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Relevance of the Type I Interferon Signature in Multiple Sclerosis Towards a Personalized Medicine Approach for Interferon-beta Therapy

Abstract: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system. The disease is characterized by progressive neurological dysfunction due to demyelination of the nerves, which leads to disability. Currently, no curative therapy is available and patients are subjected to a prolonged course of treatment. Interferon-β (IFNβ) was the first agent to show clinical efficacy in the treatment of MS, and is still the best available therapy. Unfortunately, clinical experience indicates that approximately 40% of the patients do not or only poorly respond to IFNβ treatment. Recent advances revealed the presence of an activated type I IFN pathway in a subset of treatment naïve patients with relapsing remitting MS (RRMS), as shown by the presence of an "IFN signature" and type I IFN bioactivity in the blood of these patients. Evidence exists that quantification of the IFN signature in RRMS is informative as a biomarker to predict the clinical response to IFNβ. In this review we summarize the current evidence of type I IFN activation in RRMS and its clinical relevance. ... Read more

Novel Molecular Targets for the Therapy of Renal Cell Carcinoma

Abstract: Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma (mRCC). Although the next few years may not see such broad paradigm shifts, there are ongoing areas of development including vaccine and immunotherapies which do diverge from this paradigm and hold promise to improve therapeutic outcomes for patients with mRCC. ... Read more

Specificity of the Coxsackievirus B4 VP4 Capsid Protein Investigated In Silico

Abstract: The Enterovirus genus encompasses several species and various serotypes, like coxsackievirus-B1 (CV-B1) to CV-B6, and many variants. The role of these viruses, especially CV-B4, in the pathogenesis of type 1 diabetes is strongly suspected. It has been reported that antibodies directed towards the region of amino acids 11-30 of the VP4 capsid protein enhance the infection of human peripheral blood mononuclear cells with CV-B4. In order to predict the inter- and intra-serotype specificity of the region 11-30 of CV-B4 VP4, 362 available protein sequences of CV-B1 to -B6, CV-A9, and swine vesicular disease virus (SVDV) have been aligned and levels of homology have been calculated. Serine residue substitutions in this region of VP4 were observed without predictable subsequent modification of conformation or charge. The amino acids 16-24 region was the most variable. The sequence of amino acids 16-24 of the CV-B4E2 VP4 protein was highly homologous to those of other CV-B4 (64.4%) whereas there was no homology with CV-B3 and B5 and very low levels of homology with CV-B1 and B2 (3.3% and 9.9%, respectively). In conclusion, the bioinformatic analysis suggests that the region 16-24 of the VP4 capsid protein is the feature of the specificity of the target of infection-enhancing antibodies directed towards CV-B. ... Read more

Cytokine Regulation of B-cell Migratory Behavior Favors Formation of Germinal Centers in Autoimmune Disease

Abstract: Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-α (IFNα) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFNα produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P1 chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells. ... Read more

Targeted Therapy for Renal Cell Cancer: Current Perspectives

Abstract: In the past 5 years, the introduction of targeted therapy has dramatically changed the outcome of patients with metastatic renal cell cancer (mRCC). In particular, drugs that inhibit signaling of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have significantly improved the perspectives of patients with this chemoresistant disease. Here, we review the currently approved targeted drugs for the treatment of mRCC. We describe the anti-VEGF monoclonal antibody bevacizumab, the receptor tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib as well as the mTOR inhibitors temsirolimus and everolimus and discuss their role in the contemporary management of patients with mRCC. ... Read more

Enteroviral Pathogenesis of Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by the disturbance of pancreatic insulin-producing cells, which results in hyperglycemia. The disease is associated with severe complications that impair the quality of life of individuals. The cause of T1D is unknown. Development of the disease is the result of interactions between immunological, genetic, and environmental factors. Viruses are thought to play an important role in the initiation or acceleration of the disease. This is an important issue since it opens the possibility to develop new preventive and therapeutic strategies to fight the disease. The role of enteroviruses in the development of T1D, in particular type B coxsackieviruses, is supported by epidemiological observations. It has been demonstrated that enterovirus infections were significantly more common in recently diagnosed diabetic patients, compared with control subjects. Enteroviral RNA and/or proteins can be detected in blood samples and intestine biopsies of patients with T1D. The hypothesis of a relationship between enteroviruses and the disease has been strengthened by the presence of enteroviral components or infectious particles in the pancreas of patients with T1D. In this review, arguments in favor of a relationship between enterovirus infections and T1D and the mechanisms of the enteroviral pathogenesis of the disease are presented. ... Read more

Gene-based Cancer Immunotherapy and Vaccines

Abstract: Cancer treatment has been marred by the fact that most drugs target cancer cells as well as normal cells. Gene therapy is one of a handful of methods that will make cancer cells "stand out," allowing drugs or the host's immune system to selectively target cancer cells. ... Read more

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