The effectiveness of near-infrared imaging (NIR) interrogation of epidermal growth factor receptor (EGFR) expression as a sensitive biomarker of oral squamous cell carcinoma (OSCC) response to ...arsenic trioxide therapy was studied in mice.
A431 OSCC in vitro were exposed to 0 µM, 0.5 µM, 2.5 µM, or 5 µM of As(2)O(3) for 0 h, 24 h, 48 h and 72 h. Confocal microscopy and flow cytometry confirmed EGFR expression and demonstrated a sensitivity dose-related signal decline with As(2)O(3) treatment. Next, mice with pharynx-implanted A431 cells received As(2)O(3) i.p. every 48 h at 0.0, 0.5, 2.5, or 5 mg/kg/day (n = 6/group) from day 0 to 10. An intravenous NIR probe, EGF-Cy5.5, was injected at baseline and on days 4, 8, and 12 for dynamic NIR imaging. Tumor volume and body weights were measured three times weekly.
In vitro, A431 EGFR expression was well appreciated in the controls and decreased (p<0.05) with increasing As(2)O(3) dose and treatment duration. In vivo EGFR NIR tumor signal intensity decreased (p<0.05) in As(2)O(3) treated groups versus controls from days 4 to 12, consistent with increasing dosage. Tumor volume diminished in a dose-related manner while body weight was unaffected. Immunohistochemical staining of excised tumors confirmed that EGFR expression was reduced by As(2)O(3) treatment in a dose responsive pattern.
This study demonstrates for the first time that OSCC can be interrogated in vivo by NIR molecular imaging of the EGFR and that this biomarker is effective for the longitudinal assessment of OSCC response to As(2)O(3) treatment.
Rotational stiffness characteristics of the disk lock joint have a significant effect on the load bearing capacity and stability of disk lock scaffolds. However, experimental researches on scaffold ...joints are usually expensive and time consuming, especially when different joint connection configurations and loading modes are involved. This paper explores the feasibility and effectiveness of the 3D nonlinear finite element analysis method for studying the rotational stiffness characteristics of the disk lock joint. Detailed geometric models of the disk lock joints are established and the geometric models are meshed with finite elements. The elastoplastic constitutive model based on the isotropic hardening law and the associated flow rule is used to describe the complete deformation process of the material, and the penalty stiffness method is applied to accurately simulate the interaction between different components. Thus the complete finite element models of the disk lock joints are established. Firstly, the loading processes of the one-way disk lock joint are simulated and verified by experiments. To further demonstrate the robustness and effectiveness of the finite element method, the loading processes of disk lock joints under different connection configurations and loading modes are simulated. The influences of connection configurations and loading modes on joint rotational stiffness are also investigated to reveal the load bearing mechanism of the disk lock joint, and thereby contribute to better predictions of the load bearing capacity of the disk lock scaffolds.
•Detailed geometric and finite element models of disk lock joints are established.•Elastoplastic analysis is performed to reveal the load bearing mechanism of joint.•Effectiveness of FEM for studying disk lock joint rotational stiffness is validated.•Influences of connection configurations and loading modes are investigated.
Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype ...specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.
Background
The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually ...suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification.
Objective
This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy.
Methods
We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms.
Results
The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway’s components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD.
Conclusions
The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.
Abstract
Drawing on the attention‐based view and leadership theory, this study proposes a theoretical framework for the relationship between CEOs' attention load and firms' sustainability ...orientation, with supply chain leadership and CEOs' social capital playing mediating and moderating roles, respectively. We tested the theoretical framework by analysing panel data on 236 CEOs from 102 listed companies in the agricultural and food industries in China from 2012 to 2019. We find that (a) CEOs' attention load negatively affects firms' sustainable orientation; (b) this relationship is partially mediated by firms' supply chain leadership; and (c) CEOs' social capital positively moderates this mediating effect. Lower CEO attention loads are associated with increased supply chain leadership and higher sustainability orientation for the firm. Additionally, CEOs' social capital positively moderates the relationship between attention load and sustainability orientation. This study integrates the attention‐based view and leadership theory into sustainable development research, investigating the translation mechanism of CEO attention to a firm's managerial orientation towards sustainability. It contributes to leadership theory by extending sustainable and ethical leadership from an intra‐ to inter‐organisational context.
