▶ Differential ability of GSK-3 inhibitors to decrease enzymatic activity of GSK-3. ▶ SB-216763 and kenpaullone interfere with GSK-3 mediated signaling. ▶ Potent GSK-3 inhibition increases ...neurogenesis of human neural progenitors. ▶ Potent GSK-3 inhibition does not affect cell cycle exit or cell survival.
Human neural progenitor cells provide a source for cell replacement therapy to treat neurodegenerative diseases. Therefore, there is great interest in mechanisms and tools to direct the fate of multipotent progenitor cells during their differentiation to increase the yield of a desired cell type. We tested small molecule inhibitors of glycogen synthase kinase-3 (GSK-3) for their functionality and their influence on neurogenesis using the human neural progenitor cell line ReNcell VM. Here we report the enhancement of neurogenesis of human neural progenitor cells by treatment with GSK-3 inhibitors. We tested different small molecule inhibitors of GSK-3 i.e. LiCl, sodium–valproate, kenpaullone, indirubin-3-monoxime and SB-216763 for their ability to inhibit GSK-3 in human neural progenitor cells. The highest in situ GSK-3 inhibitory effect of the drugs was found for kenpaullone and SB-216763. Accordingly, kenpaullone and SB-216763 were the only drugs tested in this study to stimulate the Wnt/β-catenin pathway that is antagonized by GSK-3. Analysis of human neural progenitor differentiation revealed an augmentation of neurogenesis by SB-216763 and kenpaullone, without changing cell cycle exit or cell survival. Small molecule inhibitors of GSK-3 enhance neurogenesis of human neural progenitor cells and may be used to direct the differentiation of neural stem and progenitor cells in therapeutic applications.
For adjuvant radiotherapy of low-risk breast cancer after breast-conserving surgery, there have been many trials of hypofractionation and partial breast irradiation (PBI) over the years, with proven ...mild long-term toxicity. The aim of this study was to introduce a short-course dose-adapted concept, proven in whole breast irradiation (WBI) for use in accelerated partial breast irradiation (APBI), while monitoring dosimetric data and toxicity.
From April 2020 to March 2022, 61 patients with low-risk breast cancer or ductal carcinoma in situ (DCIS) were treated at a single institution with percutaneous APBI of 26 Gy in five fractions every other day after breast-conserving surgery. Dosimetric data for target volume and organs at risk were determined retrospectively. Acute toxicity was evaluated.
The target volume of radiotherapy comprised an average of 19% of the ipsilateral mamma. The burden on the heart and lungs was very low. The mean cardiac dose during irradiation of the left breast was only 0.6 Gy. Two out of three patients remained without any acute side effects.
Linac-based APBI is an attractive treatment option for patients with low-risk breast cancer in whom neither WBI nor complete omission of radiotherapy appears to be an adequate alternative.
Air quality measurements usually consist of ground-based instrumentation at fixed locations. However, vertical profiles of pollutants are of interest for understanding processes, distribution, ...dilution and concentration. Therefore, a multicopter system has been developed to investigate the vertical distribution of the concentration of aerosol particles, black carbon, ozone, nitrogen oxides (NOx) and carbon monoxide and the meteorological parameters of temperature and humidity. This article presents the requirements by different users, the setup of the quadrocopter system, the instrumentation and the results of first applications. The vertical distribution of particulate matter next to a highway was strongly related to atmospheric stratification, with different concentrations below and above the temperature inversion present in the morning. After the qualification phase described in this article, two identically equipped multicopters will be used upwind and downwind of line or diffuse sources such as highways or urban areas to quantify the influence of their emissions on the local air quality.
ZusammenfassungDie adjuvante Strahlentherapie ist integraler Bestandteil der multimodalen Therapie des frühen Mammakarzinoms. Sie trägt über alle Erkrankungsstadien zur Reduktion von Lokalrezidiven ...bei. Die (moderat) hypofraktionierte Ganzbrustbestrahlung ist Behandlungsstandard. In der Niedrigrisikosituation kann eine Teilbrustbestrahlung erfolgen. Die Indikation zur adjuvanten Bestrahlung nach Mastektomie bzw. zu einer zusätzlichen Lymphabflussbestrahlung richtet sich nach dem jeweiligen Risikoprofil der Patientin. Langzeitergebnisse von Therapiestudien und die Weiterentwicklung von Bestrahlungstechniken ermöglichen heute zeitlich abgekürzte, individualisierte und gut verträgliche Behandlungen mit dem Ziel der Therapiedeeskalation.
