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Tumor cells express vascular endothelial growth factor (VEGF) that can activate VEGF receptors (VEGFRs) on or within tumor cells to promote growth in an angiogenesis-independent fashion; however, this autocrine VEGF pathway has not been reported in hepatocellular carcinoma (HCC). Sorafenib, an angiogenic inhibitor, is the only drug approved for use in advanced HCC patients. Yet the treatment efficacy is diverse and the mechanism behind it remains undetermined. Our aims were to study the molecular mechanisms underlying autocrine VEGF signaling in HCC cells and evaluate the critical role of autocrine VEGF signaling on sorafenib treatment efficacy. By immunohistochemistry, we found robust nuclear and cytoplasmic staining for active, phosphorylated VEGF receptor 1 (pVEGFR1) and phosphorylated VEGF receptor 2 (pVEGFR2), and by western blotting we found that membrane VEGFR1 and VEGFR2 increased in HCC tissues. We showed that autocrine VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2 in HCC cells, which was both pro-proliferative through a protein lipase C-extracellular kinase pathway and self-sustaining through increasing VEGF, VEGFR1, and VEGFR2 mRNA expressions. In high VEGFR1/2-expressing HepG2 cells, sorafenib treatment inhibited cell proliferation, reduced VEGFR2 mRNA expression in vitro, and delayed xenograft tumor growth in vivo. These results were not found in low VEGFR1/2-expressing Hep3B cells. In an advanced HCC population on sorafenib treatment for postoperative recurrence, we found that the absence of VEGFR1 or VEGFR2 expression in resected tumor tissues before sorafenib treatment was associated with poorer overall survival. Conclusion: Autocrine VEGF signaling directly promotes HCC cell proliferation and affects the sorafenib treatment outcome in vitro and in vivo, which may enable better stratification for clinical treatment decisions. © 2014 by the American Association for the Study of Liver Diseases.


Cuccarolo P.,Instituto Nazionale per la Ricerca sul Cancro Centro Biotecnologie Avanzate | Cuccarolo P.,University of Genoa | Viaggi S.,University of Genoa | Viaggi S.,Advanced Diagnostic Technologies LLC | Degan P.,Instituto Nazionale per la Ricerca sul Cancro Centro Biotecnologie Avanzate
FEBS Journal | Year: 2012

Fanconi's anemia (FA) patients face severe pathological consequences. Bone marrow failure, the major cause of death in FA, accounting for as much as 80-90% of FA mortality, appears to be significantly linked to excessive apoptosis of hematopoietic cells induced by oxidative stress. However, 20-25% of FA patients develop malignancies of myeloid origin. A survival strategy for bone marrow and hematopoietic cells under selective pressure evidently exists. This study reports that lymphoblastoid cell lines derived from two FA patients displayed significant resistance to oxidative stress induced by treatments with H 2O2 and various glutathione (GSH) inhibitors that induce production of reactive oxygen species, GSH depletion and mitochondrial membrane depolarization. Among the various GSH inhibitors employed, FA cells appear particularly resistant to menadione (5 μm) and ethacrynic acid (ETA, 50 μm), two drugs that specifically target mitochondria. Even after pre-treatment with buthionine sulfoximine, a GSH synthesis inhibitor that induces enhanced induction of reactive oxygen species, FA cells maintain significant resistance to these drugs. These data suggest that the resistance to oxidative stress and the altered mitochondrial and metabolic functionality found in the FA mutant cells used in this study may indicate the survival strategy that is adopted in FA cells undergoing transformation. The study of redox and mitochondria regulation in FA may be of assistance in diagnosis of the disease and in the care of patients. © 2012 FEBS.


Capitanio S.,Advanced Diagnostic Technologies LLC | Nordin A.J.,University Putra Malaysia | Noraini A.R.,National Cancer Institute | Rossetti C.,Advanced Diagnostic Technologies LLC
European Respiratory Review | Year: 2016

Positron emission tomography (PET) combined with computed tomography (CT) is an established diagnostic modality that has become an essential imaging tool in oncological practice. However, thanks to its noninvasive nature and its capability to provide physiological information, the main applications of this technique have significantly expanded. 18F-labelled fluorodeoxyglucose (FDG) is the most commonly used radiopharmaceutical for PET scanning and demonstrates metabolic activity in various tissues. Since activated inflammatory cells, like malignant cells, predominantly metabolise glucose as a source of energy and increase expression of glucose transporters when activated, FDG-PET/CT can be successfully used to detect and monitor a variety of lung diseases, such as infections and several inflammatory conditions. The added value of FDG-PET/CT as a molecular imaging technique relies on its capability to identify disease in very early stages, long before the appearance of structural changes detectable by conventional imaging. Furthermore, by detecting the active phase of infectious or inflammatory processes, disease progression and treatment efficacy can be monitored. This review will focus on the clinical use of FDG-PET/CT in nonmalignant pulmonary diseases. © ERS 2016.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.48K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I project will develop advanced methods to temporarily reprogram hematopoietic stem cells (HSCs) that will enable ex vivo production of blood in quantities suitable for transfusion. A transfection-free method will be used that can be easily translated into clinical use. Every two seconds someone in the U.S. needs blood and more than 38,000 blood donations are needed every day. In order for ex vivo blood production to be clinically relevant, the expansion cell culture must be able to produce red blood cells in the range contained in a unit of blood: 2.5x1012cells. There exists a fundamental obstacle in reaching this number of cells. CD34+(HSCs) and erythroid progenitors are typically only capable of short-term, or restricted ex vivo expansion. The main objective of this project is to reprogram CD34+(HSCs) such that cellular mechanisms are activated to force cellular proliferation. Despite research efforts from around the world, reaching clinical significant quantities of blood in culture has not been previously possible. The goal is to produce clinically relevant quantities of blood and create a shift in clinical practice paradigms for the treatment of the anemic patient as well as the blood banking industry. What are the broader impacts of the proposed activity? The broader impact/commercial potential of this project, if successful, will be to create a viable alternative to allogenic blood transfusion, and compete with traditional blood banking and the use of recombinant erythropoietin (EPO). We expect that successful development of this technique will have a high societal impact on safety and availability of blood for transfusions as well as a reduction in hemolytic transfusion reactions. Although the safety of transfusions has improved markedly there is still a non-zero probability of getting HIV (1:1.8 Million), or Hepatitis C (1:1 Million). This work is expected to significantly enhance the scientific and technological understanding of ex vivo production of blood and provide a pathway to translation into clinical medicine. This project will have a significant impact in the $20 billion global blood transfusion market, as well as the EPO market, which is valued at about $53 Billion.


