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      1. Author :
        Kimberly A. Kelly; Nabeel Bardeesy; Rajesh Anbazhagan; Sushma Gurumurthy; Justin Berger; Herlen Alencar; Ronald A. DePinho; Umar Mahmood; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        PLoS Medicine
      6. Products :
      7. Volume :
        15
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer; Biology
      11. Keywords :
        in vivo imaging; cancer
      12. Abstract :
        Background: Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.

        Methods and Findings: Here, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.

        Conclusions: Our approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.
      13. URL :
        http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050085
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4478
      1. Author :
        Rahul Anil Sheth; Umar Mahmood
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        American Journal of Physiology: Gastrointestinal and Liver Physiology
      6. Products :
      7. Volume :
        299
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        Colorectal cancer; optical imaging; molecular imaging; cancer genetics
      12. Abstract :
        Colorectal cancer remains a major cause of morbidity and mortality in the United States. The advent of molecular therapies targeted against specific, stereotyped cellular mutations that occur in this disease has ushered in new hope for treatment options. However, key questions regarding the optimal dosing schedules, dosing duration, and patient selection remain unanswered. In this review, we describe how recent advances in molecular imaging, specifically optical molecular imaging with fluorescent probes, offer potential solutions to these questions and may play a key role in improving outcomes. We begin with an overview of optical molecular imaging, including a discussion on the various methods of design for fluorescent probes and the clinically relevant imaging systems that have been built to image them. We then focus on the relevance of optical molecular imaging to colorectal cancer. We review the most recent data on how this imaging modality has been applied to the measurement of treatment efficacy for currently available as well as some as-of-yet developmental molecularly targeted therapies in animal studies. We then conclude with a discussion on how this imaging approach has already begun to be translated clinically for human use.
      13. URL :
        http://ajpgi.physiology.org/cgi/content/abstract/ajpgi.00195.2010v1
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4484
      1. Author :
        J-C Tseng; T Granot; V DiGiacomo; B Levin; D Meruelo
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Gene Therapy
      6. Products :
      7. Volume :
        17
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        Sindbis virus; viral vector; vascular leakiness; molecular imaging; chemotherapy; cancer
      12. Abstract :
        Genetic instability of cancer cells generates resistance after initial responses to chemotherapeutic agents. Several oncolytic viruses have been designed to exploit specific signatures of cancer cells, such as important surface markers or pivotal signaling pathways for selective replication. It is less likely for cancer cells to develop resistance given that mutations in these cancer signatures would negatively impact tumor growth and survival. However, as oncolytic viral vectors are large particles, they suffer from inefficient extravasation from tumor blood vessels. Their ability to reach cancer cells is an important consideration in achieving specific oncolytic targeting and potential vector replication. Our previous studies indicated that the Sindbis viral vectors target tumor cells by the laminin receptor. Here, we present evidence that modulating tumor vascular leakiness, using VEGF and/or metronomic chemotherapy regimens, significantly enhances tumor vascular permeability and directly enhances oncolytic Sindbis vector targeting in tumor models. Because host-derived vascular endothelium cells are genetically stable and less likely to develop resistance to chemotherapeutics, a combined metronomic chemotherapeutics and oncolytic vector regimen should provide a new approach for cancer therapy. This mechanism could explain the synergistic treatment outcomes observed in clinical trials of combined therapies.
      13. URL :
        http://www.nature.com/cgt/journal/v17/n4/full/cgt200970a.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4485
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Molecular Imaging and Biology
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        Optical imaging, Image-guided surgery, Molecular imaging, Near-infrared fluorescence
      12. Abstract :
        In cancer surgery, intra-operative assessment of the tumor-free margin, which is critical for the prognosis of the patient, relies on the visual appearance and palpation of the tumor. Optical imaging techniques provide real-time visualization of the tumor, warranting intra-operative image-guided surgery. Within this field, imaging in the near-infrared light spectrum offers two essential advantages: increased tissue penetration of light and an increased signal-tobackground-ratio of contrast agents. In this article, we review the various techniques, contrast agents, and camera systems that are currently used for image-guided surgery. Furthermore, we provide an overview of the wide range of molecular contrast agents targeting specific hallmarks of cancer and we describe perspectives on its future use in cancer surgery.
