Rapid in vivo Taxotere quantitative chemosensitivity response by 4.23 Tesla sodium MRI and histo-immunostaining features in N-Methyl-N-Nitrosourea induced breast tumors in rats

BACKGROUND: Sodium weighted images can indicate sodium signal intensities from different features in the tumor before and 24 hours following administration of Taxotere. AIM: To evaluate the association of in vivo intracellular sodium magnetic resonance image intensities with immuno-biomarkers and histopathological features to monitor the early tumor response to Taxotere chemotherapy in Methyl-Nitroso-Urea induced rat xenograft breast tumors. METHODS AND MATERIALS: Methyl-Nitroso-Urea (MNU) induced rat xenograft breast tumors were imaged for sodium MRI and compared with tumor histology, immunostaining after 24 hours chemotherapy. RESULTS: Sodium MRI signal intensities represented sodium concentrations. Excised tumor histological sections showed different in vitro histological end points i.e. single strand DNA content of cell nuclei during cell cycle (G1/S-G2/M), distinct S or M histograms (Feulgen labeling to nuclear DNA content by CAS 200), mitotic figures and apoptosis at different locations of breast tumors. Necrosis and cystic fluid appeared gray on intracellular (IC) sodium images while apoptosis rich regions appeared brighter on IC sodium images. After 24 hours Taxotere-treated tumors showed lower 'IC/EC ratio' of viable cells (65–76%) with higher mitotic index; apoptotic tumor cells at high risk due to cytotoxicity (>70% with high apoptotic index); reduced proliferation index (270 vs 120 per high power field) associated with enhanced IC sodium in vivo MR image intensities and decreased tumor size (3%; p < 0.001; n = 16) than that of pre-treated tumors. IC-Na MR signal intensities possibly indicated Taxotere chemosensitivity response in vivo associated with apoptosis and different pre-malignant features within 24 hours of exposure of cancer cells to anti-neoplastic Taxotere drug. CONCLUSION: Sodium MRI imaging may be used as in vivo rapid drug monitoring method to evaluate Taxotere chemosensitivity response associated with neoplasia, apoptosis and tumor histology features

Cancer-induced bone pain sequentially activates the ERK/MAPK pathway in different cell types in the rat spinal cord

<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrates that, after nerve injury, extracellular signal-regulated protein kinase (ERK) activation in the spinal cord-initially in neurons, then microglia, and finally astrocytes. In addition, phosphorylation of ERK (p-ERK) contributes to nociceptive responses following inflammation and/or nerve injury. However, the role of spinal cells and the ERK/MAPK pathway in cancer-induced bone pain (CIBP) remains poorly understood. The present study analyzed activation of spinal cells and the ERK/MAPK pathway in a rat model of bone cancer pain.</p> <p>Results</p> <p>A Sprague Dawley rat model of bone cancer pain was established and the model was evaluated by a series of tests. Moreover, fluorocitrate (reversible glial metabolic inhibitor) and U0126 (a MEK inhibitor) was administered intrathecally. Western blots and double immunofluorescence were used to detect the expression and location of phosphorylation of ERK (p-ERK). Our studies on pain behavior show that the time between day 6 and day 18 is a reasonable period ("time window" as the remaining stages) to investigate bone cancer pain mechanisms and to research analgesic drugs. Double-labeling immunofluorescence revealed that p-ERK was sequentially expressed in neurons, microglia, and astrocytes in the L4-5 superficial spinal cord following inoculation of Walker 256 cells. Phosphorylation of ERK (p-ERK) and the transcription factor cAMP response element-binding protein (p-CREB) increased in the spinal cord of CIBP rats, which was attenuated by intrathecal injection of fluorocitrate or U0126.</p> <p>Conclusions</p> <p>The ERK inhibitors could have a useful role in CIBP management, because the same target is expressed in various cells at different times.</p

CELLULAR MRI: TRACKING THE MIGRATION OF METASTATIC CANCER CELLS IN THE LYMPHATIC SYSTEM

The role of the lymphatics as a mode of tumor cell transport has been known for some time, and remains of critical importance since a majority of cancer deaths result from metastatic dissemination away from the primary tumor. In the studies performed in this thesis novel cellular MRI technology and a unique murine intranodal implantation model are used to track the movement of iron-labeled melanoma cells in vivo. With these methods we demonstrate, for the first time, that cellular MRI can be used to detect metastatic melanoma cells present at the implant site and in the draining lymph node and to track the growth of these cells into a metastatic tumor. The ability to track metastatic cancer cells in the lymphatic system in vivo may promote a better understanding of models of carcinogenesis and metastasis and in the future may help to improve on principles by which cancers are treated

Combining Transfer of TTF-1 and Pax-8 Gene: a Potential Strategy to Promote Radioiodine Therapy of Thyroid Carcinoma

