Granular flows occur in a wide range of situations of practical interest to industry, in our natural environment and in our everyday lives. This paper focuses on granular flow in the so-called ...inertial regime, when the rheology is independent of the very large particle stiffness. Such flows have been modelled with the
$\unicodeSTIX{x1D707}(I),\unicodeSTIX{x1D6F7}(I)$
-rheology, which postulates that the bulk friction coefficient
$\unicodeSTIX{x1D707}$
(i.e. the ratio of the shear stress to the pressure) and the solids volume fraction
$\unicodeSTIX{x1D719}$
are functions of the inertial number
$I$
only. Although the
$\unicodeSTIX{x1D707}(I),\unicodeSTIX{x1D6F7}(I)$
-rheology has been validated in steady state against both experiments and discrete particle simulations in several different geometries, it has recently been shown that this theory is mathematically ill-posed in time-dependent problems. As a direct result, computations using this rheology may blow up exponentially, with a growth rate that tends to infinity as the discretization length tends to zero, as explicitly demonstrated in this paper for the first time. Such catastrophic instability due to ill-posedness is a common issue when developing new mathematical models and implies that either some important physics is missing or the model has not been properly formulated. In this paper an alternative to the
$\unicodeSTIX{x1D707}(I),\unicodeSTIX{x1D6F7}(I)$
-rheology that does not suffer from such defects is proposed. In the framework of compressible
$I$
-dependent rheology (CIDR), new constitutive laws for the inertial regime are introduced; these match the well-established
$\unicodeSTIX{x1D707}(I)$
and
$\unicodeSTIX{x1D6F7}(I)$
relations in the steady-state limit and at the same time are well-posed for all deformations and all packing densities. Time-dependent numerical solutions of the resultant equations are performed to demonstrate that the new inertial CIDR model leads to numerical convergence towards physically realistic solutions that are supported by discrete element method simulations.
Summary
Background
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely ...understood.
Objective
To clarify the best discriminators of the asthma‐COPD overlap phenotype from asthma and COPD subgroups using a clustering approach.
Methods
This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell‐related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k‐means clustering. Exacerbations of asthma and COPD were recorded during the 1‐year follow‐up period.
Results
The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma‐COPD overlap phenotype; cluster 3, patients with non‐atopic and late‐onset asthma; and cluster 4, patients with early‐onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval CI, 1.1‐5.6) in cluster 1 and 2.3 (95% CI, 1.0‐5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥310 IU/mL, blood eosinophil counts ≥280 cells/μL, a higher ratio of TBX21/GATA3, FEV1/FVC ratio <0.67 and smoking ≥10 pack‐years with an area under the curve of 0.94 (95% CI, 0.90‐0.98) in the receiver operating characteristic analysis.
Conclusions and Clinical Relevance
The asthma‐COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2‐low endotype.
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone ...disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment ...resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.
We investigated a high-quality novel AlInSb buffer layer to increase the electron mobility of an InSb quantum well (QW) structure, which was grown on a (100) GaAs substrate by molecular beam epitaxy. ...We achieved high electron mobility in the InSb QW structure using an Al0.25In0.75Sb/Al0.15In0.85Sb stepped buffer layer and realized reduced compressive strain and improved surface roughness. In addition, we investigated the dependence of the Al0.25In0.75Sb layer thickness in the Al0.25In0.75Sb/Al0.15In0.85Sb stepped buffer layer on the electron mobility characteristics. We only obtained increased electron mobility using the Al0.25In0.75Sb layer within a critical thickness range.
•We investigated a novel AlInSb buffer layer to increase electron mobility.•High electron mobility was achieved in InSb Quantum-well structure.•Increased electron mobility was only realized in a layer with critical thickness.•Reduced compressive strain and improved surface roughness were realized.•A well-designed stepped buffer layer can increase electron mobility in InSb-QWs.
Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells ...specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of β-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.
Human sialidase 2 (NEU2) is a cytoplasmic sialidase that degrades sialylglycoconjugates, including glycoproteins and gangliosides, via hydrolysis of terminal sialic acids to produce asialo-type ...molecules. Here, we first report the inhibitory effects of a series of synthetic sialyldendrimers comprising three types Dumbbell(1)6-S-Neu5Ac(6), Fan(0)3-S-Neu5Ac(3) and Ball(0)4-S-NeuAc(4) toward recombinant human NEU2 in vitro. Among them, Dumbbell(1)6-S-Neu5Ac(6) exhibited the most potent inhibitory activity (concentration causing 50% inhibition (IC(50)), 0.4 ∼ 0.5 mM). In addition, NeuSLac and NeuSCel carrying thiosialyltrisaccharide moieties exhibited more potent inhibitory effects than NeuSGal and NeuSGlc carrying thiosialyldisaccharides. Docking models composed of NEU2 and the thiosialyloligosaccharide suggested that the active pocket of NEU2 prefers the second galactose-β (Galβ) to the glucose-β (Glcβ) residue in the trisaccharide structure, there being a hydrogen bond between the 4-hydroxy group of the second Galβ and the side chain of the D46 residue of NEU2. The third Glcβ residues of NeuSLac and NeuSCel were also predicted to be stabilized by hydrogen bonds with the side chains of the R21, R304, D358 and Y359 residues of NEU2. NEU2 mutants (D358A and Y359A) exhibited reduced affinity for NeuSLac carrying thiosialyltrisaccharide moieties, suggesting the significant roles of D358 and Y359 residues in recognition of thiosialyltrisaccharide moieties of NeuSLac bound in the active pocket of NEU2. Thus, the present sialyldendrimers could be utilized not only as a new class of NEU2 inhibitors but also as molecular probes for evaluating the biological functions of NEU2, including the catalytic activity and mechanism as to natural substrates carrying sialyloligosaccharides.
Summary Background Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and ...safety of TAS-102—a novel oral nucleoside antitumour agent. Methods Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2:1) to either TAS-102 (35 mg/m2 given orally twice a day in a 28-day cycle 2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880. Findings 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11·3 months (IQR 10·7–14·0). Median overall survival was 9·0 months (95% CI 7·3–11·3) in the TAS-102 group and 6·6 months (4·9–8·0) in the placebo group (hazard ratio for death 0·56, 80% CI 0·44–0·71, 95% CI 0·39–0·81; p=0·0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred. Interpretation TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies. Funding Taiho Pharmaceutical.
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