The cloud thermodynamic phase is a crucial parameter to understand the Earth’s radiation budget, the hydrological cycle, and atmospheric thermodynamic processes. Spaceborne active remote sensing such ...as the synergistic radar-lidar DARDAR product is considered the most reliable method to determine cloud phase; however, it lacks large-scale observations and high repetition rates. These can be provided by passive instruments such as SEVIRI aboard the geostationary Meteosat Second Generation (MSG) satellite, but passive remote sensing of the thermodynamic phase is challenging and confined to cloud top. Thus, it is necessary to understand to what extent passive sensors with the characteristics of SEVIRI are expected to provide a relevant contribution to cloud phase investigation. To reach this goal, we collect five years of DARDAR data to model the cloud top phase (CTP) for MSG/SEVIRI and create a SEVIRI-like CTP through an elaborate aggregation procedure. Thereby, we distinguish between ice (IC), mixed-phase (MP), supercooled (SC), and warm liquid (LQ). Overall, 65% of the resulting SEVIRI pixels are cloudy, consisting of 49% IC, 14% MP, 13% SC, and 24% LQ cloud tops. The spatial resolution has a significant effect on the occurrence of CTP, especially for MP cloud tops, which occur significantly more often at the lower SEVIRI resolution than at the higher DARDAR resolution (9%). We find that SC occurs most frequently at high southern latitudes, while MP is found mainly in both high southern and high northern latitudes. LQ dominates in the subsidence zones over the ocean, while IC occurrence dominates everywhere else. MP and SC show little seasonal variability apart from high latitudes, especially in the south. IC and LQ are affected by the shift of the Intertropical Convergence Zone. The peak of occurrence of SC is at −3 ∘C, followed by that for MP at −13 ∘C. Between 0 and −27 ∘C, the occurrence of SC and MP dominates IC, while below −27 ∘C, IC is the most frequent CTP. Finally, the occurrence of cloud top height (CTH) peaks lower over the ocean than over land, with MP, SC, and IC being undistinguishable in the tropics but with separated CTH peaks in the rest of the MSG disk. Finally, we test the ability of a state-of-the-art AI-based ice cloud detection algorithm for SEVIRI named CiPS (Cirrus Properties for SEVIRI) to detect cloud ice. We confirm previous evaluations with an ice detection probability of 77.1% and find a false alarm rate of 11.6%, of which 68% are due to misclassified cloud phases. CiPS is not sensitive to ice crystals in MP clouds and therefore not suitable for the detection of MP clouds but only for fully glaciated (i.e., IC) clouds. Our study demonstrates the need for the development of dedicated cloud phase distinction algorithms for all cloud phases (IC, LQ, MP, SC) from geostationary satellites.
Due to the frequent dysregulation of the PI3K/AKT/mTOR signaling pathway, mTOR represents a suitable therapeutic target in hepatocellular carcinoma (HCC). However, emerging data from clinical trials ...of HCC patients indicate that mTOR inhibition by RAD001 (Everolimus) alone has only moderate antitumor efficacy which may be due to the feedback activation of AKT after mTOR inhibition. In this study, we analyzed the effects of dual inhibition of mTOR and AKT on the proliferation of HCC cell lines. In addition, we measured the feedback activation of each of the AKT isoforms after mTOR inhibition in HCC cell lines and their enzymatic activity in primary samples from HCC patients.
The activation status of specific AKT isoforms in human HCC samples and corresponding healthy liver tissue was analyzed using an AKT isoform specific in vitro kinase assay. AKT isoform activation after mTOR inhibition was analyzed in three HCC cell lines (Hep3B, HepG2 and Huh7), and the impact of AKT signaling on proliferation after mTOR inhibition was investigated using the novel AKT inhibitor MK-2206 and AKT isoform specific knockdown cells.
AKT isoforms become differentially activated during feedback activation following RAD001 treatment. The combination of mTOR inhibition and AKT isoform knockdown showed only a weak synergistic effect on proliferation of HCC cell lines. However, the combinatorial treatment with RAD001 and the pan AKT inhibitor MK-2206 resulted in a strong synergism, both in vitro and in vivo. Moreover, by analyzing primary HCC tissue samples we were able to demonstrate that a hotspot mutation (H1047R) of PI3KCA, the gene encoding the catalytic subunit of PI3K, was associated with increased in vitro kinase activity of all AKT isoforms in comparison to healthy liver tissue of the patient.