      13. URL :
        http://www.springerlink.com/content/78233815221t6563/
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4486
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Angiogenesis
      6. Products :
      7. Volume :
        13
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        angiogenesis imaging; in vivo imaging; Angiogenesis; Bioluminescence; Fluorescence; Molecular imaging; Optical imaging
      12. Abstract :
        In recent years, molecular imaging gained significant importance in biomedical research. Optical imaging developed into a modality which enables the visualization and quantification of all kinds of cellular processes and cancerous cell growth in small animals. Novel gene reporter mice and cell lines and the development of targeted and cleavable fluorescent “smart” probes form a powerful imaging toolbox. The development of systems collecting tomographic bioluminescence and fluorescence data enabled even more spatial accuracy and more quantitative measurements. Here we describe various bioluminescent and fluorescent gene reporter models and probes that can be used to specifically image and quantify neovascularization or the angiogenic process itself.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911541/
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4488
      1. Author :
        M van Eekelen; LS Sasportas; R Kasmieh; S Yip; J-L Figueiredo; DN Louis; R Weissleder; K Shah
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        22
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        brain tumor; glioma; human neural stem cells; TSP-1; endothelial cells; angiogenesis; in vivo imaging
      12. Abstract :
        Novel therapeutic agents combined with innovative modes of delivery and non-invasive imaging of drug delivery, pharmacokinetics and efficacy are crucial in developing effective clinical anticancer therapies. In this study, we have created and characterized multiple novel variants of anti-angiogenic protein thrombospondin (aaTSP-1) that comprises unique regions of three type-I-repeats of TSP-1 and used engineered human neural stem cells (hNSC) to provide sustained on-site delivery of secretable aaTSP-1 to tumor-vasculature. We show that hNSC-aaTSP-1 has anti-angiogenic effect on human brain and dermal microvascular endothelial cells co-cultured with established glioma cells and CD133+ glioma-initiating cells. Using human glioma cells and hNSC engineered with different combinations of fluorescent and bioluminescent marker proteins and employing multi-modality imaging techniques, we show that aaTSP-1 targets the vascular-component of gliomas and a single administration of hNSC-aaTSP-1 markedly reduces tumor vessel-density that results in inhibition of tumor-progression and increased survival in mice bearing highly malignant human gliomas. We also show that therapeutic hNSC do not proliferate and remain in an un-differentiated state in the brains of glioma-bearing mice. This study provides a platform for accelerated development of future cell-based therapies for cancer.
      13. URL :
        http://www.nature.com/onc/journal/v29/n22/abs/onc201075a.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4492
      1. Author :
        Qingbei Zhang; Meng Yang; Jikun Shen; Lynnette M. Geerhold; Robert M Hoffman; H. Rosie Xing
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        International Journal of Cancer
      6. Products :
      7. Volume :
        126
      8. Issue :
        11
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        metastasis; hemotogenous spread; prostate cancer; GFP; in vivo imaging
      12. Abstract :
        Metastasis is primarily responsible for the morbidity and mortality of cancer. Improved therapeutic outcomes and prognosis depend on improved understanding of mechanisms regulating the establishment of early metastasis. In this study, use of green fluorescent protein (GFP)-expressing PC-3 orthotopic model of human prostate cancer and two complementary fluorescence in vivo imaging systems (Olympus OV100 and VisEn FMT) allowed for the first time real-time characterization of cancer cell-endothelium interactions during spontaneous metastatic colonization of the liver and lung in live mice. We observed that prior to the detection of extra-vascular metastases, GFP-expressing PC-3 cancer cells resided initially inside the blood vessels of the liver and the lung, where they proliferated and expressed Ki-67 and exhibited matrix metalloprotenases (MMP) activity. Thus, the intravascular cancer cells produced their own microenvironment, where they could continue to proliferate. Extravasation occurred earlier in the lung than in the liver. Our results demonstrate that the intravascular microenvironment is a critical staging area for the development of metastasis that later can invade the parenchyma. Intravascular tumor cells may represent a therapeutic target to inhibit the development of extravascular metastases. Therefore, this imageable model of intravascular metastasis may be used for evaluation of novel anti-metastatic agents.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1002/ijc.24979/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4493
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