The tetrahedral finite cell method for fluids: Immersogeometric analysis of turbulent flow around complex geometries

We present a tetrahedral finite cell method for the simulation of incompressible flow around geometrically complex objects. The method immerses such objects into non-boundary-fitted meshes of tetrahedral finite elements and weakly enforces Dirichlet boundary conditions on the objects’ surfaces. Adaptively-refined quadrature rules faithfully capture the flow domain geometry in the discrete problem without modifying the non-boundary-fitted finite element mesh. A variational multiscale formulation provides accuracy and robustness in both laminar and turbulent flow conditions. We assess the accuracy of the method by analyzing the flow around an immersed sphere for a wide range of Reynolds numbers. We show that quantities of interest such as the drag coefficient, Strouhal number and pressure distribution over the sphere are in very good agreement with reference values obtained from standard boundary-fitted approaches. We place particular emphasis on studying the importance of the geometry resolution in intersected elements. Aligning with the immersogeometric concept, our results show that the faithful representation of the geometry in intersected elements is critical for accurate flow analysis. We demonstrate the potential of our proposed method for high-fidelity industrial scale simulations by performing an aerodynamic analysis of an agricultural tractor

Toxicokinetic studies reveal variability in earthworm pollutant handling

A frequent characteristic of earthworms collected from contaminated sites is that they show considerable variation in measured tissue chemical concentrations. What is not certain is whether this variation results from local scale heterogeneity in soil concentrations and associated variation in exposure or rather from systematic and biologically based differences in earthworm pollutant handling. To assess patterns of earthworm chemical uptake and associated variation, accumulation was investigated in two bespoke toxicokinetic studies with the organic chemicals chlorpyrifos and fluoranthene and in a reanalysis of two published toxicokinetic studies with the metals Pb and Cd. The analysis of all data-sets highlighted extensive variation around one compartment model fits. Such consistently high variability, despite the homogenous nature of exposure within the test systems, hints at extensive biological variation in earthworms within the pathways involved in pollutant handling (uptake, metabolism, excretion) which goes beyond the simple methodological variation of a single test. The identified variation between individuals has important implications in areas such as biomarker analyses and secondary poisoning assessment. Further it indicates the presence of substantive selectable variation in pollutant handling that could support the development of pollutant tolerance in earthworms

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Background: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. [Figure not available: see fulltext.]SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.status: publishe

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug