Explore the vast range of titles available.

Wine micro-oxygenation is a globally used treatment and its effects were studied here by analysing by untargeted LC-MS the wine metabolomic fingerprint. Eight different procedural variations, marked by the addition of oxygen (four levels) and iron (two levels) were applied to Sangiovese wine, before and after malolactic fermentation. Data analysis using supervised and unsupervised multivariate methods highlighted some known candidate biomarkers, together with a number of metabolites which had never previously been considered as possible biomarkers for wine micro-oxygenation. Various pigments and tannins were identified among the known candidate biomarkers. Additional new information was obtained suggesting a correlation between oxygen doses and metal contents and changes in the concentration of primary metabolites such as arginine, proline, tryptophan and raffinose, and secondary metabolites such as succinic acid and xanthine. Based on these findings, new hypotheses regarding the formation and reactivity of wine pigment during micro-oxygenation have been proposed. This experiment highlights the feasibility of using unbiased, untargeted metabolomic fingerprinting to improve our understanding of wine chemistry.

Abstract Background Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date. Methods Here we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism. Results Palbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions. Conclusions Combination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.

Background and purposeFlow diversion is an innovative and increasingly used endovascular treatment for intracranial aneurysms. Its initial evaluation with the first devices available showed good efficacy of this treatment with variable safety results. The Flow Direction Endoluminal Device (FRED) has a specific design and was evaluated in a single-arm, multicenter, prospective, Good Clinical Practice study: SAFE (Safety and efficacy Analysis of FRED Embolic device in aneurysm treatment). This analysis reports clinical results at 1 year and anatomical results at 6 months and 1 year.MethodsPatients with unruptured and recanalized aneurysms located in the anterior circulation treated with FRED and FRED Jr were prospectively included. A Clinical Event Committee and a Core Laboratory independently evaluated clinical outcome and anatomical results.ResultsThirteen interventional neuroradiology centers included 103 patients/aneurysms. Aneurysm locations were supraclinoid internal carotid artery (ICA) in 71 (68.9%), cavernous ICA in 15 (14.6%), anterior cerebral or anterior communicating artery in 9 (8.7%), and middle cerebral artery in 8 (7.8%). Most aneurysms were small (<10 mm) in 71 patients (68.9%). Cumulative 1-year mortality and morbidity rates were 2/103 (1.9%) and 3/103 (2.9%), respectively, one death being related to cancer. At 1 year, anatomical results were: complete occlusion in 66/90 patients (73.3%), neck remnant in 7/90 patients (7.8%), and aneurysm remnant in 17/90 patients (18.9%).ConclusionsSAFE study analysis at 1 year confirms the excellent safety profile of the FRED device for aneurysm treatment, with low morbidity and mortality rates (2.9% and 1.9%, respectively) and demonstrates its efficacy (adequate occlusion in 73/90 (81.1%)).Clinical trial registrationUnique identifier: NCT02921698; Results.

The importance of the immune system as a potent anti-tumor defense has been consolidated in recent times, and novel immune-related therapies are today demonstrating a strong clinical benefit in the setting of several solid neoplasms. Tumor-infiltrating lymphocytes reflect the attempt of the host to eradicate malignancies, and during the last decades, they have been shown to possess an interesting prognostic utility for breast cancer, especially in case of HER2 positive and triple-negative molecular subtypes. In parallel, the clinical evaluation of tumor-infiltrating lymphocytes has been shown to effectively predict treatment outcomes in both neoadjuvant and adjuvant settings. Currently, tumor-infiltrating lymphocytes are promising further predictive utility in view of novel immune-related therapeutic strategies which are coming into the clinical setting launching a solid rationale for the future next-generation treatment options. In this scenario, tumor-infiltrating lymphocytes might represent an important resource for the selection of the most appropriate therapeutic strategy, as well as further evaluations of the molecular mechanisms underlying tumor-infiltrating lymphocytes and the immunoediting process would eventually provide new insights to augment therapeutic success. Considering these perspectives, we review the potential utility of tumor-infiltrating lymphocytes in the definition of breast cancer prognosis and in the prediction of treatment outcomes, along with the new promising molecular-based therapeutic discoveries.