Our results demonstrate that dual targeting of mTOR and AKT by use of RAD001 and the pan AKT inhibitor MK-2206 does effectively inhibit proliferation of HCC cell lines. These data suggest that combined treatment with RAD001 and MK-2206 may be a promising therapy approach in the treatment of hepatocellular carcinoma.
Early hepatocellular carcinoma (HCC) has a limited prognosis due to recurrence rates of more than 50% after liver resection. Recurrence within two years is believed to be caused by untraceable micro ...metastases at the time of resection. The objective of this study was to investigate EpCAM-positive circulating tumor cells (CTC) as liquid biomarker to identify patients with high risk of recurrence after liver resection.
61 patients undergoing resection between 2011 and 2015 were consecutively enrolled. Blood specimens were obtained prior to surgery and processed with the CellSearch
system, detecting EpCAM-positive CTC. The primary endpoint was recurrence-free survival (RFS).
13 women and 44 men (63.6 ± 11.1 years) were finally evaluated. CTC-positive patients had a significantly higher risk of recurrence with a hazard ratio (HR) of 2.3 (p=0.027), and a shorter RFS compared to CTC-negative patients (5.0 ± 1.5 vs. 12.0 ± 2.5 months, p=0.039). As expected, incomplete resection (R1) was also associated with shorter RFS (HR=2.6, p=0.035), but vascular invasion was not. However, the predictive power of CTC status was independent of R1.
Bloodstream detection of CTC prior to curative-intended liver resection discloses an elevated risk of HCC recurrence and could identify patients, who might benefit from adjuvant treatment.
Objectives
The aim of our study was to describe microbial flora associated with MRONJ and characterize the susceptibility of pathogens to help guide an effective empiric antibiotic treatment in these ...patients.
Materials and methods
A retrospective, single-center analysis was performed, using 116 bone samples from 98 patients. The bone samples were homogenized and subjected to routine culture methods. Growing bacteria were differentiated to the species level using whole-cell mass spectrometry and subjected to susceptibility testing.
Results
A highly diverse microbial flora was detected in necrotic bone, with a simultaneous presence of two or more bacterial species in 79% of all patients. In at least 65% of samples, gram-negative isolates were detected. Therefore, bacterial species resistant against β-lactamase inhibitors were present in at least 70% of all patients.
Conclusions
The empiric choice of antibiotics in MRONJ patients should consider the high rate of gram-negative bacteria and resistance against β-lactam antibiotics.
Clinical relevance
According to recent guidelines and recommendations, systemic antibiotic treatment is a key component in the treatment of all stage 2 and 3 MRONJ patients. We recommend using fluoroquinolones for empiric treatment and emphasize the use of bacterial cultivation and susceptibility testing to enable an effective antibiotic treatment.
The North Atlantic Waveguide and Downstream Impact Experiment (NAWDEX) explored the impact of diabatic processes on disturbances of the jet stream and their influence on downstream high-impact ...weather through the deployment of four research aircraft, each with a sophisticated set of remote sensing and in situ instruments, and coordinated with a suite of ground-based measurements. A total of 49 research flights were performed, including, for the first time, coordinated flights of the four aircraft: the German High Altitude and Long Range Research Aircraft (HALO), the Deutsches Zentrum für Luft- und Raumfahrt (DLR) Dassault Falcon 20, the French Service des Avions Français Instrumentés pour la Recherche en Environnement (SAFIRE) Falcon 20, and the British Facility for Airborne Atmospheric Measurements (FAAM) BAe 146. The observation period from 17 September to 22 October 2016 with frequently occurring extratropical and tropical cyclones was ideal for investigating midlatitude weather over the North Atlantic. NAWDEX featured three sequences of upstream triggers of waveguide disturbances, as well as their dynamic interaction with the jet stream, subsequent development, and eventual downstream weather impact on Europe. Examples are presented to highlight the wealth of phenomena that were sampled, the comprehensive coverage, and the multifaceted nature of the measurements. This unique dataset forms the basis for future case studies and detailed evaluations of weather and climate predictions to improve our understanding of diabatic influences on Rossby waves and the downstream impacts of weather systems affecting Europe.
