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      1. Author :
        Valdivia, Y. Alvarado M.; Wong, K.; Cheng He, T.; Xue, Z.; Wong, S. T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Vasc Interv Radiol
      6. Products :
      7. Volume :
        22
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Cell Line, Tumor; Fiber Optic Technology/*methods; Fluorescent Dyes/*administration & dosage/*diagnostic use; Humans; Injections, Intralesional; Lung Neoplasms/*pathology; Microscopy, Fluorescence/*methods; Molecular Imaging/*methods; Rabbits; Surgery, Computer-Assisted/*methods; Tomography, X-Ray Computed/methods
      12. Abstract :
        PURPOSE: To show the feasibility of computed tomography (CT) image-guided fiberoptic confocal fluorescence molecular imaging in a rabbit lung tumor model. MATERIALS AND METHODS: Eight lung tumor models were created by injection of a VX2 cell suspension. The fluorescent imaging agent IntegriSense 680 was given to the animals 3.5-4 hours before the procedure. CT images were obtained and transferred to the minimally invasive multimodality image-guided (MIMIG) system as a guidance map. A real-time electromagnetically tracked needle was inserted under the visual guidance of the MIMIG system. A second CT image was obtained to confirm the location of the needle tip. Next, fiberoptic fluorescence imaging was acquired along the needle track. Finally, tumor samples were obtained for histopathologic confirmation. RESULTS: All cases were performed during breath-hold. Tumor size was 12.5 mm +/- 1.6; the distance from the chest wall was 2.1 mm +/- 0.5. The needle tip reached the tumor in all cases with an accuracy of 3.3 mm +/- 1.6. Only one skin entry point was necessary, and no needle adjustments were required. No pneumothorax was observed. At least two-fold alpha(v)beta(3) integrin image contrast was detected in the tumor compared with normal lung tissue. Tumor samples were confirmed to have viable VX2 cells and contrast uptake. CONCLUSIONS: The MIMIG system enables effective in situ fluorescence molecular imaging in a needle biopsy lung procedure. In situ alpha(v)beta(3) integrin molecular imaging allows molecular characterization of lung tumors at multiple regions and can be used to guide biopsy procedures.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22019854
      14. Call Number :
        PKI @ kd.modi @ 14
      15. Serial :
        10383
      1. Author :
        Tsurumi, C.; Esser, N.; Firat, E.; Gaedicke, S.; Follo, M.; Behe, M.; Elsasser-Beile, U.; Grosu, A. L.; Graeser, R.; Niedermann, G.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        5
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Antigens, CD/*biosynthesis/*metabolism; Flow Cytometry/methods; Glioma/metabolism; Glycoproteins/*biosynthesis/*metabolism; Humans; Hybridomas/metabolism; Mice; Mice, Transgenic; Models, Biological; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms/*metabolism; Neoplastic Stem Cells; Peptides/*metabolism; Recurrence
      12. Abstract :
        BACKGROUND: Cancer stem cells are thought to play a pivotal role in tumor maintenance, metastasis, tumor therapy resistance and relapse. Hence, the development of methods for non-invasive in vivo detection of cancer stem cells is of great importance. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe successful in vivo detection of CD133/prominin, a cancer stem cell surface marker for a variety of tumor entities. The CD133-specific monoclonal antibody AC133.1 was used for quantitative fluorescence-based optical imaging of mouse xenograft models based on isogenic pairs of CD133 positive and negative cell lines. A first set consisted of wild-type U251 glioblastoma cells, which do not express CD133, and lentivirally transduced CD133-overexpressing U251 cells. A second set made use of HCT116 colon carcinoma cells, which uniformly express CD133 at levels comparable to primary glioblastoma stem cells, and a CD133-negative HCT116 derivative. Not surprisingly, visualization and quantification of CD133 in overexpressing U251 xenografts was successful; more importantly, however, significant differences were also found in matched HCT116 xenograft pairs, despite the lower CD133 expression levels. The binding of i.v.-injected AC133.1 antibodies to CD133 positive, but not negative, tumor cells isolated from xenografts was confirmed by flow cytometry. CONCLUSIONS/SIGNIFICANCE: Taken together, our results show that non-invasive antibody-based in vivo imaging of tumor-associated CD133 is feasible and that CD133 antibody-based tumor targeting is efficient. This should facilitate developing clinically applicable cancer stem cell imaging methods and CD133 antibody-based therapeutics.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21187924
      14. Call Number :
        PKI @ kd.modi @ 15
      15. Serial :
        10382
      1. Author :
        Themelis, G.; Harlaar, N. J.; Kelder, W.; Bart, J.; Sarantopoulos, A.; van Dam, G. M.; Ntziachristos, V.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Ann Surg Oncol
      6. Products :
      7. Volume :
        18
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Cell Line, Tumor; *Diagnostic Imaging; Female; Fluorescence; Fluorescent Dyes/*diagnostic use; Humans; Integrin alphaVbeta3/*metabolism; Luciferases/metabolism; Mammary Neoplasms, Experimental/*diagnosis/metabolism; Mice; Mice, Nude; Spectroscopy, Near-Infrared
      12. Abstract :
