Arun K. Thittai
Bio: Arun K. Thittai is an academic researcher from Indian Institute of Technology Madras. The author has contributed to research in topics: Image quality & Imaging phantom. The author has an hindex of 10, co-authored 61 publications receiving 402 citations. Previous affiliations of Arun K. Thittai include University of Texas at Austin & University of Texas MD Anderson Cancer Center.
TL;DR: PX-478 is a mechanistically appealing and potentially clinically relevant enhancer of pancreatic cancer radiosensitivity, inhibiting tumor and stromal HIF-1 proangiogenic signaling and reducing the innate radiation resistance of hypoxic tumor cells.
Abstract: Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (HIF-1α) transcription factor, resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF-1α expression is associated with tumor resistance to cytotoxic therapy and inferior patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α by PX-478 increased cell killing by radiation. In mice with Panc-1, CF-PAC-1, or SU.86.86 pancreatic xenografts, concurrent administration of PX-478 potentiated the antitumor effects of fractionated radiation, with or without combined treatment with 5-fluorouracil or gemcitabine. Alternative sequencing of PX-478 with fractionated radiotherapy suggests optimal radiosensitization with concurrent or neoadjuvant administration of drug. Early tumor responses to combined PX-478/radiation treatment could be rapidly and repeatedly quantified by vascular imaging biomarkers. Dual-tracer dynamic contrast enhanced-magnetic resonance imaging and ultrasound imaging discriminated response to combined treatment prior to detection of differences in anatomic tumor size at 10 days posttreatment. Therefore, PX-478 is a mechanistically appealing and potentially clinically relevant enhancer of pancreatic cancer radiosensitivity, inhibiting tumor and stromal HIF-1 proangiogenic signaling and reducing the innate radiation resistance of hypoxic tumor cells.
TL;DR: The results demonstrate that the NASSA feature derived from ASSE has the potential to improve BIRADS breast lesion classification of fibroadenoma and malignant tumors.
Abstract: The purpose of this work was to investigate the potential of the normalized axial-shear strain area (NASSA) feature, derived from axial-shear strain elastograms (ASSE), for breast lesion classification of fibroadenoma and cancer. This study consisted of previously acquired in vivo digital radiofrequency data of breast lesions. A total of 33 biopsy-proven malignant tumors and 30 fibroadenoma cases were included in the study, which involved three observers blinded to the original BIRADS-ultrasound scores. The observers outlined the lesions on the sonograms. The ASSEs were segmented and color-overlaid on the sonograms, and the NASSA feature from the ASSE was computed semi-automatically. Receiver operating characteristic (ROC) curves were then generated and the area under the curve (AUC) was calculated for each observer performance. A logistic regression classifier was built to compare the improvement in the AUC when using BIRADS scores plus NASSA values as opposed to BIRADS scores alone. BIRADS score ROC had an AUC of 0.89 (95% CI = 0.81 to 0.97). In comparison, the average of the AUC for all the three observers using ASSE feature alone was 0.84. However, the AUC increased to 0.94 (average of 3 observers) when BIRADS score and ASSE feature were combined. The results demonstrate that the NASSA feature derived from ASSE has the potential to improve BIRADS breast lesion classification of fibroadenoma and malignant tumors.
TL;DR: Axial-shear strain fill-in inside an inclusion may be a unique signature of stiff, loosely bonded, ellipsoidal or elongated inclusions at non-normal orientations that may be useful as a marker of benignity of benign breast lesions that are generally stiff, elongated and loosely bonded to the host tissues.
Abstract: Recently, we reported on the axial-shear strain fill-in of the interior of loosely bonded stiff elliptical inclu- sions in a soft backgroundat non-normal orientations, and the lack of fill-in in firmly bonded inclusions at any orien- tation. In this paper, we report on the experimental validation of the simulation studies using tissue-mimicking gelatin-based phantoms. We also show a few confirmatory examples of the existence of these phenomena in benign vs. malignant breast lesions in vivo. Phantom experiments showed that axial-shear strain zones caused by firmly bonded elliptical inclusions occurred only outside of the inclusion, as predicted by the simulation. By contrast, the axial-shear strain zones filled in the interior of loosely bonded elliptical inclusions at non-normal orientations. The axial-shear strain elastograms obtained from the in vivo cases appeared to be in general agreement with our experimental results. The results reported in this paper may have important clinical implications. Specifically, axial-shear strain fill-in inside an inclusion may be auniquesignature of stiff, loosely bonded, ellipsoidal or elongated inclusions at non-normal orientations. Thus, it may be useful as a marker of benignity of benign breast lesions (e.g., fibroadenomas) that are generally stiff, elongated and loosely bonded to the host tissues. (E-mail: Jonathan.Ophir@ uth.tmc.edu) 2010 World Federation for Ultrasound in Medicine & Biology.