Background Flow diverter devices (FDDs) have revolutionized the treatment of intracranial aneurysms. However, comprehensive long-term outcome data across multiple device platforms remain limited, with most prior studies focusing exclusively on Pipeline embolization device (PED) outcomes. This study reports extensive long-term clinical follow-up of patients treated with various types of FDDs, providing critical safety and efficacy data for contemporary practice. Methods We conducted a retrospective analysis of intracranial aneurysms treated with FDDs from February 2011 to July 2016 in two tertiary care centers in France. The study included 209 patients with 216 cerebral aneurysms (91.2% anterior circulation, 8.8% posterior circulation; 66.2% unruptured, 31.0% recanalized, 2.8% ruptured). The duration of clinical and angiographic follow-up ranged from 24 to 156 months. Kaplan–Meier analysis performed for complication-free survival and aneurysm occlusion durability. Multivariate analysis showed risk factors for delayed complications. Results Long-term follow-up data were available for 202/209 (96.7%) patients. The early permanent morbidity and mortality rates were 3.8% and 1.4%, respectively. Between 12 and 18 months, procedure-related complications occurred in 5 of 202 patients (2.5%): two ischemic events, one delayed rupture, one silent intrastent stenosis, and one case of seizures following antiplatelet withdrawal. Only three patients (1.5%) were symptomatic. At the 24-month follow-up, complete aneurysm occlusion achieved in 81.0% of the patients, with adequate occlusion in 93.3%. Kaplan–Meier analysis revealed 97.5% complication-free survival at 18 months, with sustained durability thereafter. Multiple FDDs were the only significant independent predictor of delayed complications (OR: 7.066, 95% CI: 1.049–47.606, P  < 0.045). No procedure-related complications or deaths occurred after 18 months. Conclusion Beyond 18 months of follow-up, FDD treatment for intracranial aneurysms proves exceptional safety with no delayed complications, regardless of device type. However, the findings of this study also show 18 months as a critical threshold for complication risk assessment, a key implication that clinicians and researchers need to be aware of. The study also underscores the need for modified management strategies when multiple overlapping FDDs are deployed, which significantly increases the risk of delayed complications.

The passing of time can be precisely measured by using clocks, whereas humans’ estimation of temporal durations is influenced by many physical, cognitive and contextual factors, which distort our internal clock. Although it has been shown that temporal estimation accuracy is impaired by non-temporal tasks performed at the same time, no studies have investigated how concurrent cognitive and motor tasks interfere with time estimation. Moreover, most experiments only tested time intervals of a few seconds. In the present study, participants were asked to perform cognitive tasks of different difficulties (look, read, solve simple and hard mathematical operations) and estimate durations of up to two minutes, while walking or sitting. The results show that if observers pay attention only to time without performing any other mental task, they tend to overestimate the durations. Meanwhile, the more difficult the concurrent task, the more they tend to underestimate the time. These distortions are even more pronounced when observers are walking. Estimation biases and uncertainties change differently with durations depending on the task, consistent with a fixed relative uncertainty. Our findings show that cognitive and motor systems interact non-linearly and interfere with time perception processes, suggesting that they all compete for the same resources.

Objective Selected patients with large vessel occlusion (LVO) strokes can benefit from endovascular therapy (EVT). However, the effectiveness of EVT is largely dependent on how quickly the patient receives treatment. Recent technological developments have led to the first neurointerventional treatments using robotic assistance, opening up the possibility of performing remote stroke interventions. Existing telestroke networks provide acute stroke care, including remote administration of intravenous thrombolysis (IVT). Therefore, the introduction of remote EVT in distant stroke centers requires an adaptation of the existing telestroke networks. The aim of this work was to propose a framework for centers that are potential candidates for telerobotics according to the resources currently available in these centers. Methods In this paper, we highlight the future challenges for including remote robotics in telestroke networks. A literature review provides potential solutions. Results Existing telestroke networks need to determine which centers to prioritize for remote robotic technologies based on objective criteria and cost-effectiveness analysis. Organizational challenges include regional coordination and specific protocols. Technological challenges mainly concern telecommunication networks. Conclusions Specific adaptations will be necessary if regional telestroke networks are to include remote robotics. Some of these can already be put in place, which could greatly help the future implementation of the technology.

