Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis

In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 \u3e 1000; Cmax:IC50 \u3c 0.01). Pacritinib\u27s inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P \u3c .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition

Comparison of 3 image-guided adaptive strategies for bladder locoregional radiotherapy

The objective of this study was to compare the dosimetric differences of a population-based planning target volume (PTV) approach and 3 proposed adaptive strategies: plan of the day (POD), patient-specific PTV (PS-PTV), and daily reoptimization (ReOpt). Bladder patients (n = 10) were planned and treated to 46 Gy in 23 fractions with a full bladder in supine position by the standard strategy using a population-based PTV. For each patient, the adaptive strategy was executed retrospectively as follows: (1) POD—multiple distributions of various PTV sizes were generated, and the appropriate distribution based on the bladder of the day was selected for each fraction; (2) PS-PTV—population-based PTV was used for the first 5 fractions and a new PTV derived using information from these fractions was used to deliver the remaining 18 fractions; and (3) ReOpt—distribution was reoptimized for each fraction based on the bladder of the day. Daily dose was computed on all cone beam computed tomographies (CBCTs) and deformed back to the planning computed tomography (CT) for dose summation afterward. V95_Accu, the volume receiving an accumulated delivered dose of 43.7 Gy (95% prescription dose), was measured for comparison. Mean V95_Accu (cm3) values were 1410 (standard deviation [SD]: 227), 1212 (SD: 186), 1236 (SD: 199), and 1101 (SD: 180) for standard, POD, PS-PTV, and ReOpt, respectively. All adaptive strategies significantly reduced the irradiated volume, with ReOpt demonstrating the greatest reduction compared with the standard (− 25%), followed by PS-PTV (− 16%) and POD (− 12%). The difference in the magnitude of reduction between ReOpt and the other 2 strategies reached statistical significance (p = 0.0006). ReOpt is the best adaptive strategy at reducing the irradiated volume because of its frequent adaptation based on the daily geometry of the bladder. The need to adapt only once renders PS-PTV to be the best alternative adaptive strategy

eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.Accepted manuscrip

AI Clinics on Mobile (AICOM): Universal AI Doctors for the Underserved and Hard-to-Reach

This paper introduces Artificial Intelligence Clinics on Mobile (AICOM), an open-source project devoted to answering the United Nations Sustainable Development Goal 3 (SDG3) on health, which represents a universal recognition that health is fundamental to human capital and social and economic development. The core motivation for the AICOM project is the fact that over 80% of the people in the least developed countries (LDCs) own a mobile phone, even though less than 40% of these people have internet access. Hence, through enabling AI-based disease diagnostics and screening capability on affordable mobile phones without connectivity will be a critical first step to addressing healthcare access problems. The technologies developed in the AICOM project achieve exactly this goal, and we have demonstrated the effectiveness of AICOM on monkeypox screening tasks. We plan to continue expanding and open-sourcing the AICOM platform, aiming for it to evolve into an universal AI doctor for the Underserved and Hard-to-Reach

Regulation of cilia abundance in multiciliated cells

Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise number of centrioles and cilia remains unknown. Airway progenitor cells contain two parental centrioles (PC) and form structures called deuterosomes that nucleate centrioles during amplification. Using an ex vivo airway culture model, we show that ablation of PC does not perturb deuterosome formation and centriole amplification. In contrast, loss of PC caused an increase in deuterosome and centriole abundance, highlighting the presence of a compensatory mechanism. Quantification of centriole abundance in vitro and in vivo identified a linear relationship between surface area and centriole number. By manipulating cell size, we discovered that centriole number scales with surface area. Our results demonstrate that a cell-intrinsic surface area-dependent mechanism controls centriole and cilia abundance in multiciliated cells

Evaluation of the performance of four chemical transport models in predicting the aerosol chemical composition in Europe in 2005

© Author(s) 2016.Four regional chemistry transport models were applied to simulate the concentration and composition of particulate matter (PM) in Europe for 2005 with horizontal resolution 20 km. The modelled concentrations were compared with the measurements of PM chemical composition by the European Monitoring and Evaluation Programme (EMEP) monitoring network. All models systematically underestimated PM10 and PM2:5 by 10–60 %, depending on the model and the season of the year, when the calculated dry PM mass was compared with the measurements. The average water content at laboratory conditions was estimated between 5 and 20% for PM2:5 and between 10 and 25% for PM10. For majority of the PM chemical components, the relative underestimation was smaller than it was for total PM, exceptions being the carbonaceous particles and mineral dust. Some species, such as sea salt and NO3, were overpredicted by the models. There were notable differences between the models’ predictions of the seasonal variations of PM, mainly attributable to different treatments or omission of some source categories and aerosol processes. Benzo(a)pyrene concentrations were overestimated by all the models over the whole year. The study stresses the importance of improving the models’ skill in simulating mineral dust and carbonaceous compounds, necessity for high-quality emissions from wildland fires, as well as the need for an explicit consideration of aerosol water content in model–measurement comparison.Peer reviewedFinal Published versio