A particle-filter-based inversion system is presented, which enables us to derive time- and altitude-resolved volcanic ash emission fluxes along with its uncertainty. The system assimilates ...observations of volcanic ash column mass loading as retrieved from geostationary satellites. It aims to estimate the temporally varying emission profile endowed with error margins. In addition, we analyze the dependency of our estimate on wind field characteristics, notably vertical shear, within variable observation intervals. Thus, the proposed system addresses the special challenge of analyzing the vertical profile of volcanic ash clouds given only 2D high temporal-resolution column mass loading data as retrieved by geostationary satellites. The underlying method rests on a linear combination of height–time emission finite elements of arbitrary resolution, each of which is assigned to a model run subject to ensemble-based space–time source inversion. Employing a modular concept, this setup builds the Ensemble for Stochastic Integration of Atmospheric Simulations (ESIAS-chem). It comprises a particle smoother in combination with a discrete-grid ensemble extension of the Nelder–Mead minimization method. The ensemble version of the EURopean Air pollution Dispersion – Inverse Model (EURAD-IM) is integrated into ESIAS-chem but can be replaced by other models. As initial validation of ESIAS-chem, the system is applied to simulated artificial observations of both ash-contaminated and ash-free atmospheric columns using identical-twin experiments. Thus, in this idealized initial performance test the underlying meteorological uncertainty is neglected. The inversion system is applied to two notional sub-Plinian eruptions of the Eyjafjallajökull volcano, Iceland, with strong ash emission changes with time and injection heights. It demonstrates the ability of ESIAS-chem to retrieve the volcanic ash emission fluxes from the assimilation of column mass loading data only. However, the analyzed emission profiles strongly differ in their levels of accuracy depending of the strength of wind shear conditions. While the error is only 10 %–20 % for the estimated emission fluxes under strong wind conditions, it increases up to 60 % under weak wind shear conditions. In case of increasing wind shear, the performance of the analysis may benefit from extending the assimilation window, in which new observations potentially contribute valuable information to the analysis system. For our test cases using an artificial volcanic eruption, we found an assimilation window length of 18 h, i.e., 10 h after the eruption terminated, to be sufficient for analyzing the extent and location of the artificial ash cloud. In the performed test cases, the analysis ensemble predicts the location of high volcanic ash column mass loading in the atmosphere with a very high probability of > 95 %. Additionally, the analysis ensemble is able to provide a vertically resolved probability map of high volcanic ash concentrations to a high accuracy for both high and weak wind shear conditions.
Although anthropogenic emissions have decreased during the last 2 decades, air pollution is still problematic in Europe. This study analyzes the air quality in Europe using simulations by EURopean ...Air pollution Dispersion—Inverse Model for the year 2016 with updated emissions in view of the annual guideline levels for particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) released in 2021 by the World Health Organization (WHO). Three different emission scenarios are applied, including a scenario for the committed emission reductions from the European Union (EU), a scenario including additional reductions to specifically mitigate PM2.5, and a scenario in which all anthropogenic emissions are eliminated. Model results show that in Europe, the concentrations of PM2.5 and NO2 exceed the annual WHO guideline levels by up to a factor of 5.6 and 5.2, respectively, in the main polluted regions and by up to a factor of 2 for O3 in Southern Europe. High concentrations of PM2.5 and O3 are homogeneously distributed across Europe with 99% and 100% of the European population exposed to concentrations above the WHO guideline levels, respectively. NO2 concentrations above the annual WHO guideline level are primarily found in populated areas, affecting 323 million inhabitants in 2016. Although the emission scenario designed to mitigate PM2.5 shows a decrease of the highest annual mean concentrations of PM2.5 from 28 µgm−3 to 12 µgm−3, 527 million European inhabitants remain affected by PM2.5 annual mean concentrations above the WHO guideline level. Seasonal mean O3 concentrations after eliminating all anthropogenic emissions (between 60 and 82 µgm−3) are found to be above the WHO guideline level for the entire European continent. The mortality attributable to air pollution is reduced by 47% in the emission scenario for committed emissions by the EU. In the more aggressive scenario designed to mitigate PM2.5, the mortality is reduced by 72%. The study reveals that the emission scenarios and, therefore, the reduction in premature deaths are subject to sectoral emission reductions between 41% and 79%.
