MicroRNA-29a activates a multi-component growth and invasion program in glioblastoma.

Background: Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.

Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity.

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits.

Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans.

Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.

Imaging of human mesenchymal stromal cells: homing to human brain tumors.

Human mesenchymal stromal cells (hMSC) can be used as a drug delivery vehicle for the treatment of GBM. However, tracking the migration and distribution of these transplanted cells is necessary to interpret therapeutic efficacy. We compared three labeling techniques for their ability to track the migration of transplanted hMSC in an orthotopic mouse xenograft model.

Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus.

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD).

SNAI2/Slug promotes growth and invasion in human gliomas.

Background: Numerous factors that contribute to malignant glioma invasion have been identified, but the upstream genes coordinating this process are poorly known.

Methods: To identify genes controlling glioma invasion, we used genome-wide mRNA expression profiles of primary human glioblastomas to develop an expression-based rank ordering of 30 transcription factors that have previously been implicated in the regulation of invasion and metastasis in cancer.

Results: Using this approach, we identified the oncogenic transcriptional repressor, SNAI2/Slug, among the upper tenth percentile of invasion-related transcription factors overexpressed in glioblastomas.

Novel local drug delivery system using thermoreversible gel in combination with polymeric microspheres or liposomes.

Background: The purpose of our study was to evaluate the application of thermoreversible gelation polymer (TGP) as a local drug delivery system for malignant glioma.

Materials And Methods: Polymeric microspheres or liposomes loaded with doxorubicin (sphere-dox or lipo-dox) were combined with TGP to provide continuous drug delivery of doxorubicin (dox) for kinetic release studies and cell viability assays on glioma cell lines in vitro. For in vivo studies, TGP loaded with dox alone (TGP-dox) was combined with sphere-dox or lipo-dox.

Bio-printing of collagen and VEGF-releasing fibrin gel scaffolds for neural stem cell culture.

Time-released delivery of soluble growth factors (GFs) in engineered hydrogel tissue constructs promotes the migration and proliferation of embedded cells, which is an important factor for designing scaffolds that ultimately aim for neural tissue regeneration. We report a tissue engineering technique to print murine neural stem cells (C17.2), collagen hydrogel, and GF (vascular endothelial growth factor: VEGF)-releasing fibrin gel to construct an artificial neural tissue.

Translational modulation of proteins expressed from bicistronic vectors.

Bicistronic vectors are useful tools for exogenous expression of two gene products from a single promoter element; however, reduced expression of protein from the second cistron compared with the first cistron is a common limitation to this approach. To overcome this limitation, we explored use of dihydrofolate reductase (DHFR) complementary DNA encoded in bicistronic vectors to induce a second protein of interest by methotrexate (MTX) treatment. Previous studies have demonstrated that levels of DHFR protein and DHFR fusion protein can be induced translationally following MTX treatment of cells.

Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy.

Glioblastoma is among the most aggressive and treatment resistant of all human cancers. Conventional therapeutic approaches are unsuccessful because of diffuse infiltrative invasion of glioma tumor cells into normal brain parenchyma. Stem cell-based therapies provide a promising approach for the treatment of malignant gliomas because of their migratory ability to invasive tumor cells.

Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance.

5-Fluorouracil (5-FU) continues to be widely used for treatment of gastrointestinal cancers. Because many tumors show primary or acquired resistance, it is important to understand the molecular basis underlying the mechanism of resistance to 5-FU. In addition to its effect on thymidylate synthase inhibition and DNA synthesis, 5-FU may also influence RNA metabolism.

Local delivery of poly lactic-co-glycolic acid microspheres containing imatinib mesylate inhibits intracranial xenograft glioma growth.

Purpose: In an effort to develop new therapeutic strategies to treat malignant gliomas, we have designed poly (lactic-co-glycolic) acid (PLGA) microparticles that deliver imatinib mesylate, a small molecule tyrosine kinase inhibitor. The local continuous release of imatinib mesylate at the tumor site overcomes many obstacles associated with systemic delivery.