Introduction Hybrid hydrogel-platinum coils (HydroCoil) have proven effective for endovascular aneurysm treatment. To overcome technical limitations (coil stiffness, time restriction for placement), a second generation of softer hydrogel coils has been brought to clinical practice (HydroSoft, HydroFrame). We report on procedural safety and core-lab-assessed angiographic results from an open-label multicenter randomized controlled trial. Methods Web-based randomization occurred in 15 medical centers in France and seven in Germany between coil embolization with second-generation hydrogel coils and treatment with any bare platinum coil. Assist devices could be used as clinically required. Primary endpoint is a composite outcome including major aneurysm recurrence and poor clinical outcome at 18 months follow-up. Results Five hundred thirteen patients were randomized (hydrogel n  = 256, bare platinum n  = 257). Twenty patients were excluded for missing informed consent and nine patients for treatment related criteria. Four hundred eighty-four patients were analyzed as randomized (hydrogel n  = 243, bare platinum n  = 241). Two hundred eight had ruptured aneurysms (43 %). Prespecified procedural complications occurred in 58 subjects (hydrogel n  = 28, bare platinum n  = 30, p  = 0.77). The 14-day mortality rate was 2.1 % in both arms of the study. The median calculated packing densities for aneurysms assigned to hydrogel and bare platinum were 39 and 31 % respectively ( p  < 0.001). No statistically significant differences were found between arms in the post procedural angiographic occlusion rate ( p  = 0.8). Conclusion Second-generation hydrogel coils can be used in a wide spectrum of aneurysms with a risk profile equivalent to bare platinum. Packing density was significantly higher in aneurysms treated with hydrogel coils. Trial registration http://www.germanctr.de , DRKS00003132

Abstract BACKGROUND: Bifurcation middle cerebral artery (MCA) aneurysms with wide neck are amenable to endovascular coiling with pCONus stent, a recent device dedicated to wide-neck bifurcation intracranial aneurysms. OBJECTIVE: To evaluate the 1-year angiographic follow-up of wide-neck MCA aneurysms treated with pCONus. METHODS: Forty MCA aneurysms (mean dome size, 7.7 mm; mean neck size, 5.6 mm) coiled with pCONus were retrospectively evaluated. “Recanalization” was defined as worsening, and “progressive thrombosis” was defined as improvement on the Raymond scale. RESULTS: Angiographic midterm (mean, 11.9 months; range, 3-20) follow-up was obtained in all aneurysms. Retreatment was performed in 9 aneurysms (22.5%) without clinical complications, and postoperative angiographic outcome included 2 complete occlusions and 7 neck remnants. Six aneurysms were followed after retreatment (mean, 8.8 months), and presented complete occlusion in 1 case, neck remnant in 4 cases, and aneurysm remnant in 1 case. Among the 31 aneurysms, follow-up showed complete occlusion in 67.7% (21/31), neck remnants in 29% (9/31), and aneurysm remnants in 3.3% (1/31). Adequate aneurysm occlusion (total occlusion and neck remnant) was obtained in 96.7% (30/31). Among these 31 aneurysms, improvement of the rate of occlusion was observed in 15 aneurysms (48.4%), and recurrence in 2 aneurysms (6.5%). There was no 1-year angiographic recurrence of 3- or 6-month totally occluded aneurysms. CONCLUSION: pCONus stent allows a safe coiling of wide-neck MCA aneurysms usually considered as surgical with a low recanalization rate for those adequately occluded at 3 to 6 months. Angiographic results improve over time due to progressive aneurysm thrombosis in around 50% of cases.