•An elastoplastic rolling resistance model was employed to capture particle shape effect.•Triaxial compression tests were simulated using superellipsoid-based DEM.•Shear-induced fabric variation and ...anisotropy were examined during shear.•Effects of rolling resistance and particle shape were comparatively investigated.
Display omitted
The rolling resistance model has been employed in the discrete element modelling in geomechanics, as an alternative computationally efficient approach to capture the resistance of particle rotation due to irregularity in shape. This paper presents a series of 3D DEM simulations of triaxial compression tests on specimens with rolling resistance and non-spherical particles using an in-house code. The non-spherical particle shapes are two kinds of special super-ellipsoids (i.e., superballs and ellipsoids) corresponding to two kinds of typical distortion in shape. A comprehensive comparison between the rolling resistance and particle shape effects on shear-induced fabric variation and anisotropy within granular materials is carried out. The simulations show that the manners in which quantifiers of fabric and anisotropy approach their respective critical state values vary with shear strain levels. Using the rolling resistance model can reproduce the main features of shear-induced fabric variation and anisotropy for most of these fabric measures. However, the effect of particle shape with just slight distortion from sphere can be captured well by the rolling resistance model. Moreover, high shear strengths can be achieved with sufficiently strong rolling resistance, but this is not recommended due to the unrealistic induced fabric. These findings highlight that the rolling resistance model should be carefully used in investigations, especially for micro-macro bridging.
Dual-process and dual-system theories in both cognitive and social psychology have been subjected to a number of recently published criticisms. However, they have been attacked as a category, ...incorrectly assuming there is a generic version that applies to all. We identify and respond to 5 main lines of argument made by such critics. We agree that some of these arguments have force against some of the theories in the literature but believe them to be overstated. We argue that the dual-processing distinction is supported by much recent evidence in cognitive science. Our preferred theoretical approach is one in which rapid autonomous processes (Type 1) are assumed to yield default responses unless intervened on by distinctive higher order reasoning processes (Type 2). What defines the difference is that Type 2 processing supports hypothetical thinking and load heavily on working memory.
In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival ...in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.
Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 42%), diarrhoea (184 39%), decreased appetite (162 34%), and decreased weight (147 31%) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 52%), diarrhoea (220 46%), hypertension (144 30%), and decreased appetite (127 27%) for sorafenib.
Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.
Eisai Inc.
To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial.
...Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS).
Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio HR, 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm.
Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC.
The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer ...development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.
PDF
