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Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0–1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0–84·4) patients achieved an objective response (complete or partial response). The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Pfizer Inc.

Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Pfizer Inc.

We investigate information processing in randomly connected recurrent neural networks. It has been shown previously that the computational capabilities of these networks are maximized when the recurrent layer is close to the border between a stable and an unstable dynamics regime, the so called edge of chaos . The reasons, however, for this maximized performance are not completely understood. We adopt an information-theoretical framework and are for the first time able to quantify the computational capabilities between elements of these networks directly as they undergo the phase transition to chaos. Specifically, we present evidence that both information transfer and storage in the recurrent layer are maximized close to this phase transition, providing an explanation for why guiding the recurrent layer toward the edge of chaos is computationally useful. As a consequence, our study suggests self-organized ways of improving performance in recurrent neural networks, driven by input data. Moreover, the networks we study share important features with biological systems such as feedback connections and online computation on input streams. A key example is the cerebral cortex, which was shown to also operate close to the edge of chaos. Consequently, the behavior of model systems as studied here is likely to shed light on reasons why biological systems are tuned into this specific regime.

Incipience of plastic flow in nanoporous metals under tension is an important point for the development of mechanical models of dynamic (spall) fracture. Here we study axisymmetric deformation with tension of nanoporous aluminum with different shapes and sizes of nanopores by means of molecular dynamics (MD) simulations. Random deformation paths explore a sector of tensile loading in the deformation space. The obtained MD data are used to train an artificial neural network (ANN), which approximates both an elastic stress–strain relationship in the form of tensor equation of state and a nucleation strain distance function. This ANN allows us to describe the elastic stage of deformation and the transition to the plastic flow, while the following plastic deformation and growth of pores are described by means of a kinetic model of plasticity and fracture. The parameters of this plasticity and fracture model are identified by the statistical Bayesian approach, using MD curves as the training data set. The present research uses a machine-learning-based approximation of MD data to propose a possible framework for construction of mechanical models of spall fracture in metals.

Sorafenib was FDA approved in 2005 for treatment of renal cell carcinoma (RCC) based on the results of the pivotal phase 3 clinical trial, TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial). Since that time, numerous clinical studies have been undertaken that substantially broaden our knowledge of the use of sorafenib for this indication. We systematically reviewed PubMed, Web of Science, Embase, Cochrane Library, and www.clinicaltrials.gov for prospective clinical studies using single agent sorafenib in RCC and published since 2005. Primary endpoints of interest were progression-free survival (PFS) and safety. PROSPERO International prospective register of systematic reviews #CRD42014010765. We identified 30 studies in which 2182 patients were treated with sorafenib, including 1575 patients who participated in randomized controlled phase 3 trials. In these trials, sorafenib was administered as first-, second- or third-line treatment. Heterogeneity among trial designs and reporting of data precluded statistical comparisons among trials or with TARGET. The PFS appeared shorter in second- vs. first-line treatment, consistent with the more advanced tumor status in the second-line setting. In some trials, incidences of grade 3/4 hypertension or hand-foot skin reaction (HFSR) were more than double that seen in TARGET (4% and 6%, respectively). These variances may be attributable to increased recognition of HFSR, or potentially differences in dose adjustments, that could be consequences of increased familiarity with sorafenib usage. Several small studies enrolled exclusively Asian patients. These studies reported notably longer PFS than was observed in TARGET. However, no obvious corresponding differences in disease control rate and overall survival were seen. Collectively, more recent experiences using sorafenib in RCC are consistent with results reported for TARGET with no marked changes of response endpoints or new safety signals observed.

In this study, we formulate a mechanical model of spall fracture of copper, which describes both solid and molten states. The model is verified, and its parameters are found based on the data of molecular dynamics simulations of this process under ultrahigh strain rate of tension, leading to the formation of multiple pores within the considered volume element. A machine-learning-type Bayesian algorithm is used to identify the optimal parameters of the model. We also analyze the influence of the initial size distribution of pores or non-wettable inclusions in copper on the strain rate dependence of its spall strength and show that these initial heterogeneities explain the existing experimental data for moderate strain rates. This investigation promotes the development of atomistically-based machine learning approaches to description of the strength properties of metals and deepens the understanding of the spall fracture process.

