Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine ...substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.
Ferritic stainless steel achieves a lower and steady price level due to low nickel content compared to duplex and austenitic stainless steels. Accordingly, the combination of ferritic stainless steel ...tube and concrete will have better application prospects in corrosive marine environments. However, the structural application of concrete-filled ferritic stainless steel tube (CFFSST) members is still limited due to the absence of performance data and design guidelines. Accordingly, this paper aims to comprehensively investigate the behaviour of eccentrically loaded concrete-filled rectangular ferritic stainless steel tubular (CFRFSST) slender columns using the nonlinear finite element (FE) method, and develop a suitable design method. Two different material models were introduced to simulate corner and flat regions of rectangular ferritic stainless steel tube. Good consistency was found between the simulation and experimental results against the failure mode, ultimate load and moment, and axial load versus mid-height deflection curves for eccentrically loaded CFRFSST slender columns. This is followed by the mechanism analysis and parameter study of the studied CFRFSST columns, which revealed that the longitudinal stress and Mises stress show significant changes perpendicular to the loading line direction, while there is almost no change along the loading line direction. In addition, the initial stiffness and ultimate load increased by increasing the cross-sectional aspect ratio, yield stress and concrete strength, while they decreased as the eccentricity ratio, slenderness ratio and width-to-thickness ratio increased. The outputs of the FE analysis and existing experimental results were used to examine the applicability of current design codes for designing the studied CFRFSST columns. The results demonstrated an unexpected deviation generated in the design predictions. At the end, a new design method for eccentrically loaded CFRFSST slender columns was proposed which achieved better predictive consistency.
•Different material models are introduced to simulate the flat and corner regions of rectangular ferritic stainless tube.•Good consistency is found between the outputs of FE analysis and experimental results.•The column parameters have significant influence on behavior of CFRFSST columns.•The practicability of existing design codes for CFRFSST columns is assessed.•A new design method for eccentrically loaded CFRFSST slender columns is proposed.
L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by ...the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.
A comprehensive experimental and numerical study of concrete-filled double skin tubular (CFDST) stub columns is presented in this paper. A total of 23 tests was carried out on CFDST specimens with ...austenitic stainless steel circular hollow section (CHS) outer tubes, high strength steel CHS inner tubes, and three different grades of concrete infill (C40, C80 and C120). The ultimate load, load-deflection histories and failure modes of the stub columns are reported. The test results were employed in a parallel numerical simulation programme for the validation of the finite element (FE) model, by means of which an extensive parametric study was undertaken to extend the available results over a wide range of cross-section slendernesses, inner tube strengths and concrete grades. The experimentally and numerically derived data were then employed to assess the applicability of the existing European, Australian and North American design provisions for composite carbon steel members to the design of the studied CFDST cross-sections. Overall, the existing design rules are shown to provide generally safe-sided (less so for the higher concrete grades) but rather scattered capacity predictions. Use of an effective concrete strength is recommended for the higher concrete grades and shown to improve the consistency of the design capacity predictions.
•Tests and numerical analysis were conducted on concrete-filled double skin sections.•Structural behaviour of stub columns was studied.•The applicability of the existing design provisions was assessed.•Use of an effective concrete strength is recommended for the higher concrete grades.•Modification to existing design rules shown the improvement on the design capacity predictions.
•Stub column tests were conducted on press-braked S960 ultra-high strength steel angle and channel sections.•Numerical models were developed and validated against test results, and then used to ...perform parametric studies.•The existing codified design rules were assessed against the test and numerical results, indicting inaccuracy.•Revised design rules were proposed and shown to yield improved design accuracy.