Uneven warming likely contributed to declining near-surface wind speeds in Northern China between 1961 and 2016

A decline in mean near-surface (10 m) wind speed has been widely reported for many land regions over recent decades, yet the underlying cause(s) remains uncertain. This study investigates changes in near-surface wind speed over northern China from 1961 to 2016, and analyzes the associated physical mechanisms using station observations, reanalysis products and model simulations from the Community Atmosphere Model version 5.1 (CAM5). The homogenized near-surface wind speed shows a significantly (p 50°N) in recent decades, which has weakened the annual and seasonal meridional air temperature gradient (−0.33°C to −0.12°C dec−1, p < 0.05, except autumn) between these regions (50°–60°N, 75°–135°E) and the northern China zone (35°–45°N, 75°–135°E). This caused a significant (p < 0.05) decrease in annual and seasonal pressure gradient (−0.43 to −0.20 hPa dec−1) between the two zones, which contributed to the slowdown of winds. CAM5 simulations demonstrate that spatially uneven air temperature increases and near-surface wind speed decreases over northern China can be realistically reproduced using the so-called “all forcing” simulation, while the “natural only forcing” simulation fails to realistically simulate the uneven warming patterns and declines in near-surface wind speed over most of northern China, except for summer.This study was supported by the Second Tibetan Plateau Scientific Expedition and Research Program (STEP, Grant No. 2019QZKK0606), the National Natural Science Foundation of China (Grant No. 41621061), and by the National Key Research and Development Program—Global Change and Mitigation Project (Grant No. 2016YFA0602404). This work was also supported by a Swedish Research Council (2017-03780) and a Swedish Research Council for Sustainable Development (2019-00509) grant, and by the IBER-STILLING project, funded by the Spanish Ministry of Science, Innovation and Universities (RTI2018-095749-A-I00; MCIU/AEI/FEDER, UE)

Variability of daily maximum wind speed across China, 1975–2016: an examination of likely causes

Assessing change in daily maximum wind speed and its likely causes is crucial for many applications such as wind power generation and wind disaster risk governance. Multidecadal variability of observed near-surface daily maximum wind speed (DMWS) from 778 stations over China is analyzed for 1975–2016. A robust homogenization protocol using the R package Climatol was applied to the DMWS observations. The homogenized dataset displayed a significant (p 0.10); that is, DMWS declined during the cold semester (October–March) and increased during the warm semester (April–September). Correlation analysis of the Arctic Oscillation, the Southern Oscillation, and the west Pacific modes exhibited significant correlation with DMWS variability, unveiling their complementarity in modulating DMWS. Further, we explored potential physical processes relating to the atmospheric circulation changes and their impacts on DMWS and found that 1) overall weakened horizontal airflow [large-scale mean horizontal pressure gradient (from −0.24 to +0.02 hPa decade−1) and geostrophic wind speed (from −0.6 to +0.6 m s−1 decade−1)], 2) widely decreased atmospheric vertical momentum transport [atmospheric stratification thermal instability (from −3 to +1.5 decade−1) and vertical wind shear (from −0.4 to +0.2 m s−1 decade−1)], and 3) decreased extratropical cyclones frequency (from −0.3 to 0 month decade−1) are likely causes of DMWS change.This study was supported by the National Natural Science Foundation of China (Grant 41621061), the National Key Research and Development Program–Global Change and Mitigation Project (Grant 2016YFA0602404), funding from STINT (CH2015-6226), and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 703733 (STILLING project). This work has been also supported by the VR project (2017-03780) funded by the Swedish Research Council and Ramon y Cajal fellowship (RYC-2017-22830) and Grant RTI2018-095749-A-I00 (MCIU/AEI/FEDER, UE)

Gamma Ray Lines from a Universal Extra Dimension

Indirect Dark Matter searches are based on the observation of secondary particles produced by the annihilation or decay of Dark Matter. Among them, gamma-rays are perhaps the most promising messengers, as they do not suffer deflection or absorption on Galactic scales, so their observation would directly reveal the position and the energy spectrum of the emitting source. Here, we study the detailed gamma-ray energy spectrum of Kaluza--Klein Dark Matter in a theory with 5 Universal Extra Dimensions. We focus in particular on the two body annihilation of Dark Matter particles into a photon and another particle, which produces monochromatic photons, resulting in a line in the energy spectrum of gamma rays. Previous calculations in the context of the five dimensional UED model have computed the line signal from annihilations into \gamma \gamma, but we extend these results to include \gamma Z and \gamma H final states. We find that these spectral lines are subdominant compared to the predicted \gamma \gamma signal, but they would be important as follow-up signals in the event of the observation of the \gamma \gamma line, in order to distinguish the 5d UED model from other theoretical scenarios.Comment: 21 pages, 6 figure