        BACKGROUND: This study was designed to improve the surgical procedure and outcome of cancer surgery by means of real-time molecular imaging feedback of tumor spread and margin delineation using targeted near-infrared fluorescent probes with specificity to tumor biomarkers. Surgical excision of cancer often is confronted with difficulties in the identification of cancer spread and the accurate delineation of tumor margins. Currently, the assessment of tumor borders is afforded by postoperative pathology or, less reliably, intraoperative frozen sectioning. Fluorescence imaging is a natural modality for intraoperative use by directly relating to the surgeon's vision and offers highly attractive characteristics, such as high-resolution, sensitivity, and portability. Via the use of targeted probes it also becomes highly tumor-specific and can lead to significant improvements in surgical procedures and outcome. METHODS: Mice bearing xenograft human tumors were injected with alphavbeta3-integrin receptor-targeted fluorescent probe and in vivo visualized by using a novel, real-time, multispectral fluorescence imaging system. Confirmatory ex vivo imaging, bioluminescence imaging, and histopathology were used to validate the in vivo findings. RESULTS: Fluorescence images were all in good correspondence with the confirming bioluminescence images in respect to signal colocalization. Fluorescence imaging detected all tumors and successfully guided total tumor excision by effectively detecting small tumor residuals, which occasionally were missed by the surgeon. Tumor tissue exhibited target-to-background ratio of ~4.0, which was significantly higher compared with white-light images representing the visual contrast. Histopathology confirmed the capability of the method to identify tumor negative margins with high specificity and better prediction rate compared with visual inspection. CONCLUSIONS: Real-time multispectral fluorescence imaging using tumor specific molecular probes is a promising modality for tumor excision by offering real time feedback to the surgeon in the operating room.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21509632
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10381
      1. Author :
        Tekabe, Y.; Klose, A.; Nizami, S.; Luma, J.; Lee, F. Y.; Johnson, L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Biophotonics
      6. Products :
      7. Volume :
        4
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Antigens, CD31/metabolism; Capillaries/metabolism; Diagnostic Imaging/*methods; Femoral Artery/surgery; Fluorescent Dyes/*diagnostic use/metabolism; Hindlimb/*blood supply/metabolism/pathology; Integrin alphaV/metabolism; Integrin alphaVbeta3/antagonists & inhibitors/metabolism; Ischemia/*pathology; Ligation; Male; Mice; Mice, Inbred Strains; Microscopy, Fluorescence; *Neovascularization, Physiologic; Plant Lectins/metabolism; Sensitivity and Specificity
      12. Abstract :
        Optical agents targeting alpha(v)beta(3) are potential tools to image the angiogenic response to limb ischemia. The left (L) femoral artery was ligated in 17 mice and sham surgery performed on the contralateral right (R) hindlimb. Seven days later, IntegriSense (2 nmol) was injected into 11 mice and 6 were probe controls. Six hours later, mice underwent optical imaging. Ratios of photon flux in the L/R limbs were calculated. Tissue was stained for alpha(v) , CD31, and lectin. The signal was increased in the ischemic limbs compared to contralateral legs and ratio of photon flux in L/R limb averaged 2.37. Control probe showed no hindlimb signal. IntegriSense colocalized with CD31 by dual fluorescent staining. Ratios for L/R hindlimbs correlated with quantitative lectin staining (r = 0.88, p = 0.003). Optical imaging can identify and quantify angiogenic response to hindlimb ischemia.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22031282
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10380
      1. Author :
        Snoeks, T. J.; Lowik, C. W.; Kaijzel, E. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Angiogenesis
      6. Products :
      7. Volume :
        13
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense,, Animals; Diagnostic Imaging/*methods; Fluorescent Dyes/metabolism; Genes, Reporter; Neovascularization, Pathologic/*diagnosis; *Optical Phenomena
      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/pubmed/20449766
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10379
      1. Author :
        Snoeks, T. J.; Khmelinskii, A.; Lelieveldt, B. P.; Kaijzel, E. L.; Lowik, C. W.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Bone
      6. Products :
      7. Volume :
        48
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Bone Neoplasms/radionuclide imaging/*secondary; Diagnostic Imaging/*methods; Forecasting; Optics and Photonics/*trends; Positron-Emission Tomography/methods; Tomography, Emission-Computed, Single-Photon/methods; X-Ray Microtomography/methods; X-Rays
      12. Abstract :
        Optical Imaging has evolved into one of the standard molecular imaging modalities used in pre-clinical cancer research. Bone research however, strongly depends on other imaging modalities such as SPECT, PET, x-ray and muCT. Each imaging modality has its own specific strengths and weaknesses concerning spatial resolution, sensitivity and the possibility to quantify the signal. An increasing number of bone specific optical imaging models and probes have been developed over the past years. This review gives an overview of optical imaging modalities, models and probes that can be used to study skeletal complications of cancer in small laboratory animals.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20688203
