Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer

Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Se's protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.     

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.     

Spinal cord compression by tophaceous gout with fluorodeoxyglucose-positron-emission tomographic/MR fusion imaging

A 36-year-old woman presented with lower extremity paralysis. Her past medical history included gout. Conventional radiography and MR imaging revealed bone erosion and soft tissue lesions of the thoracic spine. Fluorodeoxyglucose-positron-emission tomographic (FDG-PET) images revealed hypermetabolic lesions of the thoracic spine. A CT-guided biopsy was diagnostic for inflammatory tophaceous gout. This case describes the CT, MR, and FDG-PET imaging characteristics of acute inflammatory gout. FDG-PET imaging characteristics of this disorder have not been previously described.     

Multiphase contrast medium injection for optimization of computed tomographic coronary angiography

RATIONALE AND OBJECTIVES: Electron beam angiography is a minimally invasive imaging technique. Adequate vascular opacification throughout the study remains a critical issue for image quality. We hypothesized that vascular image opacification and uniformity of vascular enhancement between slices can be improved using multiphase contrast medium injection protocols. MATERIALS AND METHODS: We enrolled 244 consecutive patients who were randomized to three different injection protocols: single-phase contrast medium injection (Group 1), dual-phase contrast medium injection with each phase at a different injection rate (Group 2), and a three-phase injection with two phases of contrast medium injection followed by a saline injection phase (Group 3). Parameters measured were aortic opacification based on Hounsfield units and uniformity of aortic enhancement at predetermined slices (locations from top [level 1] to base [level 60]). RESULTS: In Group 1, contrast opacification differed across seven predetermined locations (scan levels: 1st versus 60th, P < .05), demonstrating significant nonuniformity. In Group 2, there was more uniform vascular enhancement, with no significant differences between the first 50 slices (P > .05). In Group 3, there was greater uniformity of vascular enhancement and higher mean Hounsfield units value across all 60 images, from the aortic root to the base of the heart (P < .05). CONCLUSIONS: The three-phase injection protocol improved vascular opacification at the base of the heart, as well as uniformity of arterial enhancement throughout the study.     

Upregulation of the stress-associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Cuprizone-induced demyelination is a mouse model of multiple sclerosis (MS) as cuprizone-fed mice exhibit neuroinflammation and demyelination in the brain. Upon removal of cuprizone from the diet, inflammation is resolved and reparative remyelination occurs. In an Affymetrix GeneChip analysis, the stress-associated gene p8 was strongly upregulated (>10x) during cuprizone-induced demyelination but not remyelination. We verified this upregulation (>15x) of p8 in the CNS during demyelination by real-time polymerase chain reaction (PCR). This upregulation is brain-specific, as p8 is not elevated in the liver, lung, kidney, spleen, and heart of cuprizone-treated mice. We also localized the cellular source of p8 during cuprizone treatment, and further found elevated expression during embryogenesis but not in normal adult brain. Compared with wild-type controls, the death of oligodendrocytes in p8-/- mice is delayed, as is microglial recruitment to areas of demyelination. The corpus callosum of p8-/- mice demyelinates at a slower rate than wild-type mice, suggesting that p8 exacerbates CNS inflammation and demyelination. Enhanced expression of p8 is also observed in the spinal cords of mice with acute experimental autoimmune encephalomyelitis (EAE) induced by PLP139-151 peptide (10x). Increased expression is detected during disease onset and expression wanes during the remission phase. Finally, p8 is found upregulated (8x) in post-mortem tissue from MS patients and is higher in the plaque tissue compared with adjacent normal-appearing white and gray matter. Thus, p8 is an excellent candidate as a novel biomarker of demyelination.     

Characterization of cerebral tissue by MRI map ISODATA in embolic stroke in rat

ISODATA using MRI parameter-weighted images has been previously employed to characterize ischemic cell damage after stroke in rats. In an effort to increase the objectivity and to further automate the ISODATA, MRI parameter maps were now employed. Male Wistar rats were subjected to embolic stroke and received treatment via a femoral vein at 4 h post-stroke. The control rats received saline and were sacrificed at 6, 24 and 48 h after stroke, respectively. Treated rats received rtPA alone or were treated with a combination of rtPA and an antibody, 7E3 F(ab′)₂, against the glycoprotein receptor that binds the platelet to fibrin. These rats were sacrificed at 24, or 48, h post-stroke. T₁, T₂ and diffusion maps were employed for map ISODATA analysis. H&E histological analysis of coronal sections of tissue was performed and compared with map ISODATA from the corresponding sections. ISODATA signatures were highly correlated (R ∼ 0.80, P < 0.0001) with the ischemic cell damage analyzed at 6, 24 and 48 h post-stroke. At 24 and 48 h after stroke, ISODATA lesion sizes were highly correlated (R > 0.97, P < 0.001) with lesion sizes measured histologically. The combination treatment of rtPA and 7E3 F(ab′)₂ reduced both infarction size (P < 0.002) and average signature (P < 0.03) at 48 h after stroke, compared to saline-treated animals. No significant difference was found between saline and rtPA-alone-treated rats. The map ISODATA successfully provides objective and automated quantitation of the ischemic damage in both size and severity in an embolic stroke model of rat with and without a therapeutic intervention.