•The behavior of large-size glulam bolted joints was studied experimentally.•Crack modes were classified and related crack moments were calculated.•Numerical models considering the splitting failure ...were created and validated.•Moment-rotation curves could be obtained according to the proposed equations.
This paper presents a systematic study of the rotational performance of large-size glulam bolted joints (section height of at least 600 mm). The mechanical properties were investigated experimentally considering both the section height and bolt arrangement. All specimens failed with the splitting of the lowest row of bolts, and the numerical model considering splitting failure was validated by experimental results. According to the first position of crack initiation, crack modes were classified as tensile and compressive, and theoretical derivations of the crack moment were proposed. Moment-rotation curves were accurately obtained using the proposed equations of stiffness and moment.
Objectives
This study aimed to evaluate the feasibility and reproducibility of using cardiovascular magnetic resonance feature tracking (CMR-FT) for analysis of bi-ventricular strain and strain rate ...(SR) in hypertrophic cardiomyopathy (HCM) patients as well as to explore the correlation between right ventricular (RV) and left ventricular (LV) deformation.
Methods
A total of 60 HCM patients and 48 controls were studied. Global and segmental peak values of bi-ventricular longitudinal, circumferential, radial strain, and systolic SR were analyzed. Pearson analysis was performed to investigate the correlation of RV and LV deformation. Intra-observer and inter-observer reproducibility were also assessed.
Results
LV mass in the HCM group was significantly higher than that in the control group. LV end-systolic and end-diastolic volume and RV end-systolic and end-diastolic volume in the HCM group were all significantly lower than the correlated parameters in the control group (
p
< 0.001, respectively), whereas no statistical difference was found in ejection fraction (
p
> 0.05). Global longitudinal strain (GLS), global longitudinal strain rate (GLSR), global circumferential strain (GCS), global circumferential strain rate (GCSR), global radial strain (GRS), and global radial strain rate (GRSR) of the LV and RV were all significantly lower than the control group, and segmental strain and SR were also true (
p
< 0.001, respectively). Bi-ventricular strain and SR measurements were highly reproducible at both intra- and inter-observer levels. Additionally, Pearson analysis showed RV GCS, GLS, and GRS positively correlated with LV GCS, GLS, and GRS (
r
= 0.713,
p
< 0.001;
r
= 0.728,
p
< 0.001;
r
= 0.730,
p
< 0.001, respectively).
Conclusions
CMR-FT is a promising approach to analyze impairment of global and segmental myocardium deformation in HCM patients non-invasively and quantitatively.
Key Points
•
CMR-FT allows for advanced myocardial characterization with high reproducibility.
•
As compared with controls, HCM patients have significant differences in CMR-FT strain analysis while ejection fraction was similar.
•
CMR-FT may serve as an early biomarker of HCM in subjects at risk.
•A novel overlapping finite element is presented to solve transient wave propagation problems.•The Bathe implicit time integration method is used.•The solution scheme shows monotonic convergence of ...calculated solutions with decreasing time step size.•The solution scheme shows a solution accuracy almost independent of the direction of wave propagation through the mesh.•A dispersion analysis is given and various example problems are solved to illustrate the performance of the solution scheme.
We present novel overlapping finite elements used with the Bathe time integration method to solve transient wave propagation problems. The solution scheme shows two important properties that have been difficult to achieve in the numerical solution of general wave propagations: monotonic convergence of calculated solutions with decreasing time step size and a solution accuracy almost independent of the direction of wave propagation through the mesh. The proposed scheme can be efficiently used with irregular meshes. These properties make the scheme (the combined spatial and temporal discretizations) promising to solve general wave propagation problems in complex geometries involving multiple waves. A dispersion analysis is given and various example problems are solved to illustrate the performance of the solution scheme.
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia
. This result suggests that leukaemia uses unique ...mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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