Experimental Design: Polymeric microspheres were prepared from various compositions of PLGA and loaded with imatinib mesylate.

In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model.

The correlation between glioma grade and angiogenesis suggests that antiangiogenic therapies are potentially therapeutically effective for these tumors. However, to achieve tumor suppression, antiangiogenic therapies need to be administered daily using high systemic quantities. We designed a biodegradable polymeric device that overcomes those barriers by providing sustained local delivery of a C-terminal fragment of platelet factor 4 (PF-4/CTF), an antiangiogenic agent.

Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study).

We tested the hypothesis that, compared with placebo, simvastatin would reduce the progression of coronary artery calcium (CAC) and abdominal aortic calcium (AAC) levels in participants asymptomatic for vascular disease. Total CAC and AAC were measured with multidetector cardiac computed tomography. Inclusion criteria were a CAC score of >or=50 Agatston units, high-density lipoprotein (HDL) cholesterol levelor=2 other risk factors.

Continuous intracranial administration of suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth in an orthotopic glioma model.

Object: Current treatments for malignant gliomas produce only a modest increase in survival time. New therapeutic approaches are desperately needed. Suberoylanilide hydroxamic acid (SAHA) is an effective inhibitor of the growth of many solid and hematological malignancies.

Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells.

Distinct signals that guide migration of mesenchymal stem cells (MSCs) to specific in vivo targets remain unknown. We have used rat MSCs to investigate the molecular mechanisms involved in such migration. Rat MSCs were shown to migrate to tumor microenvironment in vivo, and an in vitro migration assay was used under defined conditions to permit further mechanistic investigations.

Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression.

Purpose: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system.

Identification of amino acids required for the functional up-regulation of human dihydrofolate reductase protein in response to antifolate Treatment.

Human dihydrofolate reductase (DHFR) protein levels rapidly increase upon exposure to methotrexate, a potent inhibitor of this enzyme. A model to explain this increase proposes that DHFR inhibits its own translation by binding to its cognate mRNA and that methotrexate disrupts the DHFR protein-mRNA complex allowing its translation to resume. In the present study, Chinese hamster ovary cells lacking DHFR were transfected with wild type and mutants of human DHFR to identify amino acids that are essential for increases in DHFR in response to methotrexate.

Role of reporter gene imaging in molecular and cellular biology.

Molecular imaging, including reporter gene methods, provides a unique opportunity to study biology in a living subject, thereby allowing physiological events to be monitored in an intact microenvironment. This review takes a molecular and cell biology perspective on recent studies which utilize reporter gene imaging as a tool to non-invasively monitor specific molecular biology pathways in vivo. Studies in rodent models demonstrate the feasibility of reporter gene imaging to visualize and measure key cellular pathways, such as transcription, translation and protein-protein interactions.

Overexpression of E2F-1 in lung and liver metastases of human colon cancer is associated with gene amplification.

We have shown previously that metastatic tumors of human colorectal cancer in lung as compared to liver have high levels of thymidylate synthase (TS) mRNA expression that correlated with high levels of E2F-1 mRNA expression. We now report that Comparative Genomic Hybridization (CGH) and DNA PCR analyses of lung and liver metastases of human colon cancer show frequent gains in the region of chromosome 20q and have an increase in gene copy number of E2F-1. In as much as TS is transcriptionally regulated by E2F-1, these results provide an explanation for the high levels of TS mRNA noted in some tumor samples.

Tumor regression of B16F10 melanoma in vivo by prevention of neovascularization: study on theophylline.

The aim of this study was to determine the effect of theophylline on neovascularization and tumor regression in murine B16F10 melanoma. Theophylline had no direct toxicity to host and significantly reduced (p < 0.001) tumor volume and neovascularization in B16F10 melanoma implanted murine model.