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

Dual task interference during gait in patients with unilateral vestibular disorders

<p>Abstract</p> <p>Background</p> <p>Vestibular patients show slower and unsteady gait; they have also been shown to need greater cognitive resources when carrying out balance and cognitive dual tasks (DT). This study investigated DT interference during gait in a middle-aged group of subjects with dizziness and unsteadiness after unilateral vestibular neuronitis and in a healthy control group.</p> <p>Methods</p> <p>Fourteen individuals with subacute unilateral vestibular impairment after neuronitis and seventeen healthy subjects performed gait and cognitive tasks in single and DT conditions. A statistical gait analysis system was used and spatio-temporal parameters were considered. The cognitive task, consisting of backward counting by three, was tape recorded and the number of right figures was then calculated.</p> <p>Results</p> <p>Both patients and controls showed a more conservative gait during DT and between groups significant differences were not found. A significant decrease in cognitive performance during DT was found only in the vestibular group.</p> <p>Conclusions</p> <p>Results suggest that less attentional resources are available during gait in vestibular patients compared to controls, and that a priority is given in keeping up the motor task to the detriment of a decrease of the cognitive performance during DT.</p

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

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

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 &lt; 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

Applicability of COVID-19 Pandemic recommendations for urology practice: data from three major Italian hot spots (BreBeMi)

Background: Lombardy has been the first and one of the most affected European regions during the first and second waves of the novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]).Objective: To evaluate the impact of coronavirus disease 2019 (COVID-19) on all urologic activities over a 17-wk period in the three largest public hospitals in Lombardy located in the worst hit area in Italy, and to assess the applicability of the authorities' recommendations provided for reorganising urology practice.Design, setting, and participants: A retrospective analysis of all urologic activities performed at three major public hospitals in Lombardy (Brescia, Bergamo, and Milan), from January 1 to April 28, 2020, was performed.Outcome measurements and statistical analysis: Join-point regression was used to identify significant changes in trends for all urologic activities. Average weekly percentage changes (AWPCs) were estimated to summarise linear trends. Uro-oncologic surgeries performed during the pandemic were tabulated and stratified according to the first preliminary recommendations by Stensland et al (Stensland KD, Morgan TM, Moinzadeh A, et al. Considerations in the triage of urologic surgeries during the COVID-19 pandemic. Eur Urol 2020;77:663-6) and according to the level of priority recommended by European Association of Urology guidelines.Results and limitations: The trend for 2020 urologic activities decreased constantly from weeks 8-9 up to weeks 11-13 (AWPC range -41%, -29.9%; p < 0.001). One-third of uro-oncologic surgeries performed were treatments that could have been postponed, according to the preliminary urologic recommendations. High applicability to recommendations was observed for non-muscle-invasive bladder cancer (NMIBC) patients with intermediate/emergency level of priority, penile and testicular cancer patients, and upper tract urothelial cell carcinoma (UTUC) and renal cell carcinoma (RCC) patients with intermediate level of priority. Low applicability was observed for NMIBC patients with low/high level of priority, UTUC patients with high level of priority, prostate cancer patients with intermediate/high level of priority, and RCC patients with low level of priority.Conclusions: During COVID-19, we found a reduction in all urologic activities. High-priority surgeries and timing of treatment recommended by the authorities require adaptation according to hospital resources and local incidence.Patient summary: We assessed the urologic surgeries that were privileged during the first wave of coronavirus disease 2019 (COVID-19) in the three largest public hospitals in Lombardy, worst hit by the pandemic, to evaluate whether high-priority surgeries and timing of treatment recommended by the authorities are applicable. Pandemic recommendations provided by experts should be tailored according to hospital capacity and different levels of the pandemic. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology

Postural control anomalies in children with Tourette syndrome

The goal of the present study was to determine whether postural control is affected in Gilles-de-la-Tourette syndrome (TS). Center of pressure (COP) displacements were recorded in children with TS and unaffected siblings (7-16 yrs) in three conditions using a force platform: 1) Eyes-Open, 2) Eyes-Closed, 3) One-Leg standing with eyes open. The COP range and velocity were higher in children with TS than in unaffected siblings in all conditions. These differences could not be attributed to age, present tic severity, comorbidities (hyperactivity and compulsions) or medication. The data suggest that sub-clinical postural control anomalies are present in TS