TL;DR: The specific purpose of this review is to describe the progress of the work on elastography at the University of Texas Medical School-Houston in the past decade, and to relate it to earlier work on this topic in the pre- ceding decade.
Abstract: The specific purpose of this review is to describe the progress of our work on elastography at the University of Texas Medical School-Houston in the past decade (2000-2010), and to relate it to our earlier work on this topic in the pre- ceding decade (1991-2000). This review is neither intended to cover all specific aspects of this fast growing field, nor to be an exhaustive review of the literature. Such information is available separately and in several literary reviews. The early work in our Laboratory was started (1) with the fundamental theoretical and experimental development of elas- tography and ended with demonstration of the feasibility of producing elastograms in a clinical setting (2). During the fol- lowing decade our work has branched out into three main directions. These were (1) a continued effort to demonstrate the ability of elastography to depict the elastic properties of tissues and to develop improved algorithms for attaining quality strain estimations; (2) the development and practical in vivo demonstration of Poisson's ratio elastography (poroelastogra- phy) for the study of poroelastic materials such as lymphedematous tissues; and (3) the development of axial-shear strain elastography (ASSE) for imaging the mechanical boundary conditions at tissue interfaces, and to demonstrate the utility of this modality in the differentiation between benign and malignant breast lesions in vivo. These three areas are the main topics that are covered in this review.
TL;DR: It is demonstrated that it is feasible to reliably visualize HIFU lesion boundaries using ASSE, and it was shown that ASSE enables high-contrast visualization of a "thin" untreated region in between multiple fully-treated HifU-lesions.
Abstract: In this paper, we report on a study that investigated the feasibility of reliably visualizing high-intensity focused ultrasound (HIFU) lesion boundaries using axial-shear strain elastograms (ASSE). The HIFU-induced lesion cases used in the present work were selected from data acquired in a previous study. The samples consisted of excised canine livers with thermal lesions produced by a magnetic resonance-compatible HIFU system (GE Medical System, Milwaukee, WI, USA) and were cast in a gelatin block for the elastographic experiment. Both single and multiple HIFU-lesion samples were investigated. For each of the single-lesion samples, the lesion boundaries were determined independently from the axial strain elastogram (ASE) and ASSE at various iso-intensity contour thresholds (from -2 dB to -6 dB), and the area of the enclosed lesion was computed. For samples with multiple lesions, the corresponding ASSE was analyzed for identifying any unique axial-shear strain zones of interest. We further performed finite element modeling (FEM) of simple two-inclusion cases to verify whether the in vitro ASSE obtained were reasonable. The results show that the estimation of the lesion area using ASSE is less sensitive to iso-intensity threshold selection, making this method more robust compared with the ASE-based method. For multiple lesion cases, it was shown that ASSE enables high-contrast visualization of a "thin" untreated region in between multiple fully-treated HIFU-lesions. This contrast visualization was also noticed in the FEM predictions. In summary, the results demonstrate that it is feasible to reliably visualize HIFU lesion boundaries using ASSE.
TL;DR: Clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.
Abstract: Hypoxia-inducible factors (HIFs) mediate adaptive physiological responses to hypoxia. In human cancers that are accessible for O 2 electrode measurements, intratumoral hypoxia is common and severe hypoxia is associated with increased risk of mortality. HIF activity in regions of intratumoral hypoxia mediates angiogenesis, epithelial-mesenchymal transition, stem-cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy. A growing number of drugs have been identified that inhibit HIF activity by a variety of molecular mechanisms. Because many of these drugs are already FDA-approved for other indications, clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.
TL;DR: In this paper, the authors provide an overview of the rapidly developing field of photoacoustic imaging, which is a promising method for visualizing biological tissues with optical absorbers, compared with optical imaging and ultrasonic imaging.
Abstract: Photoacoustic imaging is a promising method for visualizing biological tissues with optical absorbers. This article provides an overview of the rapidly developing field of photoacoustic imaging. Photoacoustics, the physical basis of photoacoustic imaging, is analyzed briefly. The merits of photoacoustic technology, compared with optical imaging and ultrasonic imaging, are described. Various imaging techniques are also discussed, including scanning tomography, computed tomography and original detection of photoacoustic imaging. Finally, some biomedical applications of photoacoustic imaging are summarized.
TL;DR: This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and C SCs.
Abstract: Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the ba...
TL;DR: An update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization is provided and challenges for ionizing radiation-induced signal transduction and targeted therapy are discussed.
Abstract: Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.
TL;DR: It is reported that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival.
Abstract: Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.