ILK is implicated to be mediated by Akt pathway. © 2011 Chan et al.published_or_final_versio

Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells

Introduction Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have provided significant improvements in survival. However, their benefits are limited by tumour recurrence in a significant proportion of initially drug-responsive breast cancer patients because of acquired anti-oestrogen resistance. Relapse on such therapies clinically presents as local and/or regional recurrences, frequently with distant metastases, and the prognosis for these patients is poor. The selective ER modulator, tamoxifen, classically exerts gene inhibitory effects during the drug-responsive phase in ER-positive breast cancer cells. Paradoxically, this drug is also able to induce the expression of genes, which in the appropriate cell context may contribute to an adverse cell phenotype. Here we have investigated the effects of tamoxifen and fulvestrant treatment on invasive signalling and compared this with the direct effects of oestrogen withdrawal to mimic the action of aromatase inhibitors. Methods The effect of oestrogen and 4-hydroxy-tamoxifen on the invasive capacity of endocrine-sensitive MCF-7 cells, in the presence or absence of functional E-cadherin, was determined by Matrigel invasion assays. Studies also monitored the impact of oestrogen withdrawal or treatment with fulvestrant on cell invasion. Western blotting using phospho-specific antibodies was performed to ascertain changes in invasive signalling in response to the two anti-oestrogens versus both oestradiol treatment and withdrawal. Results To the best of our knowledge, we report for the first time that tamoxifen can promote an invasive phenotype in ER-positive breast cancer cells under conditions of poor cell-cell contact and suggest a role for Src kinase and associated pro-invasive genes in this process. Our studies revealed that although this adverse effect is also apparent for further classes of anti-oestrogens, exemplified by the steroidal agent fulvestrant, it is absent during oestrogen withdrawal. Conclusions These data highlight a previously unreported effect of tamoxifen (and potentially further anti-oestrogens), that such agents appear able to induce breast cancer cell invasion in a specific context (absence of good cell-cell contacts), where these findings may have major clinical implications for those patients with tumours that have inherently poor intercellular adhesion. In such patients oestrogen deprivation with aromatase inhibitors may be more appropriate

Trust, Salience and Deterrence: Evidence from an Antitrust Experiment

We present results from a laboratory experiment identifying the main channels through which different law enforcement strategies deter organized economic crime. The absolute level of a fine has a strong deterrence effect, even when the exogenous probability of apprehension is zero. This effect appears to be driven by distrust or fear of betrayal, as it increases significantly when the incentives to betray partners are strengthened by policies offering amnesty to “turncoat whistleblowers”. We also document a strong deterrence effect of the sum of fines paid in the past, which suggests a significant role for salience or availability heuristic in law enforcement