Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in ...combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines.
Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines.
All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations.
These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.
Because of their high operating temperatures, there has been speculation that thermal radiation may play an important role in the overall heat transfer within the electrode and electrolyte layers of ...solid oxide fuel cells (SOFCs). This paper presents a detailed characterization of the thermophysical and radiative properties of the composite materials, which are then used to define a simple 2D model incorporating the heat transfer characteristics of the electrode and electrolyte layers of a typical planar SOFC. Subsequently, the importance of thermal radiation is assessed by comparing the temperature field obtained using a conduction model with those obtained using two coupled conduction/radiation models. Contrary to some published literature, these results show that radiation heat transfer has a negligible effect on the temperature field within these components, and does not need to be accommodated in comprehensive thermal models of planar SOFCs.
Information on the movements and population connectivity of the oceanic manta ray (Manta birostris) is scarce. The species has been anecdotally classified as a highly migratory species based on the ...pelagic habitats it often occupies, and migratory behavior exhibited by similar species. As a result, in the absence of ecological data, population declines in oceanic manta have been addressed primarily with international-scale management and conservation efforts. Using a combination of satellite telemetry, stable isotope and genetic analyses we demonstrate that, contrary to previous assumptions, the species appears to exhibit restricted movements and fine-scale population structure. M. birostris tagged at four sites in the Indo-Pacific exhibited no long-range migratory movements and had non-overlapping geographic ranges. Using genetic and isotopic analysis, we demonstrate that the observed movements and population structure persist on multi-year and generational time scales. These data provide the first insights into the long-term movements and population structure of oceanic manta rays, and suggest that bottom-up, local or regional approaches to managing oceanic mantas could prove more effective than existing, international-scale management strategies. This case study highlights the importance of matching the scales at which management and relevant ecological processes occur to facilitate the effective conservation of threatened species.
•Oceanic manta rays are threatened by targeted fisheries and bycatch.•Satellite telemetry, stable isotope analysis and genetics indicate residency.•This is in contrast to other large, highly migratory pelagic species.•Isolated subpopulations face greater risk of local extirpation.•Increased emphasis on local or regional management may benefit the species.
A combined numerical and experimental investigation has been carried out to study the flow behaviour in a spacer-filled channel, representative of those used in spiral-wound membrane modules. Direct ...numerical simulation and particle image velocimetry were used to investigate the fluid flow characteristics inside a 2 × 2 cell at Reynolds numbers that range between 100 and 1000. It was found that the flow in this geometry moves parallel to and also rotates between the spacer filaments and that the rate of rotation increases with Reynolds number. The flow mechanisms, transition process and onset of turbulence in a spacer-filled channel are investigated including the use of the velocity spectra at different Reynolds numbers. It is found that the flow is steady for Re < 200 and oscillatory at Re ∼ 250 and increasingly unsteady with further increases in Re before the onset of turbulent flow at Re ∼ 1000.
Background: Type 2 diabetes is characterized by insulin resistance and the progressive loss of islet beta‐cell function. Although the former is already established at diagnosis and changes little ...thereafter, beta‐cell function continues to decline, leading to secondary failure of anti‐hyperglycaemic therapies. Aim: To develop a quantitative model of the process of beta‐cell function decay over time, using trial data. Design: Re‐analysis of published data. Methods: The results of the Belfast Diet Study were re‐analysed. Assuming patients are diagnosed at different stages in the disease process, time displacement of data was used to obtain a bi‐partite spline model describing loss of insulin secretion over a 6‐year period. Results: The model was developed combining two phases, in which a long slow gradual loss of beta‐cell function leads to a crisis in metabolic regulation, precipitating a much more rapid decay phase. This paradigm was consistent with a previous non‐linear model of beta‐cell mass regulation. Discussion: This model may have important implications for targeting appropriate therapy to patients in each phase: delaying or avoiding full clinical type 2 diabetes in the first phase; and preventing the development of diabetic complications in the second phase.
The presence of cranial tibial subluxation can aid in the detection of joint instability as a result of CrCL injury. Detection of cranial tibial subluxation has been described using the tibial ...compression test (TCT) and cranial drawer test (CDT); however, diagnosis of CrCL insufficiency by assessing cranial subluxation motion of the tibia is subjective and difficult to quantify accurately. The aim of this study was to investigate a measurement technique to assess the degree of cranial tibial displacement relative to the femoral condyles on mediolateral projection stifle radiographs at varying degrees of stifle flexion (90°, 110°, and 135°) in CrCL intact, partially, and completely transected conditions. Radiographic measurements included: CrCL length and intercondylar distance (ICD), defined as the distance between the tibial mechanical axis (TMA) and the femoral condylar axis (FCA). The influence of CrCL status, stifle flexion angle, and measurement type on measured distance was evaluated. The relationship between CrCL length and ICD measurement was also assessed.
Complete transection of the CrCL resulted in significant cranial tibial displacement. Stifle flexion angle affected ICD, but not CrCL length. Normalized measured CrCL length and ICD were significantly different; however, no differences existed between the change in distance detected by CrCL length and ICD measurements as CrCL transection status changed. Correlation coefficients detected a significant positive correlation between measured CrCL and ICD.
The ICD measurement technique was able to quantify tibial displacement at various stifle flexion angles in the intact and completely transected CrCL conditions. The ICD measurement was more affected by stifle flexion angle than was the CrCL length.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A detailed model of a solid oxide fuel cell was developed with an object‐oriented open‐source computational fluid dynamics code based on a finite‐volume method. The methodology is derived from a ...local Nernst equation with associated irreversible losses. Calculations were performed with the International Energy Agency benchmark case #1 with hydrogen as fuel, for co‐flow, counter‐flow, and cross‐flow. While agreement with the results of previous workers was satisfactory, a number of shortcomings with the benchmark case were identified and highlighted. These include over‐simplified electro‐chemical kinetics, neglect of porous transport layers, and ambiguities associated with the very low flow rates prescribed for the benchmark case.
To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or ...public health decision-making, and is a cost-effective use of health-care resources.
The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members.
A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out.
For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing.
Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.
Introduction: Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in ...hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME. Methods: In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting. Results: We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, p = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance. Conclusion: SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.
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