An Unlikely Source of Iodine Uptake: A Bronchogenic Cyst Masquerading as Metastatic Thyroid Cancer.

Radioactive iodine therapy and posttreatment scanning are essential components of differentiated thyroid carcinoma treatment and detection of metastatic disease. False-positive results can be seen on an I-131 scan and are important for clinicians to be aware of. Here, we present a case of a 33-year-old female with follicular thyroid carcinoma who was noted to have an area of moderate uptake in the chest on a whole-body scan following remnant ablation with 30 mCi of I-131 (1.11GBq) concerning for a metastatic hilar lymph node. This was determined to be a mediastinal bronchogenic cyst on surgical pathology. It has been previously proposed that the expression of sodium iodide symporters in some bronchogenic cysts could be the mechanism by which iodine uptake is seen within them. We were able to demonstrate positive immunohistochemical staining for both sodium iodide symporter and the associated paired box gene 8 transcription factor in the cyst sample, which supports the proposed theory.

Quantification of nasal airflow resistance in English bulldogs using computed tomography and computational fluid dynamics.

Stenotic nares, edematous intranasal turbinates, mucosal swelling, and an elongated, thickened soft palate are common sources of airflow resistance for dogs with brachycephalic airway syndrome. Surgery has focused on enlarging the nasal apertures and reducing tissue of the soft palate. However, objective measures of surgical efficacy are lacking. Twenty-one English bulldogs without previous surgery were recruited for this prospective, pilot study. Computed tomography was performed using conscious sedation and without endotracheal intubation using a 128 multidetector computed tomography scanner. Raw multidetector computed tomography data were rendered to create a three-dimensional surface mesh model by automatic segmentation of the air-filled nasal passage from the nares to the caudal soft palate. Three-dimensional surface models were used to construct computational fluid dynamics models of nasal airflow resistance from the nares to the caudal aspect of the soft palate. The computational fluid dynamics models were used to simulate airflow in each dog and airway resistance varied widely with a median 36.46 (Pa/mm)/(l/s) and an interquartile range of 19.84 to 90.74 (Pa/mm)/(/s). In 19/21 dogs, the rostral third of the nasal passage exhibited a larger airflow resistance than the caudal and middle regions of the nasal passage. In addition, computational fluid dynamics data indicated that overall measures of airflow resistance may significantly underestimate the maximum local resistance. We conclude that computational fluid dynamics models derived from nasal multidetector computed tomography can quantify airway resistance in brachycephalic dogs. This methodology represents a novel approach to noninvasively quantify airflow resistance and may have utility for objectively studying effects of surgical interventions in canine brachycephalic airway syndrome.

Celect Inferior Vena Cava Wall Strut Perforation Begets Additional Strut Perforation.

PURPOSE: To identify risk factors for strut perforation following Celect inferior vena cava (IVC) filter (IVCF) placement and to use finite element modeling to predict the mechanical impact of long-dwelling filters. MATERIALS AND METHODS: Ninety-one patients with three computed tomography (CT) studies were evaluated following Celect IVCF placement (2007-2013). Three-dimensional finite element models of the Celect IVCF were developed to simulate mechanical deformation of the IVCF encountered in vivo. Simulated forces applied by the primary struts on the IVC wall were measured as a function of luminal area and tilt angle. RESULTS: Although 33 patients (36%) showed primary strut perforation on initial follow-up CT, 60 patients (66%) showed progressive perforation over time (P < .0001), with 72 patients (79%) showing primary strut perforation on the final CT (average, 554 d). Female patients (P = .004) and those with malignancy history (P = .01) had significantly higher perforation rates at a given time. Caval area also decreased after primary filter strut perforation, and we therefore proposed that this was the mechanism for progressive perforation. Consistent with this mechanism, three-dimensional finite element modeling demonstrated increasing strut force with decreasing IVC diameter. CONCLUSIONS: Celect IVCF primary strut perforation is progressive over time and is more common in female patients and those with a history of malignancy. In addition, this progressive perforation may be predicted by three-dimensional finite element modeling. These patient populations may require closer follow-up after IVCF placement to prevent or reduce the risk for filter complication or worsening perforation.

Computational analysis of microbubble flows in bifurcating airways: role of gravity, inertia, and surface tension.