A comprehensive experimental and numerical study of the cross-sectional compressive behaviour and resistances of press-braked S960 ultra-high strength steel (UHSS) angle and channel section stub columns is reported in this paper. The experimental study was carried out on four equal-leg angle sections and eight plain channel sections, and comprised material testing, initial local geometric imperfection measurements and 18 stub column tests. The experimental setups, procedures and key observations were fully presented. The experimental study was then supplemented by a finite element (FE) simulation programme, in which FE models were firstly developed to replicate the test structural responses and subsequently used to generate further numerical data over a wide variety of cross-section sizes. It is worth noting that the current international standards established in Europe, America and Australia/New Zealand only cover the design of structural members with material grades up to S700, and thus the examined S960 UHSS angle and channel section stub columns are out of the scope of the existing design standards. In this study, the experimentally and numerically acquired data was adopted to assess the applicability of the codified provisions and formulations to the design of S960 UHSS angle and channel section stub columns. The assessment results generally indicated that the current European code leads to overall consistent and accurate predictions of cross-section compression resistances, but with many overestimated predicted resistances for S960 UHSS channel section stub columns, while the American and Australian/New Zealand standards yield unduly scattered design cross-section compression resistances, with unsafe and overly conservative predicted resistances respectively for S960 UHSS channel section stub columns and slender angle section stub columns. Revised codified design rules were also proposed, and shown to yield safe, accurate and consistent design cross-section compression resistances for S960 UHSS angle and channel section stub columns.
•Tests and numerical analysis were conducted on concrete-filled double skin sections.•Structural behaviour of stub columns was studied.•The applicability of the existing design provisions was ...assessed.•Use of an effective concrete strength is recommended for the higher concrete grades.•Use of a higher buckling coefficient to consider the local buckling of the steel tubes.•Modification to existing design rules shown to provide improved capacity predictions.
The use of concrete-filled double skin tubular (CFDST) cross-sections for compression members has become increasingly popular in construction. A recently proposed innovative form of CFDST cross-section, ultilising stainless steel for the outer tube, offers the combined advantages of the composite action seen in CFDST member alongside the durability and ductility associated with stainless steel. CFDST sections with stainless steel outer tubes, for which there are currently little experimental data, are the focus of the present study. A comprehensive experimental and numerical investigation into the compressive behaviour of CFDST sections with square stainless steel outer tubes is presented in this paper. A total of 19 specimens was tested under uniform axial compression, and the test observations are fully reported. The ultimate loads, load-displacement curves and failure modes from the tests were used for the validation of finite element (FE) models. Parametric finite element analyses were then performed. The combined set of experimentally and numerically derived data was employed to assess the applicability of the existing European, Australian and American design provisions for composite carbon steel members to the design of the studied CFDST cross-sections. Overall, the existing design rules are shown to provide generally safe-sided (less so for the higher concrete grades) but rather scattered capacity predictions. Modifications to the current design codes are also considered—a higher buckling coefficient k of 10.67 to consider the beneficial restraining effect of the concrete on the local buckling of the stainless steel outer tubes, as well as a reduction factor η to reflect the reduced relative effectiveness of higher concrete grades. Overall, the comparisons demonstrated that improved accuracy and consistency were achieved when the modified design rules were applied.
•Flexural behaviour of press-braked S960 UHSS channel section beams were studied.•20 beam tests were performed about the minor axes in the u and n orientations.•Numerical simulations and parametric ...studies were conducted.•The applicability of the design codes was assessed based on test and FE results.
