Neural stem cells as novel therapeutic vehicles for genetic therapy in gliomas

Introduction: Recent studies have demonstrated the existence of a small fraction of glioma cells (specially in high-grade tumors) endowed with features of primitive neural progenitor cells and tumor-initiating function. As such neural stem cells have tremendous migratory potential for pathological areas in the central nervous system, they, theoretically, could be used to produce a desired gene product against glioma tumor cells. Matherial and Methods: The authors perform a critical literature review in order to highlight recent studies about the role of neural stem cells in the origin of malignant gliomas as well as its possible role as novel vehicles for delivery of targeted genetic therapy approaches. Results: Several recent studies have adressed the possible role of stem cells in the origin of gliomas. Furthermore, recent evidence has also suggested that engraftment of such cells would be followed by integration into the “local neural milieu” and accompanied by stable gene expression, acting, this way, as ideal genetic “vectors”. In addition, the pluripotency of such stem cells would endow them with the capability to replace diseased tissues in an appropriate manner (such as demonstrated in animal models of ischemic stroke). Conclusions: A better understanding of the mechanisms by which neural stem cells migrate to specific sources of injury may allow us to harness these cells as vehicles for delivery of molecular therapies and impact survival in patients with high-grade gliomas. It is important to emphasize, however, that the promising use of neural stem cells for genetic therapy in gliomas, is adjunctive and not a replacement of current standart therapies such as surgery (with maximal possible resection, radiotherapy and chemotherapy (with Temozolamide), which are expected to continue being part of the therapeutic armamentary against gliomas, at least in the near future.

Genetic Vectors as a Tool in Association Studies: Definitions and Application for Study of Rheumatoid Arthritis

To identify putative relations between different genetic factors in the human genome in the development of common complex disease, we mapped the genetic data to an ensemble of spin chains and analysed the data as a quantum system. Each SNP is considered as a spin with three states corresponding to possible genotypes. The combined genotype represents a multispin state, described by the product of individual-spin states. Each person is characterized by a single genetic vector (GV) and individuals with identical GVs comprise the GV group. This consolidation of genotypes into GVs provides integration of multiple genetic variants for a single statistical test and excludes ambiguity of biological interpretation known for allele and haplotype associations. We analyzed two independent cohorts, with 2633 rheumatoid arthritis cases and 2108 healthy controls, and data for 6 SNPs from the HTR2A locus plus shared epitope allele. We found that GVs based on selected markers are highly informative and overlap for 98.3% of the healthy population between two cohorts. Interestingly, some of the GV groups contain either only controls or only cases, thus demonstrating extreme susceptibility or protection features. By using this new approach we confirmed previously detected univariate associations and demonstrated the most efficient selection of SNPs for combined analyses for functional studies.

Gene Delivery Strategies to Promote Spinal Cord Repair

Gene therapies hold great promise for the treatment of many neurodegenerative disorders and traumatic injuries in the central nervous system. However, development of effective methods to deliver such therapies in a controlled manner to the spinal cord is a necessity for their translation to the clinic. Although essential progress has been made to improve efficiency of transgene delivery and reduce the immunogenicity of genetic vectors, there is still much work to be done to achieve clinical strategies capable of reversing neurodegeneration and mediating tissue regeneration. In particular, strategies to achieve localized, robust expression of therapeutic transgenes by target cell types, at controlled levels over defined time periods, will be necessary to fully regenerate functional spinal cord tissues. This review summarizes the progress over the last decade toward the development of effective gene therapies in the spinal cord, including identification of appropriate target genes, improvements to design of genetic vectors, advances in delivery methods, and strategies for delivery of multiple transgenes with synergistic actions. The potential of biomaterials to mediate gene delivery while simultaneously providing inductive scaffolding to facilitate tissue regeneration is also discussed.

Construction of a pIX-modified Adenovirus Vector Able to Effectively Bind to Nanoantibodies for Targeting

Current targeting strategies for genetic vectors imply the creation of a specific vector for every targeted receptor, which is time-consuming and expensive. Therefore, the development of a universal vector system whose surface can specifically bind molecules to provide efficient targeting is of particular interest. In this study, we propose a new approach in creating targeted vectors based on the genome of human adenovirus serotype 5 carrying the modified gene of the capsid protein pIX (Ad5-EGFP-pIX-ER): recombinant pseudoadenoviral nanoparticles (RPANs). The surfaces of such RPANs are able to bind properly modified chimeric nanoantibodies that specifically recognize a particular target antigen (carcinoembryonic antigen (CEA)) with high affinity. The efficient binding of nanoantibodies (аСЕА-RE) to the RPAN capsid surfaces has been demonstrated by ELISA. The ability of the constructed vector to deliver target genes has been confirmed by experiments with the tumor cell lines A549 and Lim1215 expressing CEA. It has been shown that Ad5-EGFP-pIX-ER carrying аСЕА-RE on its surface penetrates into the tumor cell lines A549 and Lim1215 via the CAR-independent pathway three times more efficiently than unmodified RPAN and Ad5-EGFP-pIX-ER without nanoantibodies on the capsid surface. Thus, RPAN Ad5-EGFP-pIX-ER is a universal platform that may be useful for targeted gene delivery in specific cells due to nanoantibody-modified RPAN binding.

Gear Incipient Diagnosing Based on EEMD and Genetic-Support Vector Machine

Due to the incipient fault attributes of gear are not obvious, So a hybrid diagnosis model to gear diagnosing based on Ensemble Empirical Mode Decomposition (EEMD) and Genetic-Support Vector Machine (GSVM) was proposed. With the method of EEMD,the gear vibration signals are adaptively decomposed into a finite number of Intrinsic Mode Function (IMF),which can alleviate model mixing that may appear in conventional EMD method. It calculates the energy character vectors of every IMF components,energy feature extracted from a number of IMFs that contained the most dominant fault information could serve as input genetic-vectors of support vector machine. The proposed model is applied to the gear testing system, and the results show that the diagnosis approach was effectively.