Magnetic Resonance Elastography and Computational Modeling Identify Heterogeneous Lung Biomechanical Properties during Cystic Fibrosis.

The lung is a dynamic mechanical organ and several pulmonary disorders are characterized by heterogeneous changes in the lung's local mechanical properties (i.e. stiffness). These alterations lead to abnormal lung tissue deformation (i.e. strain) which have been shown to promote disease progression. Although heterogenous mechanical properties may be important biomarkers of disease, there is currently no non-invasive way to measure these properties for clinical diagnostic purposes. In this study, we use a magnetic resonance elastography technique to measure heterogenous distributions of the lung's shear stiffness in healthy adults and in people with Cystic Fibrosis. Additionally, computational finite element models which directly incorporate the measured heterogenous mechanical properties were developed to assess the effects on lung tissue deformation. Results indicate that consolidated lung regions in people with Cystic Fibrosis exhibited increased shear stiffness and reduced spatial heterogeneity compared to surrounding non-consolidated regions. Accounting for heterogenous lung stiffness in healthy adults did not change the globally averaged strain magnitude obtained in computational models. However, computational models that used heterogenous stiffness measurements predicted significantly more variability in local strain and higher spatial strain gradients. Finally, computational models predicted lower strain variability and spatial strain gradients in consolidated lung regions compared to non-consolidated regions. These results indicate that spatial variability in shear stiffness alters local strain and strain gradient magnitudes in people with Cystic Fibrosis. This imaged-based modeling technique therefore represents a clinically viable way to non-invasively assess lung mechanics during both health and disease.

Professional Self-Concept, Job Stress, and Triage Competency Among Emergency Nurses: Secondary Data Analysis of a Cross-Sectional Survey.

INTRODUCTION: This study aimed to evaluate the indirect relationship of job stress with triage competency through professional self-concept among emergency nurses in Korea. METHODS: A secondary data analysis of survey data from 132 questionnaires was used. A convenience sample of emergency nurses working in regional or local emergency centers in 2 Korean cities was recruited for the survey. Study variables were analyzed using descriptive statistics, correlation, and a model tested using the Hayes PROCESS macro (Model 4) mediation model. RESULTS: Job stress alone was not associated directly with triage competency (ß = 0.01, P = .74). An indirect pathway was observed between job stress and triage competency through professional self-concept (F = 5.85, P < .001, R2 = 0.33). In the tested model, job stress was associated with professional self-concept (ß = -0.05, P < .05) and professional self-concept was associated with triage competency (ß = 0.79, P ≤ .001). CONCLUSION: Professional self-concept may be an important determinant of triage competency among emergency nurses. To increase triage competency among emergency nurses, individual nurse and management efforts are recommended to foster professional self-concept and reduce emergency nurse job stress.

Reduced stiffness and augmented traction force in type 2 diabetic coronary microvascular smooth muscle.

Type 2 diabetic (T2DM) coronary resistance microvessels (CRMs) undergo inward hypertrophic remodeling associated with reduced stiffness and reduced coronary blood flow in both mice and pig models. Since reduced stiffness does not appear to be due to functional changes in the extracellular matrix, this study tested the hypothesis that decreased CRM stiffness in T2DM is due to reduced vascular smooth muscle cell (VSMC) stiffness, which impacts the traction force generated by VSMCs. Atomic force microscopy (AFM) and traction force microscopy (TFM) were conducted on primary low-passage CRM VSMCs from normal Db/db and T2DM db/db mice in addition to low-passage normal and T2DM deidentified human coronary VSMCs. Elastic modulus was reduced in T2DM mouse and human coronary VSMCs compared with normal (mouse: Db/db 6.84 ± 0.34 kPa vs. db/db 4.70 ± 0.19 kPa, P < 0.0001; human: normal 3.59 ± 0.38 kPa vs. T2DM 2.61 ± 0.35 kPa, P = 0.05). Both mouse and human T2DM coronary microvascular VSMCs were less adhesive to fibronectin compared with normal. T2DM db/db coronary VSMCs generated enhanced traction force by TFM (control 692 ± 67 Pa vs. db/db 1,507 ± 207 Pa; P < 0.01). Immunoblot analysis showed that T2DM human coronary VSMCs expressed reduced ß1-integrin and elevated ß3-integrin (control 1.00 ± 0.06 vs. T2DM 0.62 ± 0.14, P < 0.05 and control 1.00 ± 0.49 vs. T2DM 3.39 ± 1.05, P = 0.06, respectively). These data show that T2DM coronary VSMCs are less stiff and less adhesive to fibronectin but are able to generate enhanced force, corroborating previously published computational findings that decreasing cellular stiffness increases the cells' ability to generate higher traction force.NEW & NOTEWORTHY We show here that a potential causative factor for reduced diabetic coronary microvascular stiffness is the direct reduction in coronary vascular smooth muscle cell stiffness. These cells were also able to generate enhanced traction force, validating previously published computational models. Collectively, these data show that smooth muscle cell stiffness can be a contributor to overall tissue stiffness in the coronary microcirculation, and this may be a novel area of interest for therapeutic targets.

Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland.

The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten-/- fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.

Glioblastoma stem cells are regulated by interleukin-8 signaling in a tumoral perivascular niche.

Glioblastoma multiforme contains a subpopulation of cancer stem-like cells (CSC) believed to underlie tumorigenesis and therapeutic resistance. Recent studies have localized CSCs in this disease adjacent to endothelial cells (EC) in what has been termed a perivascular niche, spurring investigation into the role of EC-CSC interactions in glioblastoma multiforme pathobiology. However, these studies have been limited by a lack of in vitro models of three-dimensional disease that can recapitulate the relevant conditions of the niche. In this study, we engineered a scaffold-based culture system enabling brain endothelial cells to form vascular networks. Using this system, we showed that vascular assembly induces CSC maintenance and growth in vitro and accelerates tumor growth in vivo through paracrine interleukin (IL)-8 signaling. Relative to conventional monolayers, endothelial cells cultured in this three-dimensional system not only secreted enhanced levels of IL-8 but also induced CSCs to upregulate the IL-8 cognate receptors CXCR1 and CXCR2, which collectively enhanced CSC migration, growth, and stemness properties. CXCR2 silencing in CSCs abolished the tumor-promoting effects of endothelial cells in vivo, confirming a critical role for this signaling pathway in GMB pathogenesis. Together, our results reveal synergistic interactions between endothelial cells and CSCs that promote the malignant properties of CSCs in an IL-8-dependent manner. Furthermore, our findings underscore the relevance of tissue-engineered cell culture platforms to fully analyze signaling mechanisms in the tumor microenvironment.