January-February 2010 l Vol 16 l No 1-2

Research Articles

High Incidence of MGMT and RARβ Promoter Methylation in Primary Glioblastomas:  Association with Histopathological Characteristics, Inflammatory Mediators and Clinical Outcome
Christina Pipieri, Marios S Themistocieous, George A Papavassiliou, Elena Farmaki, Georgia Levidou, Penelope Korkolopoulou, Christos Adamopoulos, and Athanasios G Papavassiliou
The successful treatment of glioblastoma multiforme (GBM), a life-threatening intracranial malignant tumor, is hindered by difficulties in early diagnosis, rapid progression and frequent recurrence. Since the methylation status of specific gene loci can be used as a prognostic tool for different tumor types, Piperi et al. examined four genes involved in glioma tumorigenesis: MGMT, RARβ, RASSF1A and CDH13. The authors found that two of these genes, MGMT and RARβ were significantly more methylated in 70.58% and 58.8% of analysed GBM cases, respectively. This study also highlights a potential link between methylation patterns and IL-6, suggesting a specific role for inflammation mediators in the regulation of gene methylation. These results could generate new insight regarding patient survival and treatment options for this devastating disease.
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Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer
Stephanie L Nott, Yanfang Huang, Aja Kaikanoglu, Kathryn Harper, Ming Chen, Scott F Paoni, Bruce M Fenton, and Mesut Muyan
Abnormalities in the growth and death programs of breast-ductal epithelial cells can lead to breast cancer, the initiation and progression of which can be influenced by 17β-estradiol (E2). Current treatments include reduction of circulating E2 and inhibition of estrogen receptor (ER) functions, approaches that are ineffective in de novo endocrine-resistant breast cancers. Nott et al. tested whether specific regulation of estrogen responsive element (ERE)-driven genes by the constitutively active transcription factor monotransregulator is a viable treatment alternative for this cancer. The authors found that the monotransregulator repressed cellular proliferation and motility and induced apoptosis by regularting ERE-driven gene expressions. Monotransregulators also limited xenograft tumor growth in nude mice. This study demonstrates the potential use of targeted regulation of endogenous genes for the treatment of cancers that are refractory to current approaches.
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Supplementary Data: PDF (908 KB)

RNA Recognition Motif (RRM) of La/SSB: The Bridge for Interparticle Spreading of Autoimmune Response to U1-RNP
John G Routsias, Nikolaos Kyriakidis, Michael Latreille, and Athanasios G Tzioufas
Autoimmune diseases such as systemic lupus erythematosus (SLE) are caused by the diminution of self-tolerance, which results in numerous health complications involving the skin, joints, kidneys, lungs, nervous system and serous membranes. SLE is caused by diversification and augmentation of the immune response via epitope spreading, whereby the immune response “jumps” from one antigen to another. Routsias et al. demonstrated the ability of autoantigens to induce antibodies to cross-recognize components of protein particles corresponding to RRMs (RNA recognition motifs) of different nuclear autoanitgens via molecular mimicry. The investigators discovered that the RRM region of La/SSB can trigger interparticle B cell diversification to U1-RNP. This confirms the importance of the RRM region pathway, resulting in autoimmunity in lupus. Understanding the molecular mechanisms involved in the initial events of the autoimmune process could lead to the development of therapeutic strategies that block the cascade of events resulting in the development of SLE.
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Association of a Single Nucleotide Polymorphism in the C-Reactive Protein Gene (–286) with Susceptibility to Plasmodium falciparum Malaria
Hayder A Giha, Amre Nasr, Mattias Ekström, Elisabeth Israelsson, Gishanthi Arambepola, David Arnot, Thor G Theander, Marita Troye-Blomberg, Klavs Berzins, Per Tornvall, and Gehad ElGhazali
Every year there are between 300 and 500 million new cases of malaria worldwide, making malaria a major cause of morbidity and mortality in equatorial regions of the globe. Inflammation in malaria pathogenesis is induced by non-specific acute phase proteins, such as C-reactive protein (CRP). The CRP gene is highly polymorphic, and single nucleotide polymorphisms (SNPs) have been identified at several loci. Of these, the triallelic –286 (C > T > A) SNP was strongly associated with plasma CRP concentration. Giha et al. examined the CRP –286 SNP in a population of Sudanese donors and found the CRP –286 A-allele was associated with an increase in malaria susceptibility. This study identifies a genetic marker for malaria susceptibility and elucidates the role of inflammation in malaria infection.
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Integration of HIV-1 DNA Is Regulated by Interplay between Viral Rev and Cellular LEDGF/p75 Proteins
Aviad Levin, Joseph Rosenbluh, Zvi Hayouka, Assaf Friedler, and Abraham Loyter
Human immunodeficiency virus (HIV) integration into the host cell DNA is the central event in the life cycle of the retrovirus. For this to occur, a combination of the viral integrase (IN) and host LEDGF/p75 proteins are required. In their latest efforts, Levin et al. examined the early viral integration pathway and demonstrate that the viral Rev protein, an inhibitor of viral integration, associates with LEDGF/p75. Furthermore, they demonstrate a role for Rev in the dissociation of the IN-LEDGF/p75 complex. The authors propose a model whereby viral integration is regulated by the interplay between LEDGF/p75, Rev and IN, with the LEDGF/p75-Rev and IN-Rev complexes leading to inhibition of viral integration. This work could ultimately lead to new strategies for preventing and treating HIV infection.
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Supplementary Data: PDF (1.6 MB)

