Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes ...with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Kα mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer.
The collection of in situ data is generally a costly process, with the Arctic being no exception. Indeed, there has been a perception that the Arctic is lacking in situ sampling; however, after many ...years of concerted effort and international collaboration, the Arctic is now rather well sampled, with many cruise expeditions every year. For example, the GLODAP (Global Ocean Data Analysis Project) product has a greater density of in situ sampling points within the Arctic than along the Equator. While this is useful for open-ocean processes, the fjords of the Arctic, which serve as crucially important intersections of terrestrial, coastal, and marine processes, are sampled in a much more ad hoc process. This is not to say they are not well sampled but rather that the data are more difficult to source and combine for further analysis. It was therefore noted that the fjords of the Arctic are lacking in FAIR (findable, accessible, interoperable, and reusable) data. To address this issue, a single dataset has been created from publicly available, predominantly in situ data from seven study sites in Svalbard and Greenland. After finding and accessing the data from a number of online platforms, they were amalgamated into a single project-wide standard, ensuring their interoperability. The dataset was then uploaded to PANGAEA so that it can be findable and reusable in the future. The focus of the data collection was driven by the key drivers of change in Arctic fjords identified in a companion review paper. To demonstrate the usability of this dataset, an analysis of the relationship between the different drivers was performed. Via the use of an Arctic biogeochemical model, these relationships were projected forward to 2100 via Representative Carbon Pathways (RCPs) 2.6, 4.5, and 8.5. This dataset is a work in progress, and as new datasets containing the relevant key drivers are released, they will be added to an updated version planned for the middle of 2024.
Marine heatwaves (MHWs), or prolonged periods of anomalously warm sea water temperature, have been increasing in duration and intensity globally for decades. However, there are many coastal, oceanic, ...polar, and sub-surface regions where our ability to detect MHWs is uncertain due to limited high quality data. Here we investigate the effect that short time series length, missing data, or linear long-term temperature trends may have on the detection of MHWs. We show that MHWs detected in time series as short as 10 years did not have durations or intensities appreciably different from events detected in a standard 30 year long time series. We also show that the output of our MHW algorithm for time series missing less than 25% data did not differ appreciably from a complete time series, and that the level of allowable missing data could cautiously be increased to 50% when gaps were filled by linear interpolation. Finally, linear long-term trends of 0.10°C/decade or greater added to a time series caused larger changes (increases) to the count and duration of detected MHWs than shortening a time series to 10 years or missing more than 25% of the data. The long-term trend in a time series has the largest effect on the detection of MHWs and has the largest range in added uncertainty in the results. Time series length has less of an effect on MHW detection than missing data, but adds a larger range of uncertainty to the results. We provide suggestions for best practices to improve the accuracy of MHW detection with sub-optimal time series and show how the accuracy of these corrections may change regionally.
•Extreme events occur on average at least once per year at every coastal site.•Significant differences in duration and intensity between different coasts.•Significant difference in events recorded in ...satellite and in situtemperature data.•Co-occurrence rates of large events very low between different datasets.•Mesoscale temperature forcing likely not main driver of extreme coastal events.
A changing global climate places shallow water ecosystems at more risk than those in the open ocean as their temperatures may change more rapidly and dramatically. To this end, it is necessary to identify the occurrence of extreme ocean temperature events – marine heatwaves (MHWs) and marine cold-spells (MCSs) – in the nearshore (<400m from the coastline) environment as they can have lasting ecological effects. The occurrence of MHWs have been investigated regionally, but no investigations of MCSs have yet to be carried out. A recently developed framework that defines these events in a novel way was applied to ocean temperature time series from (i) a nearshore in situ dataset and (ii) 14° NOAA Optimally Interpolated sea surface temperatures. Regional drivers due to nearshore influences (local-scale) and the forcing of two offshore ocean currents (broad-scale) on MHWs and MCSs were taken into account when the events detected in these two datasets were used to infer the links between offshore and nearshore temperatures in time and space. We show that MHWs and MCSs occur at least once a year on average but that proportions of co-occurrence of events between the broad- and local scales are low (0.20–0.50), with MHWs having greater proportions of co-occurrence than MCSs. The low rates of co-occurrence between the nearshore and offshore datasets show that drivers other than mesoscale ocean temperatures play a role in the occurrence of at least half of nearshore events. Significant differences in the duration and intensity of events between different coastal sections may be attributed to the effects of the interaction of oceanographic processes offshore, as well as with local features of the coast. The decadal trends in the occurrence of MHWs and MCSs in the offshore dataset show that generally MHWs are increasing there while MCSs are decreasing. This study represents an important first step in the analysis of the dynamics of events in nearshore environments, and their relationship with broad-scale influences.
