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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment

Head and neck squamous cell carcinoma (HNSCC) is a debilitating and deadly disease with a high prevalence of recurrence and treatment failure. To develop ...

University of Colorado Denver - Anschutz Medical Campus

Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) Criteria have been traditionally used for the evaluation of therapeutic response to chemotherapeutic treatment regimens. They determine anatomic criteria for patients response to anti-cancer therapy based on morphological measurements of each target lesion. While this assessment is justified for cytotoxic (chemotherapeutic) drugs, it is now recognized that morphological imaging protocols are poorly suited to the evaluation of the efficacy of novel signal transduction inhibitors (STIs) which exhibit cytostatic rather than cytotoxic properties. New imaging technologies are now designed to evaluate, in a functional manner, modifications in tumor metabolic activity, cellularity, and vascularization before a reduction in tumor volume can be detected. Introduction of physiological imaging end-points, derived from dynamic contrast-enhanced (DCE) imaging protocols--including magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound (US)--allow for early assessment of disruption in tumor perfusion and permeability for targeted anti-angiogenic agents. Diffusion-weighted MRI (DWI) provides another physiological imaging end-point since tumor necrosis and cellularity are seen early in response to anti-angiogenic treatment. Changes in glucose and phospholipid turnover, based on metabolic MRI and positron emission tomography (PET), provide reliable markers for therapeutic response to novel receptor-targeting agents. Finally, novel molecular imaging techniques of protein and gene expression have been developed in animal models followed by a successful human application for gene therapy-based protocols.

Translational imaging endpoints to predict treatment response to novel targeted anticancer agents.

Nuclear magnetic resonance spectroscopy (called NMR for ex vivo techniques and MRS for in vivo techniques) has become a useful analytical and diagnostic tool in biomedicine. In the past two decades, an MR-based spectroscopic approach for translational and clinical research has emerged that allows for biochemical characterization of the tissue of interest either ex vivo (NMR-based metabolomics) or in vivo (localized MRS-single voxel or multivoxel-spectroscopic imaging). The greatest advantages of MRS techniques are their ability to detect multiple tissue-specific metabolites in a single experiment, their quantitative nature and translational component (in vitro/ex vivo-discovered metabolic biomarkers can be translated into noninvasive spectroscopic imaging protocols). Disadvantages of MRS include low sensitivity and spectral resolution and, in case of NMR-metabolomics, metabolite degradation and incomplete recovery in processed samples. In vivo MRS has worse spectral resolution than ex vivo high-resolution NMR due to the inherently wider lines of metabolites in vivo and the difficulty of using traditional line-narrowing methods (e.g., sample spinning). It also suffers from poor time-resolution, therefore offering fewer metabolic biomarkers to be followed in vivo. In the present review article, we provide considerations for establishing reliable protocols (both in vivo and ex vivo) for metabolite detection, recovery and quantification from in vivo and ex vivo MR spectra.

Quantitative analysis in magnetic resonance spectroscopy: from metabolic profiling to in vivo biomarkers.

Traumatic brain injury (TBI) is a major public health problem estimated to affect nearly 1.7 million people in the United States annually. Due to the often debilitating effects of TBI, novel preventative agents are highly desirable for at risk populations. Here, we tested a whey protein supplement, Immunocal®, for its potential to enhance resilience to TBI. Immunocal® is a non-denatured whey protein preparation which has been shown to act as a cysteine delivery system to increase levels of the essential antioxidant glutathione (GSH). Twice daily oral supplementation of CD1 mice with Immunocal for 28 days prior to receiving a moderate TBI prevented an ~ 25% reduction in brain GSH/GSSG observed in untreated TBI mice. Immunocal® had no significant effect on the primary mechanical injury induced by TBI, as assessed by MRI, changes in Tau phosphorylation, and righting reflex time or apnea. However, pre-injury supplementation with Immunocal® resulted in statistically significant improvements in motor function (beam walk and rotarod) and cognitive function (Barnes maze). We also observed a significant preservation of corpus callosum width (axonal myelination), a significant decrease in degenerating neurons, a reduction in Iba1 (microglial marker), decreased lipid peroxidation, and preservation of brain-derived neurotrophic factor (BDNF) in the brains of Immunocal®-pretreated mice compared to untreated TBI mice. Taken together, these data indicate that pre-injury supplementation with Immunocal® significantly enhances the resilience to TBI induced by a moderate closed head injury in mice. We conclude that Immunocal® may hold significant promise as a preventative agent for TBI, particularly in certain high risk populations such as athletes and military personnel.

The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact.

Natalie Serkova

Department of Radiation Oncology,
Department of Anesthesiology,
Division of Radiology

University of Colorado Denver - Anschutz Medical Campus

Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment

Natalie Serkova

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Radiation Oncology,Department of Anesthesiology,Division of Radiology

University of Colorado Denver - Anschutz Medical Campus

Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment

Department of Radiation Oncology,
Department of Anesthesiology,
Division of Radiology