Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies

An intron polymorphism of the fibronectin gene is associated with end-stage knee osteoarthritis in a Han Chinese population: two independent case-control studies

BACKGROUND: Knee osteoarthritis (OA) is a complex disease involving both biomechanical and metabolic factors that alter the tissue homeostasis of articular cartilage and subchondral bone. The catabolic activities of extracellular matrix degradation products, especially fibronectin (FN), have been implicated in mediating cartilage degradation. Chondrocytes express several members of the integrin family which can serve as receptors for FN including integrins α5β1, αvβ3, and αvβ5. The purpose of this study was to determine whether polymorphisms in the FN (FN-1) and integrin genes are markers of susceptibility to, or severity of, knee OA in a Han Chinese population. METHODS: Two independent case–control studies were conducted on 928 patients with knee OA and 693 healthy controls. Ten single nucleotide polymorphisms (SNPs) of FN-1 and the integrin αV gene (ITGAV) were detected using the ABI 7500 real-time PCR system. RESULTS: The AT heterozygote in FN-1 (rs940739A/T) was found to be significantly associated with knee OA (adjusted OR = 1.44; 95% CI = 1.16–1.80) in both stages of the study. FN-1 rs6725958C/A and ITGAV rs10174098A/G SNPs were only associated with knee OA when both study groups were combined. Stratifying the participants by Kellgren-Lawrence (KL) score identified significant differences in the FN-1 rs6725958C/A and rs940739 A/T genotypes between patients with grade 4 OA and controls. Haplotype analyses revealed that TGA and TAA were associated with a higher risk of OA, and that TAG conferred a lower risk of knee OA in the combined population. CONCLUSIONS: Our study suggests that the FN-1 rs940739A/T polymorphism may be an important risk factor of genetic susceptibility to knee OA in the Han Chinese population

Molecular models for studying CNS associated tumors and dysmyelination

JC virus is the etiologic agent of the rapidly fatal demyelinating disease Progressive Multifocal Leukoencephalopathy. This virus has an extremely narrow host range and tissue tropism. It replicates efficiently only in human oligodendrocytes in vivo. An interesting feature of the papovaviral family is its ability to integrate into the host genome and cause tumorigenesis in cells which are not permissive for viral DNA replication. In the work presented here, the intention is to investigate the ability of T antigen to cause neuroectodermal tumors in an animal model: a transgenic mouse line containing the JC viral early region. The potential association of JC virus with human brain tumors is explored using tissue obtained from a human oligoastrocytoma arising in an immunocompetent individual. In both of these studies DNA and RNA were detected using PCR and RT-PCR respectively. Protein was identified using immunoprecipitation techniques. These preliminary studies lay the groundwork for more intensive investigation. PCR screening of human glial brain tumors to identify papovaviral DNA may prove that these viruses indeed contribute to human tumorigenesis, while the animal model may be used to dissect more clearly the molecular mechanism of oncogenesis. Additionally, the role of the p107, which is known to be functionally inactivated by T antigen, will be examined through transient transfections using chloramphenicol acetyl transferase assays, as well as immunoprecipitation studies to assess protein-protein interactions among the transcription factors known to be involved in murine myelination. A novel interaction between p107 and the transcription factor, pur$\alpha,$ and the interaction between pur$\alpha$ and Sp1. Pur$\alpha$ and Sp1 activate MBP transcription, while p107 represses. A potential mechanism for p107 repression of the MBP promoter is through its interaction with these transcription factors, which normally activate transcription. The amino terminus of p107 is known to interact with Sp1, while preliminary data suggests that the pocket region is responsible for the p107-pur$\alpha$ interaction. The ability of each of these proteins to interact with one another, different regions of each appear to mediate their interaction suggests the attractive model that all three proteins may form a complex together to developmentally regulate transcription of MBP