Climate change is transforming marine ecosystems through the expansion and contraction of species’ ranges. Sea ice loss and warming temperatures are expected to expand habitat availability for ...macroalgae along long stretches of Arctic coastlines. To better understand the current distribution of kelp forests in the Eastern Canadian Arctic, kelps were sampled along the coasts for species identifications and percent cover. The sampling effort was supplemented with occurrence records from global biodiversity databases, searches in the literature, and museum records. Environmental information and occurrence records were used to develop ensemble models for predicting habitat suitability and a Random Forest model to predict kelp cover for the dominant kelp species in the region –
Agarum clathratum
,
Alaria esculenta
, and Laminariaceae species (
Laminaria solidungula
and
Saccharina latissima
). Ice thickness, sea temperature and salinity explained the highest percentage of kelp distribution. Both modeling approaches showed that the current extent of arctic kelps is potentially much greater than the available records suggest. These modeling approaches were projected into the future using predicted environmental data for 2050 and 2100 based on the most extreme emission scenario (RCP 8.5). The models agreed that predicted distribution of kelp in the Eastern Canadian Arctic is likely to expand to more northern locations under future emissions scenarios, with the exception of the endemic arctic kelp
L. solidungula
, which is more likely to lose a significant proportion of suitable habitat. However, there were differences among species regarding predicted cover for both current and future projections. Notwithstanding model-specific variation, it is evident that kelps are widespread throughout the area and likely contribute significantly to the functioning of current Arctic ecosystems. Our results emphasize the importance of kelp in Arctic ecosystems and the underestimation of their potential distribution there.
The aim of the present study was to establish normative data for the Automated Neuropsychological Assessment Metrics (v4) Traumatic Brain Injury (ANAM4 TBI) battery in a military context. ANAM4 data ...from over 107,500 active duty service members ranging from 17 to 65 years of age were included in this study. The influence of the demographic variables of age and gender were also examined. These norms, stratified by age and gender, represent a more comprehensive set of norms than previously available and are provided as a representative set of norms for clinical practice. Additionally, base rates of below average performance in a normal population are provided to help inform clinical decision making.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control ...advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells.
We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts.
When lymphocytes (and other cells) die by apoptosis, they orchestrate their own orderly removal by macrophages, and thereby prevent the inflammation that would otherwise attend cell lysis. As part of ...their demise, apoptotic cells disrupt the normal asymmetric distribution of phospholipids across their plasma membranes, an asymmetry normally maintained by an aminophospholipid translocase. This disruption of asymmetry, mediated by an activity known as the scramblase, generates ligands on the cell surface that trigger phagocytosis of the dying cell before lysis can occur. This crucial alteration of the plasma membrane is not dependent on caspase-mediated proteolysis, but quite unexpectedly, it is required both on the apoptotic target cell and on the phagocyte that engulfs it. At least in the phagocyte, this rearrangement may depend on the activity of an ABC ATPase, termed ABC1 in mammals and ced-7 in
C. elegans.
Comparison of protein A affinity sorbents Hahn, Rainer; Schlegel, Robert; Jungbauer, Alois
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences,
06/2003, Letnik:
790, Številka:
1
Journal Article
Recenzirano
Protein A is a popular generic ligand for purification of monoclonal and recombinant antibodies. The performance of 15 commercially available protein A media was studied. Equilibrium and dynamic ...binding capacity for human IgG was determined and the capture of IgG from a crude feed-stock was investigated. For initial screening the dynamic binding capacity was determined at small scale. Media with good performance were further tested with increased column height. Comparing the data from the two different column heights it could be shown that the dynamic capacity strongly depends on the residence time. Agarose based media exhibited higher binding capacity at residence times longer than 3 min whereas polymeric media or media based on porous glass showed a lesser dependence on the flow velocity and the residence time. A quantitative description of this behavior was derived by determination of the adsorption isotherms and fitting the breakthrough profiles with the Thomas solution. Agarose based media exhibited higher maximum equilibrium binding capacities and the dissociation constants derived from adsorption isotherms were smaller. The other media exhibited higher apparent rate constants, indicating a faster mass transfer. This can be explained by the smaller particle diameter of these media and it can be assumed that constant pattern conditions are thereby obtained more quickly. Selectivity was tested by performing antibody purification under standardized conditions. Polyclonal human IgG in cell culture supernatant containing 2.5% fetal calf serum was used as a representative feed-stock. Under the applied conditions several sorbents showed very tight binding of IgG and in some cases most of the sample remained on the sorbent. The study can be useful as a guide for optimization of large-scale purification processes.
Climate Change in Coastal Waters Schlegel, Robert W.; Smit, Albertus J.
Journal of climate,
12/2016, Letnik:
29, Številka:
24
Journal Article
Recenzirano
Odprti dostop
In South Africa, 129 in situ temperature time series of up to 43 years are used for investigations of the thermal characteristics of coastal seawater. They are collected with handheld thermometers or ...underwater temperature recorders (UTRs) and are recorded at precisions from 0.5° to 0.001°C. Using the natural range of seasonal signals and variability for 84 of these time series, their length, decadal trend, and data precision were systematically varied before fitting generalized least squares (GLS) models to study the effect these variables have on trend detection. The variables that contributed most to accurate trend detection, in decreasing order, were time series length, decadal trend, variance, percentage of missing data (% NA), and measurement precision. Time series greater than 30 years in length are preferred and although larger decadal trends are modeled more accurately, modeled significance (p value) is largely affected by the variance present. The risk of committing both type-1 and type-2 errors increases when ≥5% NA is present. There is no appreciable effect on model accuracy between measurement precision of 0.1°–0.001°C. Measurement precisions of 0.5°C require longer time series to give equally accurate model results. The implication is that the thermometer time series in this dataset, and others around the world, must be at least two years longer than their UTR counterparts to be useful for decadal-scale climate change studies. Furthermore, adding older lower-precision UTR data to newer higher-precision UTR data within the same time series will increase their usefulness for this purpose.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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