Treatment of breast cancer patients with distant metastases represents one of the biggest challenges in today's gynecological oncology. Therefore, a better understanding of mechanisms promoting the ...development of metastases is of paramount importance. The serine/threonine kinase AKT was shown to drive cancer progression and metastasis. However, there is emerging data that single AKT isoforms (i.e. AKT1, AKT2 and AKT3) have different or even opposing functions in the regulation of cancer cell migration in vitro, giving rise to the hypothesis that inhibition of distinct AKT isoforms might have undesirable effects on cancer dissemination in vivo.
The triple negative breast cancer cell line MDA-MB-231 was used to investigate the functional roles of AKT in migration and metastasis. AKT single and double knockdown cells were generated using isoform specific shRNAs. Migration was analyzed using live cell imaging, chemotaxis and transwell assays. The metastatic potential of AKT isoform knockdown cells was evaluated in a subcutaneous xenograft mouse model in vivo.
Depletion of AKT3, but not AKT1 or AKT2, resulted in increased migration in vitro. This effect was even more prominent in AKT2,3 double knockdown cells. Furthermore, combined downregulation of AKT2 and AKT3, as well as AKT1 and AKT3 significantly increased metastasis formation in vivo. Screening for promigratory proteins revealed that downregulation of AKT3 increases the expression of S100A4 protein. In accordance, depletion of S100A4 by siRNA approach reverses the increased migration induced by knockdown of AKT3.
We demonstrated that knockdown of AKT3 can increase the metastatic potential of triple negative breast cancer cells. Therefore, our results provide a rationale for the development of AKT isoform specific inhibitors.
Temporomandibular joint osteoarthritis (TMJ-OA) is a chronic degenerative disease that is often characterized by progressive impairment of the temporomandibular functional unit. The aim of this ...randomized controlled animal trial was a comparative analysis regarding the chondroregenerative potency of intra-articular stem/stromal cell therapy. Four weeks after combined mechanical and biochemical osteoarthritis induction in 28 rabbits, therapy was initiated by a single intra-articular injection, randomized into the following groups: Group 1: AB Serum (ABS); Group 2: Hyaluronic acid (HA); Group 3: Mesenchymal stromal cells (STx.); Group 4: Mesenchymal stromal cells in hyaluronic acid (HA + STx.). After another 4 weeks, the animals were euthanized, followed by histological examination of the removed joints. The histological analysis showed a significant increase in cartilage thickness in the stromal cell treated groups (HA + STx. vs. ABS,
= 0.028; HA + ST.x vs. HA,
= 0.042; STx. vs. ABS,
= 0.036). Scanning electron microscopy detected a similar heterogeneity of mineralization and tissue porosity in the subchondral zone in all groups. The single intra-articular injection of a stem cell containing, GMP-compliant advanced therapy medicinal product for the treatment of iatrogen induced osteoarthritis of the temporomandibular joint shows a chondroregenerative effect.
Cholangiocarcinoma (CCA) is a rare, but devastating disease arising from the epithelium of intrahepatic and extrahepatic bile ducts. There are neither effective systemic therapies nor satisfying ...treatment options for inoperable CCA. Histopathological and biochemical studies of CCA show frequent dysregulation of the phosphatidylinositol 3‐kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Therefore, we investigated the efficacy of the mTOR inhibitor RAD001 and the impact of AKT signaling following mTOR inhibition in the treatment of CCA. RAD001 significantly inhibits proliferation of CCA cell lines, however, a concentration‐dependent and isoform specific feedback activation of the three AKT isoforms (AKT1, AKT2 and AKT3) was observed after mTOR inhibition. As activation of AKT might limit the RAD001‐mediated anti‐tumor effect, the efficacy of combined mTOR and AKT inhibition was investigated using the allosteric AKT inhibitor MK‐2206. Our results show that inhibition of AKT potentiates the efficacy of mTOR inhibition both in vitro and in a xenograft mouse model in vivo. Mechanistically, the antiproliferative effect of the pan‐AKT inhibitor MK2206 in the CCA cell line TFK‐1 was due to inhibition of AKT1 and AKT2, because knockdown of either AKT1 or AKT2, but not AKT3, showed a synergistic reduction of cell proliferation in combination with mTOR treatment. Finally, using an AKT isoform specific in vitro kinase assay, enzymatic activity of each of the three AKT isoforms was detected in all tissue samples from CCA patients, analyzed. In summary, our preclinical data suggest that combined targeting of mTOR and AKT using RAD001 and MK‐2206 might be a new, effective strategy for the treatment of CCA.
