Phase 1 dose escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer-Lack of association between activating AKT mutation and AKT inhibition-derived efficacy

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring th

Pair neutron transfer in Ni 60 + Sn 116 probed via γ -particle coincidences

D. Montanari et al. ; 6 págs.; 5 figs.; 1 tab.We performed a γ-particle coincidence experiment for the Ni60+Sn116 system to investigate whether the population of the two-neutron pickup channel leading to Ni62 is mainly concentrated in the ground-state transition, as has been found in a previous work [D. Montanari et al., Phys. Rev. Lett. 113, 052501 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.052501]. The experiment has been performed by employing the PRISMA magnetic spectrometer coupled to the Advanced Gamma Tracking Array (AGATA) demonstrator. The strength distribution of excited states corresponding to the inelastic, one- and two-neutron transfer channels has been extracted. We found that in the two-neutron transfer channel the strength to excited states corresponds to a fraction (less than 24%) of the total, consistent with the previously obtained results that the 2n channel is dominated by the ground-state to ground-state transition. ©2016 American Physical SocietyThis work was partly supported by the EU FP7/2007-2013 under Grant No. 262010-ENSAR and by the Croatian Science Foundation under Project No. 7194. A.G. was partially supported by MINECO and Generalitat Valenciana, Spain, under Grants No. FPA2014-57196-C5 and No. PROMETEOII/2014/019 and the EU under the FEDER program.Peer Reviewe

Polyelectrolyte/surfactant films: from 2D to 3D structural control

Reversible control of the 3D structure of polyelectrolyte/surfactant films at the air/water interface is showcased. A recently discovered mechanism is exploited to form highly efficient, stable and biocompatible films by spreading aggregates composed of poly-L-lysine and sodium dodecyl sulfate on the surface of water. Reversible control of: (1) the surface monolayer coverage, (2) the switching on or off discrete extended structures, and (3) the extended structure coverage is demonstrated for the first time. The intricacy by which the film structures can be controlled is unprecedented and opens exciting potential to optimize film properties by chemical design for novel biomedical transfer applications.We thank the Institut Laue-Langevin for beam time on FIGARO (DOIs: https://doi.org/10.5291/ILL-DATA.9-12-614 and https://doi.org/10.5291/ILL-DATA.9-12-631), Simon Wood for technical assistance and the Partnership for Soft Condensed Matter (PSCM) for lab support. IV acknowledges the financial support from the Hungarian National Research, Development and Innovation Office (NKFIH K116629). AM acknowledges the financial support from MICINN under grant PID2021-129054NA-I00 and the IKUR Strategy of the Basque Government.Peer reviewe

The psychological consequences of the ecological crisis: Three new questionnaires to assess eco-anxiety, eco-guilt, and ecological grief

As climate change develops reactions such as eco-anxiety, eco-guilt and ecological grief are becoming increasingly common. Our aim was to develop questionnaires to assess these psychological consequences, and to examine their relationship with pro-environmental behavior (PEB). Items of the questionnaires were generated based on literature review and the qualitative analysis of semi-structured interviews (N = 17). The first item pool was administered to a large adult sample (N = 4608) along with assessing PEB. The Eco-Guilt Questionnaire (EGuiQ-11) and the Ecological Grief Questionnaire (EGriQ-6) each had a one-factor structure, while the Eco-Anxiety Questionnaire (EAQ-22) consisted of two factors: habitual ecological worry and the negative consequences of eco-anxiety. The factors were positively associated with PEB. The questionnaires had a robust factor structure, and they are suitable for the assessment of a wide range of negative emotional states related to climate change and the ecological crisis. Our results indicate the possible utility of negative emotions in reinforcing PEB

Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

Improved Characterization of EV Preparations Based on Protein to Lipid Ratio and Lipid Properties.

In recent years the study of extracellular vesicles has gathered much scientific and clinical interest. As the field is expanding, it is becoming clear that better methods for characterization and quantification of extracellular vesicles as well as better standards to compare studies are warranted. The goal of the present work was to find improved parameters to characterize extracellular vesicle preparations. Here we introduce a simple 96 well plate-based total lipid assay for determination of lipid content and protein to lipid ratios of extracellular vesicle preparations from various myeloid and lymphoid cell lines as well as blood plasma. These preparations included apoptotic bodies, microvesicles/microparticles, and exosomes isolated by size-based fractionation. We also investigated lipid bilayer order of extracellular vesicle subpopulations using Di-4-ANEPPDHQ lipid probe, and lipid composition using affinity reagents to clustered cholesterol (monoclonal anti-cholesterol antibody) and ganglioside GM1 (cholera toxin subunit B). We have consistently found different protein to lipid ratios characteristic for the investigated extracellular vesicle subpopulations which were substantially altered in the case of vesicular damage or protein contamination. Spectral ratiometric imaging and flow cytometric analysis also revealed marked differences between the various vesicle populations in their lipid order and their clustered membrane cholesterol and GM1 content. Our study introduces for the first time a simple and readily available lipid assay to complement the widely used protein assays in order to better characterize extracellular vesicle preparations. Besides differentiating extracellular vesicle subpopulations, the novel parameters introduced in this work (protein to lipid ratio, lipid bilayer order, and lipid composition), may prove useful for quality control of extracellular vesicle related basic and clinical studies

Brightness and mass accretion rate evolution during the 2022 burst of EX~Lupi

EX Lupi is the prototype by which EXor-type outbursts were defined. It has experienced multiple accretion-related bursts and outbursts throughout the last decades, whose study have greatly extended our knowledge about the effects of these types of events. This star experienced a new burst in 2022. We used multi-band photometry to create color-color and color-magnitude diagrams to exclude the possibility that the brightening could be explained by a decrease in extinction. We obtained VLT/X-shooter spectra to determine the Lacc and Macc during the peak of the burst and after its return to quiescence using 2 methods: empirical relationships between line luminosity and Lacc, and a slab model of the whole spectrum. We examined the 130 year light curve of EX Lupi to provide statistics on the number of outbursts experienced during this period of time. Our analysis of the data taken during the 2022 burst confirmed that a change in extinction is not responsible for the brightening. Our two approaches in calculating the Macc were in agreement, and resulted in values that are 2 orders of magnitude above what had previously been estimated, thus suggesting that EX Lupi is a strong accretor even when in quiescence. We determined that in 2022 March the Macc increased by a factor of 7 with respect to the quiescent level. We also found hints that even though the Macc had returned to almost its pre-outburst levels, certain physical properties of the gas had not returned to the quiescent values. We found that the mass accreted during this three month event was 0.8 lunar masses, which is approximately half of what is accreted during a year of quiescence. We calculated that if EX Lupi remains as active as it has been for the past 130 years, during which it has experienced at least 3 outbursts and 10 bursts, then it will deplete the mass of its circumstellar material in less than 160000 yr

An appraisal: How notifiable infectious diseases are reported by Hungarian family physicians

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