Although mechanical ventilation is a life-saving therapy for patients with severe lung disorders, the microbubble flows generated during ventilation generate hydrodynamic stresses, including pressure and shear stress gradients, which damage the pulmonary epithelium. In this study, we used computational fluid dynamics to investigate how gravity, inertia, and surface tension influence both microbubble flow patterns in bifurcating airways and the magnitude/distribution of hydrodynamic stresses on the airway wall. Direct interface tracking and finite element techniques were used to simulate bubble propagation in a two-dimensional (2D) liquid-filled bifurcating airway. Computational solutions of the full incompressible Navier-Stokes equation were used to investigate how inertia, gravity, and surface tension forces as characterized by the Reynolds (Re), Bond (Bo), and Capillary (Ca) numbers influence pressure and shear stress gradients at the airway wall. Gravity had a significant impact on flow patterns and hydrodynamic stress magnitudes where Bo > 1 led to dramatic changes in bubble shape and increased pressure and shear stress gradients in the upper daughter airway. Interestingly, increased pressure gradients near the bifurcation point (i.e., carina) were only elevated during asymmetric bubble splitting. Although changes in pressure gradient magnitudes were generally more sensitive to Ca, under large Re conditions, both Re and Ca significantly altered the pressure gradient magnitude. We conclude that inertia, gravity, and surface tension can all have a significant impact on microbubble flow patterns and hydrodynamic stresses in bifurcating airways.

Loss of myoferlin redirects breast cancer cell motility towards collective migration.

Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT) and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF) is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET) and reduced invasion through extracellular matrix (ECM). However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231(MYOF-KD)) leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA-231(LTVC)) and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA-231(MYOF-KD) cells migrated directionally and collectively, while MDA-231(LTVC) cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231(MYOF-KD) cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA-231(MYOF-KD) cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA-231(MYOF-KD) tumors were highly circularized and did not invade locally into the adventia in contrast to MDA-231(LTVC)-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate that changes in biomechanical properties following loss of this protein may be an effective way to alter the invasive capacity of cancer cells.

Finite element analysis of traction force microscopy: influence of cell mechanics, adhesion, and morphology.

The interactions between adherent cells and their extracellular matrix (ECM) have been shown to play an important role in many biological processes, such as wound healing, morphogenesis, differentiation, and cell migration. Cells attach to the ECM at focal adhesion sites and transmit contractile forces to the substrate via cytoskeletal actin stress fibers. This contraction results in traction stresses within the substrate/ECM. Traction force microscopy (TFM) is an experimental technique used to quantify the contractile forces generated by adherent cells. In TFM, cells are seeded on a flexible substrate and displacements of the substrate caused by cell contraction are tracked and converted to a traction stress field. The magnitude of these traction stresses are normally used as a surrogate measure of internal cell contractile force or contractility. We hypothesize that in addition to contractile force, other biomechanical properties including cell stiffness, adhesion energy density, and cell morphology may affect the traction stresses measured by TFM. In this study, we developed finite element models of the 2D and 3D TFM techniques to investigate how changes in several biomechanical properties alter the traction stresses measured by TFM. We independently varied cell stiffness, cell-ECM adhesion energy density, cell aspect ratio, and contractility and performed a sensitivity analysis to determine which parameters significantly contribute to the measured maximum traction stress and net contractile moment. Results suggest that changes in cell stiffness and adhesion energy density can significantly alter measured tractions, independent of contractility. Based on a sensitivity analysis, we developed a correction factor to account for changes in cell stiffness and adhesion and successfully applied this correction factor algorithm to experimental TFM measurements in invasive and noninvasive cancer cells. Therefore, application of these types of corrections to TFM measurements can yield more accurate estimates of cell contractility.

Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury.

To test the hypothesis that interleukin-6 (IL-6) contributes to the development of ventilator-associated lung injury (VALI), IL-6-deficient (IL6(-/-)) and wild-type control (WT) mice received intratracheal hydrochloric acid followed by randomization to mechanical ventilation (MV + IT HCl) or spontaneous ventilation (IT HCl). After 4 hours, injury was assessed by estimation of lung lavage protein concentration and total and differential cell counts, wet/dry lung weight ratio, pulmonary cell death, histologic inflammation score (LIS), and parenchymal myeloperoxidase (MPO) concentration. Vascular endothelial growth factor (VEGF) concentration was measured in lung lavage and homogenate, as IL-6 and stretch both regulate expression of this potent mediator of permeability. MV-induced increases in alveolar barrier dysfunction and lavage VEGF were attenuated in IL6(-/-) mice as compared with WT controls, whereas tissue VEGF concentration increased. The effects of IL-6 deletion on alveolar permeability and VEGF concentration were inflammation independent, as parenchymal MPO concentration, LIS, and lavage total and differential cell counts did not differ between WT and IL6(-/-) mice following MV + IT HCl. These data support a role for IL-6 in promoting VALI in this two-hit model. Strategies to interfere with IL-6 expression or signaling may represent important therapeutic targets to limit the injurious effects of MV in inflamed lungs.

Pulmonary epithelial neuropilin-1 deletion enhances development of cigarette smoke-induced emphysema.

RATIONALE: Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development. OBJECTIVES: We sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS. METHODS: Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1-deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides. MEASUREMENTS AND MAIN RESULTS: Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide. CONCLUSIONS: These data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development.