      14. Call Number :
        PKI @ kd.modi @ 19
      15. Serial :
        10378
      1. Author :
        Pickert, G.; Lim, H. Y.; Weigert, A.; Haussler, A.; Myrczek, T.; Waldner, M.; Labocha, S.; Ferreiros, N.; Geisslinger, G.; Lotsch, J.; Becker, C.; Brune, B.; Tegeder, I.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Int J Cancer
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense
      12. Abstract :
        GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22753274
      14. Call Number :
        PKI @ kd.modi @ 17
      15. Serial :
        10377
      1. Author :
        Pello, O. M.; Chevre, R.; Laoui, D.; De Juan, A.; Lolo, F.; Andres-Manzano, M. J.; Serrano, M.; Van Ginderachter, J. A.; Andres, V.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense
      12. Abstract :
        Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice, which lack c-Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1alpha) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23028984
      14. Call Number :
        PKI @ kd.modi @ 33
      15. Serial :
        10376
      1. Author :
        Nahrendorf, M.; Keliher, E.; Marinelli, B.; Waterman, P.; Feruglio, P. F.; Fexon, L.; Pivovarov, M.; Swirski, F. K.; Pittet, M. J.; Vinegoni, C.; Weissleder, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Proc Natl Acad Sci U S A
      6. Products :
      7. Volume :
        107
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Flow Cytometry; Fluorescent Dyes/*diagnostic use; Image Processing, Computer-Assisted/methods; Mice; Mice, Inbred C57BL; Nanoparticles/*diagnostic use; Neoplasms/*diagnosis; Positron-Emission Tomography/*methods; Tomography, X-Ray Computed/*methods
      12. Abstract :
        Fusion imaging of radionuclide-based molecular (PET) and structural data [x-ray computed tomography (CT)] has been firmly established. Here we show that optical measurements [fluorescence-mediated tomography (FMT)] show exquisite congruence to radionuclide measurements and that information can be seamlessly integrated and visualized. Using biocompatible nanoparticles as a generic platform (containing a (18)F isotope and a far red fluorochrome), we show good correlations between FMT and PET in probe concentration (r(2) > 0.99) and spatial signal distribution (r(2) > 0.85). Using a mouse model of cancer and different imaging probes to measure tumoral proteases, macrophage content and integrin expression simultaneously, we demonstrate the distinct tumoral locations of probes in multiple channels in vivo. The findings also suggest that FMT can serve as a surrogate modality for the screening and development of radionuclide-based imaging agents.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20385821
      14. Call Number :
        PKI @ kd.modi @ 21
      15. Serial :
        10375
      1. Author :
        Motohara, T.; Masuko, S.; Ishimoto, T.; Yae, T.; Onishi, N.; Muraguchi, T.; Hirao, A.; Matsuzaki, Y.; Tashiro, H.; Katabuchi, H.; Saya, H.; Nagano, O.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Carcinogenesis
      6. Products :
      7. Volume :
        32
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Antigens, Neoplasm/genetics/metabolism; Apoptosis; Blotting, Western; Cell Adhesion; Cell Adhesion Molecules/genetics/metabolism; Cell Differentiation; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic/metabolism/*pathology; Female; Flow Cytometry; Immunoenzyme Techniques; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells/metabolism/*pathology; Ovarian Neoplasms/genetics/metabolism/*pathology; Ovary/metabolism/*pathology; Peritoneal Neoplasms/genetics/metabolism/*secondary; Proto-Oncogene Proteins c-myc/genetics/metabolism; Proto-Oncogene Proteins p21(ras)/genetics/metabolism; RNA, Messenger/genetics; RNA, Small Interfering/genetics; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/*metabolism
      12. Abstract :
        Although the existence of tumor-initiating cells (T-ICs) in several types of human cancer has been documented, the contribution of somatic stem cells to the development of T-ICs has remained unclear. Here, we show that normal mouse ovary contains epithelial cell adhesion molecule (EpCAM)-expressing stem-like cells that possess the ability to differentiate into cytokeratin 8 (CK8)-expressing epithelial progeny cells. Furthermore, RNA interference-mediated transient depletion of the tumor suppressor p53 followed by retrovirus-mediated transfer of c-Myc and K-Ras oncogenes in EpCAM-expressing ovarian stem-like cells resulted in the generation of ovarian T-ICs. The established ovarian T-ICs gave rise to hierarchically organized lethal tumors in vivo and were able to undergo peritoneal metastasis. Finally, subsequent RNA interference-mediated knockdown of p53 in tumor cells triggered the expansion of EpCAM-expressing stem-like tumor cells and induced further tumor growth. These data reveal a role for p53 in the development and expansion of ovarian stem-like tumor cells and subsequent malignant progression.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21828057
      14. Call Number :
        PKI @ kd.modi @ 16
      15. Serial :
        10374