Journal Article

IntegriSense, Animals; Bronchoalveolar Lavage Fluid/chemistry; Ceramides/metabolism; Female; Gene Deletion; Gene Expression Regulation/physiology; Lung/*radiation effects; Lysophospholipids/*chemistry/*pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; *Radiation Injuries, Experimental; Receptors, Lysosphingolipid/genetics/metabolism; Sphingolipids/*metabolism; Sphingosine/*analogs & derivatives/chemistry/pharmacology

Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1(-/-)) or with reduced expression of S1P receptors (S1PR1(+/-), S1PR2(-/-), and S1PR3(-/-)) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2x/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2x/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.

Journal Article

IntegriSense, Angiogenesis Inhibitors/therapeutic use; Animals; Diagnostic Imaging/*methods; Fluorescence; Humans; Luminescence/diagnostic use; Magnetic Resonance Angiography/methods; Magnetic Resonance Imaging/methods; Microscopy/methods; Neoplasms/*blood supply/therapy; *Neovascularization, Pathologic/pathology/ultrasonography; Positron-Emission Tomography/methods; Tomography/methods; Tomography, Emission-Computed, Single-Photon/methods; Tomography, X-Ray Computed/methods; X-Ray Microtomography/methods

Significant advances have been made in understanding the role of tumor angiogenesis and its influence on tumor progression in cancer. Based on this knowledge, a series of inhibitors of angiogenesis have been developed and evaluated in preclinical and clinical trials. Since detailed information of tumor progression in response to therapy is important to assess the efficacy of anti-tumor treatment in vivo, noninvasive imaging techniques emerge more and more as important tools to monitor alterations in tumor growth and vessel recruitment, as well as metastatic spread over time. So far, remarkable efforts have been made to improve the technical capability of these imaging modalities based on better resolution, as well as to implement multimodal approaches combining molecular with anatomical information. Advanced imaging techniques not only allow the detection and monitoring of tumor development, but also facilitate a broad understanding of the cellular and molecular events that propagate tumor angiogenesis, as well as those occurring in response to therapy. This review provides an overview of different imaging techniques in preclinical settings of oncological research and discusses their potential impact on clinical translation. Imaging modalities will be presented that have been implemented to address key biological issues by exploring tumor angiogenic processes and evaluating antiangiogenic therapy.

Journal Article

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

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.

Journal Article

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

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.

Journal Article

Xen5, Xen 5, Pseudomonas aeruginosa Xen 5, Anti-Bacterial Agents/administration & dosage/*pharmacology/therapeutic; use; Antimicrobial Cationic Peptides/chemistry; Biofilms/drug effects; Cholic Acid/chemistry; Cystic Fibrosis/microbiology; Hemolysis/drug effects; Humans; *Poloxamer; Pseudomonas Infections/drug therapy; Pseudomonas aeruginosa/drug effects/growth & development; Skin Diseases, Bacterial/drug therapy; Staphylococcus aureus/drug effects; Steroids/administration & dosage/*pharmacology/therapeutic use; *Surface-Active Agents

AIMS: Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. METHODS AND RESULTS: CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC/MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (-) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). CONCLUSION: These results suggest that CSA-13 may be useful to prevent and treat topical infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity.