Arun Thitaikumar

Bio: Arun Thitaikumar is an academic researcher from University of Texas at Austin. The author has contributed to research in topics: Elasticity (physics) & Vascular endothelial growth factor A. The author has an hindex of 7, co-authored 7 publications receiving 649 citations. Previous affiliations of Arun Thitaikumar include University of Houston & University of Texas MD Anderson Cancer Center.

IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control

Abstract: This page shows some examples of multimedia files. It is also available at: http://www.ieee-uffc.org/tr/mexample.pdf. For submission of multimedia manuscripts to TUFFC, please follow “Information for Contributors” at: http://www.ieeeuffc.org/tr/contrib.pdf. Multimedia Example Created by Jian-yu Lu, Editor-in-Chief, 07/07/03 IEEE Ultrasonics, Ferroelectrics, and Frequency Control Society 1. Color Figure: The IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control (TUFFC) now accepts color figures online with corresponding grayscale figures in print without additional charges if authors follow the multimedia manuscript submission procedure in the “Information for Contributors”. The “color figures” icon below indicates in the print that a color version of the figure is available online. It also links to the color figure submitted originally by the authors for viewing details. Because of the sizes of color figures and the additional editorial work such as making two sets of PostScript files in which they remain identical after replacing grayscale with color, authors should request color figures online only when it is necessary. The color figure must be in JPEG (Joint Photographic Expert Group) or GIF (Graphics Interchange Format) format to reduce file size and to decrease the bandwidth usage on the TUFFC server. Fig. 1. An eight-layer printed circuit board (PCB) used primarily for multi-channel ultrasound signal reception and storage. The board was designed in the Ultrasound Lab at The University of Toledo, led by Dr. Jian-yu Lu. It is one of the many PCBs designed for a high-frame rate medical ultrasound imaging system [1], which consists of 128 linear, ±144V peak, 0.05-10MHz, and 12-bit arbitrary waveform generators for the production of ultrasound signals or for other research purposes. 2. Movies: Please click on the movie icon to see a movie. The two movies below give you an idea on the file size versus movie quality. “VCD quality” here means 1150kbits/s for video and 224kbits/s for 16-bit MP2 stereo audio at 44.1KHz sampling rate. Fig. 2. An introduction to the Ultrasound Lab at The University of Toledo. 3. Movies and Animations: Please click on the movie icons to see movies or animations. Fig. 3. Circuit design and construction of the imaging system. 4. Movies and Animation: Please click on the movie icons to see movies or animation. Movie [File size: 785KB; Format: MPEG1; Resolution: 320X240; Duration: 9 seconds]

Breast tumor classification using axial shear strain elastography: a feasibility study

Abstract: Recently, the feasibility of visualizing the characteristics of bonding at an inclusion-background boundary using axial-shear strain elastography was demonstrated. In this paper, we report a feasibility study on the utility of the axial-shear strain elastograms in the classification of in vivo breast tumor as being benign or malignant. The study was performed using data sets obtained from 15 benign and 15 malignant cases that were biopsy proven. A total of three independent observers were trained, and their services were utilized for the study. A total of 9 cases were used as training set and the remaining cases were used as testing set. The feature from the axial-shear strain elastogram, namely, the area of the axial-shear region, was extracted by the observers. The observers also outlined the tumor area on the corresponding sonogram, which was used to normalize the area of the axial-shear strain region. There are several observations that can be drawn from the results. First, the result indicates that the observers consistently (~82% of the cases) noticed the characteristic pattern of the axial-shear strain distribution data as predicted in the previous simulation studies, i.e. alternating regions of positive and negative axial-shear strain values around the tumor–background interface. Second, the analysis of the result suggests that in approximately 57% of the cases in which the observers did not visualize tumor in the sonogram, the elastograms helped them to locate the tumor. Finally, the analysis of the result suggests that for the discriminant feature value of 0.46, the number of unnecessary biopsies could be reduced by 56.3% without compromising on sensitivity and on negative predictive value (NPV). Based on the results in this study, feature values greater than 0.75 appear to be indicative of malignancy, while values less than 0.46 to be indicative of benignity. Feature values between 0.46 and 0.75 may result in an overlap between benign and malignant cases.

The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.

Abstract: Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.

Visualization of bonding at an inclusion boundary using axial-shear strain elastography: a feasibility study.

