Citations

Interstitial lung disease manifested as fibrotic and stiffened lung tissue, resulting in symptoms such as dyspnea and may lead to respiratory failure. We recently developed a lung ultrasound surface wave elastography for evaluating the elastic properties of superficial lung tissue. In this abstract, we present a finite element analysis to investigate the effects of pleural effusion on the shear wave propagation of superficial lung tissue. The muscle, pleural effusion, and lung tissue were simulated by a 2D planar model of an infinite elastic medium with densities for different materials. A nearly incompressible, linear elastic model was used to model muscle, pleural effusion and lung. The model was excited using a line source on the muscle surface. Harmonic excitations were performed at 100, 150 and 200 Hz with duration of 0.1 s. The boundaries of lung and muscle were attached to an infinite. The mesh of muscle, pleural effusion, and lung were constructed using linear quadrilateral elements. The infinite region was meshed by infinite elements (type CINPE4). The dynamic responses of the tissue model to the excitations were solved by the ABAQUS explicit dynamic solver with automatic step size control. Insignificant difference in shear wave speeds of lung tissue at different excitation frequencies was found in both simulations with and without taking into account the pleural effusion, indicating that pleural effusion does not affect the measurements of shear wave speeds in ultrasound elastography.

Lung ultrasound surface wave elastography (LUSWE) was developed as a non-invasive tool for assessing pulmonary fibrosis. In this research, the effect of the fleural fluid on surface wave speed measurement of the lung is studied. Low-cost sponges [J. Ultrasound Med. 2017; 36, 2133], as good lung phantoms, were used in this study. The ultrasound transmission gel was used to simulate the pleural fluid. A harmonic vibration was generated at sponge surfaces using a shaker at 100, 150, and 200 Hz. The sponge surface wave speeds were measured with a 6 MHz ultrasound probe for both with and without a thin layer gel. The ultrasound features of A and B-lines were clearly observed in every sponge model in our experiment. The surface wave speeds for the sponges with the gel were indistinguishable from those without the gel for each frequency. The surface wave speeds were faster at higher excitation frequencies which is consistent with our patient study results. It was conclude that the pleural fluid may not affect the lung surface wave speed measurement based upon our lung phantom sponge models.

Color flow imaging is an ultrasound imaging technique widely used to image the blood movement through arteries and veins. Quantification of velocity is urgently demanding. The objective of this study is to use ultrafast plane wave imaging to measure the flow in speed in vitro. For the flow phantom, the diagonal vessel (2-mm inner diameter at 40° angle) was studied with injection of blood mimic fluid via syringe pump at various volume rates (15, 20, 25, and 30 ml/min). Verasonics Vantage system (Verasonics Inc., Kirkland, WA, USA) and a linear array transducer L11-4v (Verasonics Inc., Kirkland, WA, USA) were used for ultrasound acquisition, a 8-angle (−7° to 7°) plane wave compounding with effective pulse-repetition frequency (PRF) of 1000 Hz was used (central frequency = 6.42 MHz, number of transmit cycles = 4). A total of 600 ensembles were acquired. The frame rate was 1000/s.[XZ1] [BZ2] The ultrasound in-phase quadrature data size was 195 × 156 × 600 (axial x lateral x temporal) with data type of complex double. Singular value decomposition (SVD)-based ultrasound blood flow clutter filters was used for ultrafast plane wave imaging.[XZ3] [BZ4] Randomized SVD was utilized to filter noise and tissue motion. Power Doppler image was generated. The color flow images were generated by using the 2-D autocorrelation method. Results showed that color flow measurement can quantitatively evaluate the flow speed in the tube of the flow phantom.

A lung ultrasound surface wave elastography (LUSWE) technique is developed for assessing interstitial lung disease (ILD). In LUSWE, a 0.1 second harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration indenter in the same intercostal region to measure the generated surface wave speed of the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume. The upper anterior lungs are tested through the second intercostal space in the mid-clavicular line. The lower lateral lungs are tested in the mid-axillary line and the lower posterior lungs are tested in the mid-scapular line. In a prospective clinical study, we measure both lungs through the six intercostal regions for patients and healthy controls. The surface wave speed is measured at 100 Hz, 150 Hz, and 200 Hz. Significant differences of wave speed between patients and controls were found in all lung regions at all frequencies. We also found positive correlation between LUSWE and CT analyses. LUSWE is a safe and noninvasive technique for generating and measuring surface wave propagation on the lung. LUSWE may be useful for assessing ILD.