Plasma Cytokine Profiles in Preprotachykinin-A Knockout Mice Subjected to Polymicrobial Sepsis
Akhil Hegde, Mahesh Uttamchandani, Shabbir M Moochhala, and Madhav Bhatia
Understanding gene expression of immune regulators such as cytokines is essential to developing better prognostic tools and therapeutic strategies for treating sepsis. Hegde et al. investigated circulating cytokine profiles in preproptachykinin-A  knockout (PPTA^-/-) mice, a gene found to induce expression of immunoregulatory proteins that protect against microbial sepsis. A range of both pro- and anti- inflammatory cytokines was analyzed using multiplexed bead–suspension arrays. Deletion of the PPTA  gene resulted in an increase of both pro- and antiinflammatory cytokines in septic mice and improved survival. This study reveals that multiple factors controlled by PPTA are involved in the response to microbial sepsis, some of which may be detrimental to survival from sepsis. This work provides insight into the molecular mechanisms underlying the immune response to sepsis and identifies a technique for rapid and cost-effective biomarker identification, which has implications for improved clinical diagnostic tools for septic patients.
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Review  Articles

RNA Surveillance: Molecular Approaches in Transcript Quality Control and their Implications in Clinical Diseases
Karen CM Moraes
Understanding RNA processing and surveillance mechanisms is essential to advancing clinical diagnosis and therapeutic procedures. Numerous diseases are caused by errors and mutations of significant RNA sequences leading to the expression of pathological proteins. Recent studies have elucidated our understanding of molecular mechanisms of mRNA processing and the complex series of events that lead to loss or gain of both functional and deleterious proteins. In this review, Dr. Moraes discusses mRNA quality control mechanisms and their clinical relevance to developing therapeutic strategies.
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Pattern Recognition Receptor–Dependent Mechanisms of Acute Lung Injury
Meng Xiang and Jie Fan
Acute respiratory distress syndrome (ARDS), a central cause of morbidity and mortality in intensive care units, is caused by an uncontrolled systemic inflammatory response to such conditions as sepsis, major surgery, and trauma. Innate immunity can be triggered through pattern recognition receptors (PRRs), which recognize conserved microbial motifs or pathogen associated molecular patterns (PAMPs) and endogenous danger signals. The activation of PRRs initiates extracellular as well as intracellular signaling cascades that ultimately promote inflammatory responses. Drs. Xiang and Fan focus on recent advances on the role of PRRs in the mechanisms of ARDS. A greater understanding of these complex pathways is necessary to explore new treatment options for ARDS patients.
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