A thorough experimental and numerical study of the flexural behaviour and strengths of press-braked S960 ultra-high strength steel (UHSS) channel section beams bent about the minor principal axes is reported in this paper. The experimental study was conducted on eight different UHSS plain channel sections, and included measurements on the material flat and corner properties and initial local geometric imperfections of the beam specimens as well as 20 four-point bending tests performed about the minor principal axes in both the ‘u’ and ‘n’ orientations. A complementary numerical investigation was then conducted, where finite element (FE) models were firstly developed and validated against the experimental results, followed by parametric studies carried out to acquire further numerical data over a broader range of cross-section dimensions. It is worth noting that the existing design codes for steel structures, as established in Europe, America and Australia/New Zealand, are only applicable to those with material grades up to S690 (or S700 for Eurocode) and cannot be directly used for S960 UHSS structural members. In the present study, the applicability of the codified design provisions and formulations for flexural members to the examined S960 UHSS channel section beams was evaluated, based on the ultimate moments derived from structural testing and numerical modelling. The quantitative evaluation results generally revealed that the current European code provides overall consistent and precise flexural strength predictions for Class 1 and Class 2 S960 UHSS channel sections in minor-axis bending, but leads to a high level of inaccuracy (scatter and conservatism) for the design of their Class 3 and Class 4 counterparts, whilst the American specification and Australian/New Zealand standard result in scattered and excessively underestimated design flexural strengths, except for the cases of slender S960 UHSS channel section beams in ‘u’-orientation bending.
Cancer side population (SP) cells, which are often referred to as cancer stem cells, are thought to be responsible for lung cancer chemotherapy resistance, and currently no drug can specifically ...target these cells. We hypothesize low-molecular-weight heparin (LMWH) may affect the biological properties of SP cells and could be used to clinically target these cells. To test this, SP cells were isolated from cisplatin (DDP)-resistant lung adenocarcinoma A549/DDP cells by flow cytometric sorting. Compared to non-SP cells, SP cells formed increased numbers of colonies in vitro, and had a 1000-fold increase in tumorigenicity in vivo. Proliferation and apoptosis assays demonstrated LMWH had no significant effect on lung SP cell proliferation or apoptosis. However, LMWH reduced lung SP cell colony formation ability and protein expression of the multidrug transporter, ABCG2, by FACS and western blot analyses without affecting its mRNA levels by RT-PCR. Consistently, immunohistochemistry stainings of ABCG2 in LMWH-treated tumor tissues were significantly reduced compared with those in controls. Further, we found proteasomal inhibitor MG132, but not lysosomal inhibitors leupeptin and pepstatin A, could restore ABCG2 protein levels in LMWH-treated SP cells. These suggest LMWH ablates lung SP cell chemoresistance by proteasome-mediated reduction of ABCG2 protein levels without affecting its mRNA levels. We also determined LMWH combined with cisplatin could overcome cisplatin-resistance and induced lung SP cells apoptosis both in vitro and in vivo. This study provides an experimental basis for using a combination of LMWH, which targets lung SP cells, with chemotherapy to improve lung cancer survival.
•Tests and numerical analysis conducted on concrete-filled double skin sections in bending.•Applicability of existing structural design provisions assessed.•Use of an effective concrete strength ...recommended for higher concrete grades.•Modification to existing design rules shown to provide improved capacity predictions.
The structural performance of circular concrete-filled double skin tubular (CFDST) cross-sections with stainless steel outer tubes has been examined herein based on experiments and numerical modelling. A laboratory testing programme comprising a total of 22 four-point bending tests was performed on seven CFDST cross-sections with varying concrete grades. The details of the test rig and procedures, as well as the key test observations, including the failure moment capacities, moment–curvature curves and failure modes, are fully reported. A numerical modelling programme was then carried out; a finite element (FE) model was first established to replicate the test observations, and then adopted to conduct a parametric study to acquire further FE data over a broader spectrum of material strengths and cross-section slendernesses. Based on the combined set of test and FE results, the general design provisions for concrete-filled carbon steel members in the current European and American design codes were evaluated for their applicability to the studied CFDST cross-sections. Overall, the results revealed that both of the examined design codes yield unduly conservative (less so for the higher concrete grades) and scattered moment resistance predictions, though some moment resistances predicted from the European code were on the unsafe side. Modifications, including a concrete reduction factor η to reflect the reduced relative effectiveness of using higher concrete grades and a modified stress distribution considering the partial spread of plasticity, were proposed and shown to improve the consistency of the resistance predictions. Finally, the reliability of the current and modified design rules was demonstrated through statistical analyses.
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