What's new?
Cholangiocarcinoma (CCA) has a dismal prognosis, and currently there is no effective systemic therapy available. The PI3K/AKT/mTOR pathway is frequently activated in CCA. In this study, the authors found that dual targeting of mTOR and AKT can synergistically inhibit the proliferation of CCA cells, both in vitro and in a xenograft mouse model in vivo. Mechanistically, the anti‐proliferative effect of the AKT inhibitor MK2206 was due to inhibition of AKT1 and AKT2, but not AKT3. Combined targeting of mTOR and AKT may be a promising new strategy for the treatment of CCA.
Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Nevertheless, single targeting of this pathway ...is not sufficient to inhibit MPNST growth. In this report, we demonstrate that combined treatment with the allosteric pan-AKT inhibitor MK-2206 and the mTORC1/mTORC2 inhibitor AZD8055 has synergistic effects on the viability of MPNST cell lines in comparison to the treatment with each compound alone. However, when treating animals bearing experimental MPNST with the combined AKT/mTOR regime, no influence on tumour growth was observed. Further analysis of the MPNST xenograft tumours resistant to AKT/mTOR treatment revealed a reactivation of both AKT and mTOR in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects on the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a promising treatment option that should be further analysed in an experimental MPNST mouse model in vivo.
ACRIDICON–CHUVA CAMPAIGN Wendisch, Manfred; Pöschl, Ulrich; Andreae, Meinrat O. ...
Bulletin of the American Meteorological Society,
10/2016, Letnik:
97, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Between 1 September and 4 October 2014, a combined airborne and ground-based measurement campaign was conducted to study tropical deep convective clouds over the Brazilian Amazon rain forest. The new ...German research aircraft, High Altitude and Long Range Research Aircraft (HALO), a modified Gulfstream G550, and extensive ground-based instrumentation were deployed in and near Manaus (State of Amazonas). The campaign was part of the German–Brazilian Aerosol, Cloud, Precipitation, and Radiation Interactions and Dynamics of Convective Cloud Systems–Cloud Processes of the Main Precipitation Systems in Brazil: A Contribution to Cloud Resolving Modeling and to the GPM (Global Precipitation Measurement) (ACRIDICON–CHUVA) venture to quantify aerosol–cloud–precipitation interactions and their thermodynamic, dynamic, and radiative effects by in situ and remote sensing measurements over Amazonia. The ACRIDICON–CHUVA field observations were carried out in cooperation with the second intensive operating period of Green Ocean Amazon 2014/15 (GoAmazon2014/5). In this paper we focus on the airborne data measured on HALO, which was equipped with about 30 in situ and remote sensing instruments for meteorological, trace gas, aerosol, cloud, precipitation, and spectral solar radiation measurements. Fourteen research flights with a total duration of 96 flight hours were performed. Five scientific topics were pursued: 1) cloud vertical evolution and life cycle (cloud profiling), 2) cloud processing of aerosol particles and trace gases (inflow and outflow), 3) satellite and radar validation (cloud products), 4) vertical transport and mixing (tracer experiment), and 5) cloud formation over forested/deforested areas. Data were collected in near-pristine atmospheric conditions and in environments polluted by biomass burning and urban emissions. The paper presents a general introduction of the ACRIDICON–CHUVA campaign (motivation and addressed research topics) and of HALO with its extensive instrument package, as well as a presentation of a few selected measurement results acquired during the flights for some selected scientific topics.
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