We present a high-resolution air quality study over São Paulo, Brazil with the EURopean Air Pollution Dispersion - Inverse Model (EURAD-IM) used for the first time over South America simulating ...detailed features of aerosols. Modeled data are evaluated with observational surface data and a Lidar. Two case studies in 2016 with distinct meteorological conditions and pollution plume features show transport (i) from central South America, associated to biomass burning activities, (ii) from the rural part of the state of São Paulo, (iii) between the metropolitan areas of Rio de Janeiro and São Paulo (MASP) either through the Paraíba Valley or via the ocean, connecting Brazil's two largest cities, (iv) from the port-city Santos to MASP and also from MASP to the city Campinas, and vice versa. A Pearson coefficient of 0.7 was found for PM10 at MASP CENTER and EURAD-IM simulations vary within the observational standard deviation, with a Mean Percentual Error (MPE) of 10%. The model's vertical distributions of aerosol layers agree with the Lidar profiles that show either characteristics of long-range transported biomass burning plumes, or of local pollution. The distinct transport patterns that agree with satellite Aerosol Optical Death and fire spot images as well as with the ground-based observations within the standard deviations, allows us exploring patterns of air pollution in a detailed manner and to understand the complex interactions between local to long-range transport sources.
•Model demonstrated pollution exchange between São Paulo and Rio de Janeiro states.•The model's vertical distributions of aerosol layers agree with Lidar measurements.•The model presented strong correlation with surface measurements in São Paulo city.•Modeled city aerosols match observational standard deviations with 10% mean error.
An intercomparison of four regional air quality models is performed in the tropical megacity of São Paulo with the perspective of developing a forecasting system based on a model ensemble. Modeled ...concentrations of the main regulated pollutants are compared with combined observations in the megacity center, after analyzing the spatial scale of representativeness of air monitoring stations. During three contrasting periods characterized by different types of pollution events, the hourly concentrations of carbon monoxide (CO), nitrogen oxides (NOx), sulfur dioxide (SO2), and particulate matter (PM2.5 and PM10) modeled by the ensemble are in moderate agreement with observations. The median of the ensemble provides the best performance (R ≈ 0.7 for CO, 0.7 for NOx, 0.5 for SO2, 0.5 for PM2.5, and 0.4 for PM10) because each model has periods and pollutants for which it has the best agreement. NOx concentration is modeled with a large inter‐model variability, highlighting potential for improvement of anthropogenic emissions. Pollutants transported by biomass burning events strongly affect the air quality in São Paulo and are associated with significant inter‐model variability. Modeled hourly concentration of ozone (O3) is overestimated during the day (≈20 ppb) and underestimated at night (≈10 ppb), while nitrogen dioxide (NO2) is overestimated at night (≈20 ppb). The observed O3 concentration is best reproduced by the median of the ensemble (R ≈ 0.8), taking advantage of the variable performance of the models. Therefore, an operational air quality forecast system based on a regional model ensemble is promising for São Paulo.
Plain Language Summary
Forecasting air quality in megacities is particularly difficult due to the diversity and temporal variability of emission sources. São Paulo is the largest metropolitan area in South America and has no operational air quality forecast. We perform an intercomparison of four regional air quality models with the perspective of developing an air quality forecasting system. During three contrasting periods characterized by different types of pollution events, we analyze the modeled concentrations of the main regulated pollutants (trace gases and aerosols) compared to observations from the São Paulo air quality monitoring network. The modeled concentrations of the main regulated pollutants agree well with the observations range of variation, although we show the potential in improving the treatment of anthropogenic emissions. In addition, the long‐range transport of pollutants due to forest fires strongly affects the air quality in São Paulo and also reduces the performance of the models. The observed hourly ozone concentration is well reproduced by the models, and its median has the best performance, taking advantage of the capabilities of each model. Therefore, an operational air quality forecasting system for the megacity of São Paulo is promising.
Key Points
An ensemble of regional air quality models performs well in the São Paulo megacity for the main regulated pollutants (CO, NOx, O3, SO2, PM2.5, and PM10)
Transport of pollutants due to biomass burning events, affecting strongly the air quality of the megacity, is represented with high variability by the ensemble
In the center of the megacity, the median of the regional model ensemble leads to the best performance for these pollutants compared to each model that composes it
Even though supplemental oxygen is used for the treatment of patients with hypoxemic respiratory failure, the most effective oxygenation targets are not known. In this randomized trial, a lower ...oxygenation target did not result in lower mortality than a higher target.
Abstract Background Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between ...inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. Methods Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. Results Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06–7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05–5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43–36.6, p = 0.010). Conclusions In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.
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