Abstract: Ultrasound elastography produces strain images of compliant tissues under quasi-static compression. In axial-shear strain elastography, the local axial-shear strain resulting from application of quasi-static axial compression to an inhomogeneous material is imaged. The overall hypothesis of this work is that the pattern of axial-shear strain distribution around the inclusion/background interface is completely determined by the bonding at the interface after normalization for inclusion size and applied strain levels, and that it is feasible to extract certain features from the axial-shear strain elastograms to quantify this pattern. The mechanical model used in this study consisted of a single stiff circular inclusion embedded in a homogeneous softer background. First, we performed a parametric study using finite-element analysis (FEA) (no ultrasound involved) to identify possible features that quantify the pattern of axial-shear strain distribution around an inclusion/background interface. Next, the ability to extract these features from axial-shear strain elastograms, estimated from simulated pre- and post-compression noisy RF data, was investigated. Further, the feasibility of extracting these features from in vivo breast data of benign and malignant tumors was also investigated. It is shown using the FEA study that the pattern of axial-shear strain distribution is determined by the degree of bonding at the inclusion/background interface. The results suggest the feasibility of using normalized features that capture the region of positive and negative axial-shear strain area to quantify the pattern of the axial-shear strain distribution. The simulation results showed that it was feasible to extract the features, as identified in the FEA study, from axial-shear strain elastograms. However, an effort must be made to obtain axial-shear strain elastograms with the highest signal-to-noise ratio (SNR(asse)) possible, without compromising the resolution. The in vivo results demonstrated the feasibility of producing and extracting features from the axial-shear strain elastograms from breast data. Furthermore, the in vivo axial-shear strain elastograms suggest an additional feature not identified in the simulations that may potentially be used for distinguishing benign from malignant tumors-the proximity of the axial-shear strain regions to the inclusion/background interface identified in the sonogram.

Effect of lesion boundary conditions on axial strain elastograms: a parametric study.

Abstract: Ultrasound elastography produces strain images of compliant tissues under quasi-static compression. When a material is compressed, there are several parameters that affect the stress-distribution and, hence, the strain distribution in the material. The state of bonding of an inclusion to the background material is a critical parameter. Heretofore, in the field of elastography, the inclusion was considered to be firmly bonded to the background material and analytical solutions were derived for the elasticity problem involving simple geometries like circular inclusion (for two dimensional [2D]) and spherical inclusion (three dimensional [3D]). Under these conditions, simple analytical expressions relating the strain contrast to the modulus contrast were derived. However, it is known that the state of bonding of some tumors to their surrounding tissues depends on the type of the lesion. For example, benign lesions of the breast are known to be loosely bonded to the surrounding tissue, while malignant breast lesions are firmly bonded. In this study, we perform a parametric study using finite element modeling (FEM) to investigate the validity of the analytical expression relating the strain contrast to the modulus contrast, when the state of bonding at the inclusion/background interface spans a large dynamic range. The results suggest that estimated modulus contrast using the analytical expression is sensitive to the region-of-interest within the inclusion that is considered in the computation of the strain contrast. By considering the inclusion region lying along the axis of lateral symmetry instead of whole region of the inclusion, the estimated modulus contrast (obtained using the analytical expression present in the literature) can be computed to within a systematic error of 10% of the actual modulus contrast. Additional estimation errors are expected to accrue in experimental and in vivo conditions.

Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics

Abstract: Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.

The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy.

Abstract: Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.

EFSUMB Guidelines and Recommendations on the Clinical Use of Ultrasound Elastography. Part 1: Basic Principles and Technology

Abstract: The technical part of these Guidelines and Recommendations, produced under the auspices of EFSUMB, provides an introduction to the physical principles and technology on which all forms of current commercially available ultrasound elastography are based. A difference in shear modulus is the common underlying physical mechanism that provides tissue contrast in all elastograms. The relationship between the alternative technologies is considered in terms of the method used to take advantage of this. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided on optimisation of scanning technique, image display, image interpretation and some of the known image artefacts.

Imaging the elastic properties of tissue: the 20 year perspective.

Abstract: After 20 years of innovation in techniques that specifically image the biomechanical properties of tissue, the evolution of elastographic imaging can be viewed from its infancy, through a proliferation of approaches to the problem to incorporation on research and then clinical imaging platforms. Ultimately this activity has culminated in clinical trials and improved care for patients. This remarkable progression represents a leading example of translational research that begins with fundamentals of science and engineering and progresses to needed improvements in diagnostic and monitoring capabilities applied to major categories of disease, surgery and interventional procedures. This review summarizes the fundamental principles, the timeline of developments in major categories of elastographic imaging, and concludes with recent results from clinical trials and forward-looking issues.

Photoacoustic microscopy: Photoacoustic microscopy

Abstract: Photoacoustic microscopy (PAM) is a hybrid in vivo imaging technique that acoustically detects optical contrast via the photoacoustic effect. Unlike pure optical microscopic techniques, PAM takes advantage of the weak acoustic scattering in tissue and thus breaks through the optical diffusion limit (~1 mm in soft tissue). With its excellent scalability, PAM can provide high-resolution images at desired maximum imaging depths up to a few millimeters. Compared with backscattering-based confocal microscopy and optical coherence tomography, PAM provides absorption contrast instead of scattering contrast. Furthermore, PAM can image more molecules, endogenous or exogenous, at their absorbing wavelengths than fluorescence-based methods, such as wide-field, confocal, and multi-photon microscopy. Most importantly, PAM can simultaneously image anatomical, functional, molecular, flow dynamic and metabolic contrasts in vivo. Focusing on state-of-the-art developments in PAM, this Review discusses the key features of PAM implementations and their applications in biomedical studies.