Subependymoma at the foramen of Monro presenting with intermittent hydrocephalus: case report and review of the literature.

Subependymomas are benign neoplasms, accounting for 0.5 % of all central nervous system tumors. These tumors are frequently asymptomatic, often discovered incidentally at autopsy. However, patients may be symptomatic with the symptoms depending on location of the tumor. Since subependymomas typically arise from the ventricular wall, obstruction of cerebrospinal fluid is a major cause of onset symptoms. We present a rare case report of a subependymoma at the foramen of Monro presenting with intermittent hydrocephalus. The patient's tumor was asymptomatic for many years. Imaging findings included asymmetry of the lateral ventricles. The patient developed sudden onset of headache and altered mental status followed by complete resolution, likely due to intermittent hydrocephalus. She developed two more such episodes necessitating an emergent external ventricular drain placement followed by surgical resection. Our report illustrates a case of intermittent hydrocephalus due to a sessile subependymoma. Even though our patient presented with a histologically benign ventricular tumor, she demonstrated rapidly worsening symptoms that culminated in herniation. By presenting our case report, we hope to draw attention to this rare but potentially life-threatening presentation of subependymoma. Once diagnosed, we recommend early tumor removal and restoration of normal cerebrospinal fluid (CSF) pathways for these intraventricular tumors.

Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling.

BACKGROUND: Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs. Polymorphisms of MDR1 disrupt the effects of P-glycoprotein antagonists and limit the success of drug resistance reversal in clinical trials. GCS converts ceramide to glucosylceramide, reducing the impact of ceramide-induced apoptosis and increasing glycosphingolipid (GSL) synthesis. Understanding the molecular mechanisms underlying MDR1 overexpression and how it interacts with GCS may find effective approaches to reverse drug resistance. RESULTS: MDR1 and GCS were coincidently overexpressed in drug-resistant breast, ovary, cervical and colon cancer cells; silencing GCS using a novel mixed-backbone oligonucleotide (MBO-asGCS) sensitized these four drug-resistant cell lines to doxorubicin. This sensitization was correlated with the decreased MDR1 expression and the increased doxorubicin accumulation. Doxorubicin treatment induced GCS and MDR1 expression in tumors, but MBO-asGCS treatment eliminated "in-vivo" growth of drug-resistant tumor (NCI/ADR-RES). MBO-asGCS suppressed the expression of MDR1 with GCS and sensitized NCI/ADR-RES tumor to doxorubicin. The expression of P-glycoprotein and the function of its drug efflux of tumors were decreased by 4 and 8 times after MBO-asGCS treatment, even though this treatment did not have a significant effect on P-glycoprotein in normal small intestine. GCS transient transfection induced MDR1 overexpression and increased P-glycoprotein efflux in dose-dependent fashion in OVCAR-8 cancer cells. GSL profiling, silencing of globotriaosylceramide synthase and assessment of signaling pathway indicated that GCS transfection significantly increased globo series GSLs (globotriaosylceramide Gb3, globotetraosylceramide Gb4) on GSL-enriched microdomain (GEM), activated cSrc kinase, decreased beta-catenin phosphorylation, and increased nuclear beta-catenin. These consequently increased MDR1 promoter activation and its expression. Conversely, MBO-asGCS treatments decreased globo series GSLs (Gb3, Gb4), cSrc kinase and nuclear beta-catenin, and suppressed MDR-1 expression in dose-dependent pattern. CONCLUSION: This study demonstrates, for the first time, that GCS upregulates MDR1 expression modulating drug resistance of cancer. GSLs, in particular globo series GSLs mediate gene expression of MDR1 through cSrc and beta-catenin signaling pathway.

A new mixed-backbone oligonucleotide against glucosylceramide synthase sensitizes multidrug-resistant tumors to apoptosis.

Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C(18)-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent.

Effects of the endothelin-converting enzyme inhibitor SM-19712 in a mouse model of dextran sodium sulfate-induced colitis.

BACKGROUND: Ingestion by mice of dextran sodium sulfate (DSS) induces colonic vasoconstriction and inflammation, with some of the effects potentially mediated by the vasoconstrictor endothelin-1 (ET-1). METHODS: In this study, mice given 5% 40 kD DSS for 5-6 days had elevated colonic immunostaining for ET-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1). Increased ET-1 can induce microvascular constriction; however, the increase in PECAM-1 is consistent with angiogenesis that could decrease flow resistance. RESULTS: Our measurements of intestinal blood flow, via infused microspheres, suggests that these 2 factors may offset each other, with only a nonsignificant tendency for a DSS-induced decrease in flow. Daily administration of the endothelin converting enzyme inhibitor SM-19712 (15 mg/kg) attenuated DSS-induced increases in colonic immunostaining of ET-1 and PECAM-1. CONCLUSIONS: SM-19712 attenuated histologic signs of tissue injury and inflammation induced by DSS, and decreased the extent of loose stools and fecal blood. However, the inhibitor did not significantly decrease DSS-induced colon shortening or tissue levels of myeloperoxidase (an indicator of neutrophil infiltration).

T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade.

The inflammatory bowel diseases (Crohn's disease; ulcerative colitis) are idiopathic chronic inflammatory disorders of the intestine and/or colon. A major advancement in our understanding of the pathogenesis of these diseases has been the development of mouse models of chronic gut inflammation. One model that has been instrumental in delineating the immunological mechanisms responsible for the induction as well as regulation of intestinal inflammation is the T cell transfer model of chronic colitis. This paper presents a detailed protocol describing the methods used to induce chronic colitis in mice. Special attention is given to the immunological concepts that explain disease pathogenesis in this model, considerations and potential pitfalls in using this model, and finally different "tricks" that we have learned over the past 12 years that have allowed us to develop a more simplified version of this model of experimental IBD.

In vivo survivors of transformed mouse ovarian surface epithelial cells display diverse phenotypes for gene expression and tumorigenicity.

Ovarian cancer is the fifth most common cause of cancer death in women. Due to a lack of appropriate animal models, studies involving tumorigenicity, tumor progression and immune response at the molecular level are limited. We isolated many clones derived from thesurvivors of a transformed mouse ovarian epithelial cell line IG-10 in immune- competent mice and found that the clones displayed diverse phenotypes. Most clones were deficient in components of the MHC-I antigen presentation pathway. Soft-agarose colony assays showed different growth rates among clones. However, this did not completely correlate with each clone's in vivo tumorigenicity regarding growth, tumor mass and ascites formation, suggesting the possibility that the clones may display contrasting intrinsic gene expression. We therefore performed two types of arrays to evaluate gene expression at transcriptional and translational levels. The results showed differences in expression of COL4alpha5, NOS-2, and SOCS-1 genes at the transcriptional level, MIP-2 gene at the protein level and CCL5, CXCL-10, IL-1alpha genes at both transcriptional and protein levels between low and high tumorigenic clones. Thus, our animal cell model together with the identified genes may provide a useful tool to study ovarian cancer immune response, tumorigenicity and tumor-host cell interactions in the tumor microenvironment.