Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Growing evidence suggests that different types of CSC lead to the formation of GBM. This has prompted the present comparison of gene expression profiles between 17 GBM CSC lines and their different putative founder cells. Using a newly derived 24-gene signature, we can now distinguish two subgroups of GBM: Type I CSC lines display "proneural" signature genes and resemble fetal neural stem cell (fNSC) lines, whereas type II CSC lines show "mesenchymal" transcriptional profiles similar to adult NSC (aNSC) lines. Phenotypically, type I CSC lines are CD133 positive and grow as neurospheres. Type II CSC lines, in contrast, display (semi-)adherent growth and lack CD133 expression. Molecular differences between type I and type II CSC lines include the expression of extracellular matrix molecules and the transcriptional activity of the WNT and the transforming growth factor-β/bone morphogenetic protein signaling pathways. Importantly, these characteristics were not affected by induced adherence on laminin. Comparing CSC lines with their putative cells of origin, we observed greatly increased proliferation and impaired differentiation capacity in both types of CSC lines but no cancer-associated activation of otherwise silent signaling pathways. Thus, our data suggest that the heterogeneous tumor entity GBM may derive from cells that have preserved or acquired properties of either fNSC or aNSC but lost the corresponding differentiation potential. Moreover, we propose a gene signature that enables the subclassification of GBM according to their putative cells of origin. Cancer Res; 70(5); 2030-40. ©2010 AACR.
The feasibility of topical delivery of pGTmCMV.IFN-GFP plasmid in mice using gemini cationic surfactant based delivery systems was demonstrated. IFNgamma expression after treatment with gemini-DNA formulations in the skin was 3-5-fold higher compared to the treatment with naked DNA (p<0.05), and 4-6-fold higher than the Dc-chol-DNA complex, indicating a significant advance in topical DNA delivery across intact skin in vivo.
These findings suggest that EEG responses to novel events in this rapid, simple, and inexpensive test have tremendous promise for tracking individual trajectories of cognitive dysfunction in Parkinson's disease.
Cyclic AMP is a ubiquitous messenger that integrates many processes of the cell. Diverse families of adenylate cyclases and phosphodiesterases stringently regulate the intracellular concentration of cAMP. Any alteration in the cytosolic concentration of cAMP has a profound effect on the various processes of the cell. Disruption of these cellular processes in vivo is often the most critical event in the pathogenesis of infectious diseases for animals and humans. Many pathogenic bacteria secrete toxins to alter the intracellular concentration of cAMP. These toxins either disrupt the normal regulation of the host cell's adenylate cyclases/phosphodiesterases or they themselves catalyze the synthesis of cAMP in the host cell. The latter are known as the adenylate cyclase toxins. Four such toxins have been identified: the invasive adenylate cyclase of Bordetella pertussis, the edema factor of Bacillus anthracis, ExoY of Pseudomonas aeruginosa, and the adenylate cyclase of Yersinia pestis. These adenylate cyclase toxins enter the eukaryotic host cells and get activated by eukaryotic cofactors, like calmodulin, to trigger the synthesis of cAMP in these cells. By accumulating cAMP in the target cells, these toxins either modulate the cellular function or completely deactivate the cell for further function. The immune effector cells appear to be the primary target of these adenylate cyclase toxins. By accumulating cAMP in the immune effector cells, these adenylate cyclase toxins poison the immune system and thus facilitate the survival of the bacteria in the host.
Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.
Survivin is one of the rare proteins that is differentially expressed in normal and cancer cells and is directly or indirectly involved in numerous pathways required for tumor maintenance. It is expressed in almost all cancers and its expression has been detected at early stages of cancer. These traits make survivin an exceptionally attractive target for cancer therapeutics. Even with these promising features to be an oncotherapeutic target, there has been limited success in the clinical trials targeting survivin. Only recently it has emerged that survivin was not being specifically targeted which could have resulted in the negative clinical outcome. Also, focus of research has now shifted from survivin expression in the overall heterogeneous tumor cell populations to survivin expression in cancer stem cells as these cells have proved to be the major drivers of tumors. Therefore, in this review we have analyzed the expression of survivin in normal and cancer cells with a particular focus on its expression in cancer stem cell compartment. We have discussed the major signaling pathways involved in regulation of survivin. We have explored the current development status of various types of interventions for inhibition of survivin. Furthermore, we have discussed the challenges involving the development of potent and specific survivin inhibitors for cancer therapeutics. Finally we have given insights for some of the promising future anticancer treatments.
Serotonin (5-hydroxytraptamin, 5-HT) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocytes (OL) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying SSRIs-induced OL and myelin abnormalities, we investigated the effect of 5-HT exposure on OL development, cell death, and myelination in cell culture models. First, we showed that 5-HT receptor 1A and 2A subtypes were expressed in OL lineages, using immunocytochemistry, Western blot, as well as intracellular Ca2+ measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified OL and neuron-OL myelination cultures. For pure OL cultures, our results showed that 5-HT exposure led to disturbance of OL development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development-dependent cell death, as immature OLs exhibited increasing susceptibility to 5-HT treatment compared to OL progenitor cells (OPCs). We showed further that 5-HT-induced immature OL death was mediated at least partially via 5-HT2A receptor, since cell death could be mimicked by 5-HT2A receptor agonist DOI, but attenuated by pre-treatment with 5-HT2A receptor antagonist ritanserin. Utilizing a neuron-OL myelination co-culture model, our data showed that 5-HT exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure OL cultures, 5-HT exposure did not lead to OL death or reduced OL density in neuron-OL co-cultures. However, abnormal patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals.
Noninvasive transdermal insulin delivery could provide diabetic patients with sustained physiological levels of basal insulin in a pain-free manner. We have developed a novel transdermal lipid-based system (Biphasix) suitable for macromolecule delivery across the skin. The objective of this study was to evaluate the pharmacological effects of the Biphasix-insulin delivery system in a diabetic rat model. Transdermal patches (one per animal) containing Biphasix-insulin formulation (10 mg of recombinant human insulin dose) were applied to the shaved abdominal skin of streptozotocin-induced diabetic rats for 48 h. Blood glucose was monitored every 2-4 h using a Lifescan glucose meter. Serum insulin levels were analysed by enzyme-linked immunosorbent assay. A decrease in blood glucose of 43.7 +/- 3.8% (mean +/- SEM, n = 25) was observed compared with initial blood glucose levels. The duration of the response was 51.5 +/- 3.7 h (mean +/- SEM, n = 25). Serum insulin after application of the transdermal Biphasix-insulin patch was 20.08 +/- 5.44 micro IU/mL (mean +/- SEM, n = 13) during the steady state, which was not statistically different from the insulin levels obtained 2 h after subcutaneous injection of 1 mg of recombinant human insulin solution. Insulin bioavailability from the transdermal Biphasix-insulin patches was 21.5 +/- 6.9% (mean +/- SEM, n = 13) based on serum insulin and 39.5 +/- 8.5% (mean +/- SEM, n = 25) based on the pharmacodynamic blood glucose-lowering effects. The Biphasix system successfully delivered insulin transdermally, as evidenced by a significant sustained decrease in blood glucose in diabetic rats, with a corresponding increase in serum insulin. These results support the feasibility of developing a transdermal insulin patch for human applications.
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