Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor

Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients

Multiparametric magnetic resonance imaging and clinical variables: Which is the best combination to predict reclassification in active surveillance patients?

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Does Observation of Postural Imbalance Induce a Postural Reaction?

Import JabRef | WosArea Life Sciences and Biomedicine - Other TopicsInternational audienceBackground: Several studies bring evidence that action observation elicits contagious responses during social interactions. However automatic imitative tendencies are generally inhibited and it remains unclear in which conditions mere action observation triggers motor behaviours. In this study, we addressed the question of contagious postural responses when observing human imbalance. Methodology/Principal Findings: We recorded participants' body sway while they observed a fixation cross (control condition), an upright point-light display of a gymnast balancing on a rope, and the same point-light display presented upside down. Our results showed that, when the upright stimulus was displayed prior to the inverted one, centre of pressure area and antero-posterior path length were significantly greater in the upright condition compared to the control and upside down conditions. Conclusions/Significance: These results demonstrate a contagious postural reaction suggesting a partial inefficiency of inhibitory processes. Further, kinematic information was sufficient to trigger this reaction. The difference recorded between the upright and upside down conditions indicates that the contagion effect was dependent on the integration of gravity constraints by body kinematics. Interestingly, the postural response was sensitive to habituation, and seemed to disappear when the observer was previously shown an inverted display. The motor contagion recorded here is consistent with previous work showing vegetative output during observation of an effortful movement and could indicate that lower level control facilitates contagion effects

Using a 3-tier Training Model for Effective Exchange of Good Practices in as ERASMUS+ Project

VISIR+ is an Erasmus+ project that aims to develop educational modules for electric and electronic circuits theory and practice following an enquiry-based teaching and learning methodology. The project has installed five new VISIR remote labs in Higher Education Institutions located in Argentina and Brazil, to allow students doing more experiments and hence acquire better experimental skills, through a combination of traditional (hands-on), remote and virtual laboratories. A key aspect for the success of this project was to motivate and train teachers in the underpinning educational methodology. As such, VISIR+ adopted a 3-tier training process to effectively support the use of VISIR in the Institutions that received it. This process is based on the “train the trainer” approach, which required the participating partner institutions to identify and engage a number of associated partners, interested in using their newly installed remote lab. To measure the quality of the training process, the same satisfaction questionnaire was used in all training actions. This paper presents a detailed description of the training actions along with the analysis of the satisfaction questionnaire results. Major conclusions are that the quality level of the training process remained practically the same across all training actions and that trainees sometimes considered the practical use of the VISIR remote lab as difficult, irrespectively of where and when the training action took place.info:eu-repo/semantics/publishedVersio

An Ensemble Analysis of Electromyographic Activity during Whole Body Pointing with the Use of Support Vector Machines

We explored the use of support vector machines (SVM) in order to analyze the ensemble activities of 24 postural and focal muscles recorded during a whole body pointing task. Because of the large number of variables involved in motor control studies, such multivariate methods have much to offer over the standard univariate techniques that are currently employed in the field to detect modifications. The SVM was used to uncover the principle differences underlying several variations of the task. Five variants of the task were used. An unconstrained reaching, two constrained at the focal level and two at the postural level. Using the electromyographic (EMG) data, the SVM proved capable of distinguishing all the unconstrained from the constrained conditions with a success of approximately 80% or above. In all cases, including those with focal constraints, the collective postural muscle EMGs were as good as or better than those from focal muscles for discriminating between conditions. This was unexpected especially in the case with focal constraints. In trying to rank the importance of particular features of the postural EMGs we found the maximum amplitude rather than the moment at which it occurred to be more discriminative. A classification using the muscles one at a time permitted us to identify some of the postural muscles that are significantly altered between conditions. In this case, the use of a multivariate method also permitted the use of the entire muscle EMG waveform rather than the difficult process of defining and extracting any particular variable. The best accuracy was obtained from muscles of the leg rather than from the trunk. By identifying the features that are important in discrimination, the use of the SVM permitted us to identify some of the features that are adapted when constraints are placed on a complex motor task

Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

Transperitoneal vs retroperitoneal minimally invasive partial nephrectomy: comparison of perioperative outcomes and functional follow-up in a large multi-institutional cohort (The RECORD 2 Project)

Background Aim of this study was to evaluate and compare perioperative outcomes of transperitoneal (TP) and retroperitoneal (TR) approaches in a multi-institutional cohort of minimally invasive partial nephrectomy (MI-PN). Material and methods All consecutive patients undergone MI-PN for clinical T1 renal tumors at 26 Italian centers (RECORd2 project) between 01/2013 and 12/2016 were evaluated, collecting the pre-, intra-, and postoperative data. The patients were then stratified according to the surgical approach, TP or RP. A 1:1 propensity score (PS) matching was performed to obtain homogeneous cohorts, considering the age, gender, baseline eGFR, surgical indication, clinical diameter, and PADUA score. Results 1669 patients treated with MI-PN were included in the study, 1256 and 413 undergoing TP and RP, respectively. After 1:1 PS matching according to the surgical access, 413 patients were selected from TP group to be compared with the 413 RP patients. Concerning intraoperative variables, no differences were found between the two groups in terms of surgical approach (lap/robot), extirpative technique (enucleation vs standard PN), hilar clamping, and ischemia time. Conversely, the TP group recorded a shorter median operative time in comparison with the RP group (115 vs 150 min), with a higher occurrence of intraoperative overall, 21 (5.0%) vs 9 (2.1%);p = 0.03, and surgical complications, 18 (4.3%) vs 7 (1.7%);p = 0.04. Concerning postoperative variables, the two groups resulted comparable in terms of complications, positive surgical margins and renal function, even if the RP group recorded a shorter median drainage duration and hospital length of stay (3 vs 2 for both variables),p < 0.0001. Conclusions The results of this study suggest that both TP and RP are feasible approaches when performing MI-PN, irrespectively from tumor location or surgical complexity. Notwithstanding longer operative times, RP seems to have a slighter intraoperative complication rate with earlier postoperative recovery when compared with TP