Lung density is directly associated with lung pathology. Computed Tomography (CT) evaluates lung pathology using the Hounsfield unit (HU) but not directly the lung density. We recently developed a lung ultrasound surface wave elastography (LUSWE) technique for measuring the surface wave speed of superficial lung tissue. The objective of this study is to analyze lung density of superficial lung tissue using deep neural network (DNN) and wave speed measurements obtained from LUSWE. The synthetic training dataset (7,88,000 in total) in terms of wave speeds of superficial lung tissue at different excitation frequencies from LUSWE, viscoelasticity and density of lung tissue was used to train the DNN. DNN is composed of 3 hidden layers of 1024 neurons and trained for 10 epochs with a batch size of 4096 and a learning rate of 0.001 with Adam optimizer. Test dataset in terms of wave speeds at different excitation frequencies (100, 150, and 200 Hz) as well as elasticity was used to predict the lung density and evaluate its accuracy. The obtained results showed that predictions matched well with test dataset (validation accuracy is 0.997). This method may be useful to analyze lung density based on the LUSWE measurements.

Abstract Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.

Key Points We conducted the first exome-wide association study between germ line variant genotype and survival outcomes after unrelated-donor BMT. A number of novel genes were found to significantly affect survival outcomes.

Normalization is the first critical step in microbiome sequencing data analysis used to account for variable library sizes. Current RNA-Seq based normalization methods that have been adapted for microbiome data fail to consider the unique characteristics of microbiome data, which contain a vast number of zeros due to the physical absence or under-sampling of the microbes. Normalization methods that specifically address the zero-inflation remain largely undeveloped. Here we propose geometric mean of pairwise ratios—a simple but effective normalization method—for zero-inflated sequencing data such as microbiome data. Simulation studies and real datasets analyses demonstrate that the proposed method is more robust than competing methods, leading to more powerful detection of differentially abundant taxa and higher reproducibility of the relative abundances of taxa.

Abstract Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a human cell surface protein expressed exclusively on eosinophils, mast cells, and basophils that, when engaged, induces eosinophil apoptosis and inhibits mast cell mediator release. This makes Siglec-8 a promising therapeutic target to treat diseases involving these cell types. However, preclinical studies of Siglec-8 targeting in vivo are lacking because this protein is only found in humans, apes, and some monkeys. Therefore, we have developed a mouse strain in which SIGLEC8 transcription is activated by Cre recombinase and have crossed this mouse with the eoCre mouse to achieve eosinophil-specific expression. We confirmed that Siglec-8 is expressed exclusively on the surface of mature eosinophils in multiple tissues at levels comparable to those on human blood eosinophils. Following ovalbumin sensitization and airway challenge, Siglec-8 knock-in mice generated a pattern of allergic lung inflammation indistinguishable from that of littermate controls, suggesting that Siglec-8 expression within the eosinophil compartment does not alter allergic eosinophilic inflammation. Using bone marrow from these mice, we demonstrated that, during maturation, Siglec-8 expression occurs well before the late eosinophil developmental marker C-C motif chemokine receptor 3, consistent with eoCre expression. Antibody ligation of the receptor induces Siglec-8 endocytosis and alters the phosphotyrosine profile of these cells, indicative of productive signaling. Finally, we demonstrated that mouse eosinophils expressing Siglec-8 undergo cell death when the receptor is engaged, further evidence that Siglec-8 is functional on these cells. These mice should prove useful to investigate Siglec-8 biology and targeting in vivo in a variety of eosinophilic disease models. We have developed a novel eosinophil-specific Siglec-8 knock-in mouse strain that facilitates the in vivo study of Siglec-8 targeting and biology.