Grant
Agency: Department of Defense | Branch: Defense Health Program | Program: SBIR | Phase: Phase II | Award Amount: 717.46K | Year: 2014

Surgical training requires an understanding of the human body"s complex 3-dimensional anatomical structures and the spatial relationships of nerves, blood vessels and other vital structures. Learning these spatial skills requires a lengthy training period and much practice that usually takes place in the operating room while under the supervision of a senior surgeon at great financial cost and potential risk to patients. Alternatively, there exist expensive models that may be used before a student can master the necessary skills. Advanced Diagnostic Technologies (ADxT) has developed a novel, low cost, 3D printer for synthetic tissue deposition. This 3D printing tool is useful for a wide range of applications including surgery simulation, endoscopic and intravascular procedures, as well as clinical task training, basic medical skills development, medical device design verification or visualization.


Grant
Agency: Department of Defense | Branch: Defense Health Program | Program: SBIR | Phase: Phase II | Award Amount: 726.12K | Year: 2014

Currently there are over 20 types of procedural simulation models available for surgical skill training. Despite the large number of simulators currently available, there is a definite need for low cost anatomical training models with integrated sensors capable of recording the location and pressure measurements of a user"s performance in training of surgical cuts, manipulation and suture. Ideally, the model will have pressure sensor arrays with large grids of tactels that detect normal forces, which are capable of measuring: exact anatomical location of the trainee"s manipulation within the tissue simulator, force exerted on the tissue, direction the force applied, cutting or tearing of tissue, approximation of tissue (location of cut or pressure),occlusion and the release of occlusion of tissue ,application of energy onto the tissue and measurement of"fluids"within the vasculature.


Grant
Agency: Department of Defense | Branch: Defense Health Program | Program: SBIR | Phase: Phase I | Award Amount: 149.99K | Year: 2013

Despite the large number of procedural simulation models currently available, there is a definite need for low cost anatomical training models with integrated sensors capable of recording the location and pressure measurements of a user"s performance in training of cuts, and sutures. A paradigm shift in medical training is possible if sensors can either be fabricated independently and embedded into the model, or ideally incorporated in the fabrication process directly such that the user"s manipulation of the mode are tracked and recorded. Unfortunately, current synthetic models require validation and most still need an expert to review the novice"s actions subjectively. In an ideal system, extensive data on the performance of the user could be fed into realistic overall systemic models. In this work we propose a method of incorporating force sensors heterogeneously with synthetic tissue by using a multi-material 3D printing platform. This approach is expected to enable low cost sensing that can be integrated with additional sensors in a simulator to accurately track the performance of a student without requiring an instructor to watch.


Grant
Agency: Department of Defense | Branch: Defense Health Program | Program: SBIR | Phase: Phase I | Award Amount: 149.99K | Year: 2013

The DOD and commercial markets have a distinct need for low cost anatomically accurate, complex synthetic human tissue in order to improve training and improve surgical precision. In this project a novel multiple material print-head is developed using a 3D printer capable of depositing a wide range of materials such that bone, skin, blood vessels, adipose tissue, and muscle material properties are tightly matched with live human tissue.


Grant
Agency: National Aeronautics and Space Administration | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.98K | Year: 2011

NASA has a serious unmet need for miniature biologic sensors capable of on orbit sample analysis and in situ, real time analysis of astronaut health. We propose an alternative way to monitor the health or illness of the crew members that would provide continuous monitoring of blood analytes. This information can be transmitted back to ground control in real time. The method could bypass the need to preserve biological specimens. This novel multivariate system would measure the optical rotation of laser polarized light reflected from human skin as well as scattering and absorption characteristics directly related to the concentration of certain blood analytes that reliably indicate the state of health of the individual.


PubMed | Advanced Diagnostic Technologies LLC, University Putra Malaysia and National Cancer Institute
Type: Journal Article | Journal: European respiratory review : an official journal of the European Respiratory Society | Year: 2016

Positron emission tomography (PET) combined with computed tomography (CT) is an established diagnostic modality that has become an essential imaging tool in oncological practice. However, thanks to its noninvasive nature and its capability to provide physiological information, the main applications of this technique have significantly expanded.(18)F-labelled fluorodeoxyglucose (FDG) is the most commonly used radiopharmaceutical for PET scanning and demonstrates metabolic activity in various tissues. Since activated inflammatory cells, like malignant cells, predominantly metabolise glucose as a source of energy and increase expression of glucose transporters when activated, FDG-PET/CT can be successfully used to detect and monitor a variety of lung diseases, such as infections and several inflammatory conditions.The added value of FDG-PET/CT as a molecular imaging technique relies on its capability to identify disease in very early stages, long before the appearance of structural changes detectable by conventional imaging. Furthermore, by detecting the active phase of infectious or inflammatory processes, disease progression and treatment efficacy can be monitored.This review will focus on the clinical use of FDG-PET/CT in nonmalignant pulmonary diseases.

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