Background Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. Methods Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIM SM database. Patient characteristics, toxicity and efficacy were analyzed. Results A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. Conclusion In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.

IntroductionThe coronavirus pandemic has led to sudden changes in the lives of people around the world. The health threat, earthquakes and epidemiological measures caused certain psychological reactions in everyone. Psychiatric patients are particularly vulnerable to stress, so we were interested in how the changes at the beginning of the pandemic affected their psychological functioning.ObjectivesTo check changes in some areas of psychological functioning of outpatient psychiatric patients after the “lockdown” in 2020 and to examine their connection with some sociodemographic and treatment variables.MethodsPatients of the University Psychiatric Hospital Sveti Ivan filled out a survey questionnaire designed for the purpose of research, which consisted of sociodemographic data and items examining different areas of psychological functioning, when they arrived for an outpatient check-up.ResultsVariables were formed that examine: changes in unpleasant emotions, lack of support, lack of social interaction, changes in performing daily duties, changes in self-help behaviors and health concerns. Statistical analysis showed a significant increase in all variables, with the largest occurring in lack of social interaction, health concerns, and unpleasant emotions. The predictors of changes in psychological functioning were female gender, younger age in combination with cohabitation with parents, and the number of hospitalizations.ConclusionsAfter the “lockdown” in 2020, psychiatric patients report a deterioration in psychological functioning.Disclosure of InterestNone Declared

Taylor impact tests involving the collision of a cylindrical sample with an anvil are widely used to study the dynamic properties of materials and to test numerical methods. We apply a combined experimental-numerical approach to study the dynamic plasticity of cold-rolled oxygen-free high thermal conductivity OFHC copper. In the experimental part, impact velocities up to 113.6 m/s provide a strain up to 0.3 and strain rates up to 1.7 × 104 s−1 at the edge of the sample. Microstructural analysis allows us to find out pore-like structures with a size of about 15–30 µm and significant refinement of the grain structure in the deformed parts of the sample. In terms of modeling, the dislocation plasticity model, which was previously tested for the problem of a shock wave upon impact of a plate, is implemented in the 3D case using the numerical scheme of smoothed particle hydrodynamics (SPH). The model includes an equation of state implemented in the form of an artificial neural network (ANN) and trained according to molecular dynamics (MD) simulations of uniform isothermal stretching/compression of representative volumes of copper. The dislocation friction coefficient is taken from previous MD simulations. These two efforts are aimed at building a fully MD-based material model. Comparison of the final shape of the projectile, the reduction of the sample length and increase in the diameter of the impacted edge of the sample confirm the applicability of the developed model and allow us to optimize the model parameters for the case of cold-rolled OFHC copper.

One of the desired traits in rootstocks for stone fruits is tolerance to abiotic stresses, such as water deficit, which is one of the factors associated to peach tree short life syndrome that constitutes one of the main agronomic problems in Rio Grande do Sul’s peach cultivation. This research aimed to discern the rootstock that best sustain water status and influences proline synthesis regulation in seven-year-old ‘BRS-Kampai’ peach trees grown non-irrigated sandy soil during the post-harvest period. Stem water potential in ‘BRS-Kampai’ peach trees was distinctly affected by the choice of rootstock, revealing heightened sensitivity to soil moisture depletion and atmospheric vapor pressure deficit escalation. When confronted with reduced gravimetric soil moisture (<7.0%), ‘BRS-Kampai’ peach trees grafted onto Clone 15 ( Prunus mume ) exhibited less negative stem water potential and higher leaf proline content, indicative of physiological adjustment to edaphoclimatic conditions. Conversely, ‘BRS-Kampai’ peach trees graffet onto ‘Flordaguard’ displayed increased vegetative growth. Notably, ‘BRS-Kampai’ own-rooted trees exhibited stem growth, leaf proline contents, and stem water potential similar to those of peach trees grafted onto ‘Capdeboscq’, thereby demonstrating robust adaptation to prevailing edaphoclimatic conditions.