Cotransfer of TTF-1 and Pax-8 gene to tumor cells, resulting in the reexpression of iodide metabolism-associated proteins, such as sodium iodide symporter (NIS), thyroglobulin (Tg), thyroperoxidase (TPO), offers the possibility of radioiodine therapy to non-iodide-concentrating tumor because the expression of iodide metabolism-associated proteins in thyroid are mediated by the thyroid transcription factors TTF-1 and Pax-8. The human TTF-1 and Pax-8 gene were transducted into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus, AdTTF-1 and AdPax-8. Reexpression of NIS mRNA and protein, but not TPO and Tg mRNA and protein, was detected in AdTTF-1-infected F133 cells, following with increasing radioiodine uptake (6.1~7.4 times), scarcely iodide organification and rapid iodide efflux (t1/2&#x2248;8 min in vitro, t1/2&#x2248;4.7 h in vivo).&#xd;&#xa;In contrast, all of the reexpression of NIS, TPO and Tg mRNA and proteins in F133 cells were induced by the synergetic effect of TTF-1 and Pax-8. AdTTF-1 and AdPax-8 coinfected K1 and F133 cells could effectively accumulate radioiodine (6.6-7.5 times) and obviously retarded radioiodine retention (t1/2&#x2248;25-30 min in vitro, t1/2&#x2248;12 h in vivo) (p&#x3c;0.05).&#xd;&#xa;Accordingly, the effect of radioiodine therapy of TTF-1 and Pax-8 cotransducted K1 and&#xd;&#xa;F133 cells (21-25% survival rate in vitro) was better than that of TTF-1-transducted cells&#xd;&#xa;(40% survival rate in vitro) (p&#x3c;0.05). These results indicate that single TTF-1 gene transfer may have limited efficacy of radioiodine therapy because of rapid radioiodine efflux. The cotransduction of TTF-1 and Pax-8 gene, with resulting NIS-mediated radioiodine accumulation and TPO and Tg-mediated radioiodine organification and intracellular retention, may lead to effective radioiodine therapy of thyroid carcinoma

Three-Dimensional Imaging of the Mouse Neurovasculature with Magnetic Resonance Microscopy

Knowledge of the three-dimensional (3D) architecture of blood vessels in the brain is crucial because the progression of various neuropathologies ranging from Alzheimer's disease to brain tumors involves anomalous blood vessels. The challenges in obtaining such data from patients, in conjunction with development of mouse models of neuropathology, have made the murine brain indispensable for investigating disease induced neurovascular changes. Here we describe a novel method for “whole brain” 3D mapping of murine neurovasculature using magnetic resonance microscopy (μMRI). This approach preserves the vascular and white matter tract architecture, and can be combined with complementary MRI contrast mechanisms such as diffusion tensor imaging (DTI) to examine the interplay between the vasculature and white matter reorganization that often characterizes neuropathologies. Following validation with micro computed tomography (μCT) and optical microscopy, we demonstrate the utility of this method by: (i) combined 3D imaging of angiogenesis and white matter reorganization in both, invasive and non-invasive brain tumor models; (ii) characterizing the morphological heterogeneity of the vascular phenotype in the murine brain; and (iii) conducting “multi-scale” imaging of brain tumor angiogenesis, wherein we directly compared in vivo MRI blood volume measurements with ex vivo vasculature data

In Vivo Application of Proton-Electron Double-Resonance Imaging

This work was partially supported by NIH grants 1ZIABC010477-14 (MKC), CA194013 (VVK), CA192064 (VVK), U54GM104942 (VVK); by KAKENHI grant 16H05113 (H.U.) from the Japan Society for the Promotion of Science (HU) and start-up grant from the WVCTSI (VVK).Peer reviewedPostprin

Imaging of the Breast

Early detection of breast cancer combined with targeted therapy offers the best outcome for breast cancer patients. This volume deal with a wide range of new technical innovations for improving breast cancer detection, diagnosis and therapy. There is a special focus on improvements in mammographic image quality, image analysis, magnetic resonance imaging of the breast and molecular imaging. A chapter on targeted therapy explores the option of less radical postoperative therapy for women with early, screen-detected breast cancers

Characterizing the Role of the Neuropeptide Y-Y5R System in Breast Cancer

Studies have demonstrated a correlation between stress and an increased risk of breast cancer. Neuropeptide Y (NPY) is up- regulated in chronic stress and induces proliferation and chemotaxis of 4T1 breast cancer cells via Y5 receptor (Y5R) activation. In the studies performed in this thesis, we characterize NPY-Y5R as a regulatory system that promotes breast cancer metastasis. We compared three cancer cell sublines derived from the same murine mammary fat pad tumour, that greatly differ in metastatic potential (67NR, 168FARN, and 4T1) in addition to a 4T1-Y5R knockdown established in our labs. In this thesis we demonstrate significance of up-regulation and cytoplasmic localization of Y5R to support an aggressively metastasizing breast cancer cell line. Using cellular MRI we characterized the knockdown of Y5R to alter breast carcinogenesis and metastasis. In this respect, NPY and its Y5 receptor could be therapeutic targets to combat breast cancer metastasis