Adv Exp Med Biol
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Pulmonary tuberculosis (TB) remains a global health concern with an astounding 9 million new cases and 2 million deaths per year. This leading infectious cause of death remains highly prevalent with one third of the world's population latently infected with Mycobacterium tuberculosis (M.tb) despite routine vaccination against TB in endemic areas. The only approved TB vaccine is the Bacille Calmette-Guerin (BCG), which provides protection against childhood miliary tuberculosis and has been administered intradermally in humans for almost a century. ⋯ Growing evidence supports that the route of immunization dictates the geographical location of TB-reactive T cells, and it is this distribution which predicts the protective outcome of such vaccine-elicited immunity. Such vaccines that are able to localize TB-reactive T cells to the lung and airway mucosa are thought to fill the "immunological gap" in the lung that is required for enhanced protection against M.tb infection. This chapter focuses on the critical importance of T cell geography when designing new immunization strategies against pulmonary TB.
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Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23-nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the translation and stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and invasion. miRNA targeting is initiated through specific base-pairing interactions between the 5' end ("seed" region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. ⋯ To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis, and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease specific expression, they hold potential as therapeutic targets and novel biomarkers.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by complement-mediated hemolytic anemia, thrombophilia, and bone marrow failure. PNH is due to a somatic, acquired mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene, which impairs the membrane expression on affected blood cells of a number of proteins, including the complement regulators CD55 and CD59. The most evident clinical manifestations of PNH arise from dysregulated complement activation on blood cells; in fact, the hallmark of PNH is chronic, complement-mediated, intravascular hemolysis, which results in anemia, hemoglobinuria, fatigue, and other hemolysis-related disabling symptoms. ⋯ These findings have renewed the interest for the development of novel complement inhibitors which aim to modulate early phases of complement activation, more specifically at the level of C3 activation. As proof of principle of this concept, an anti-C3 monoclonal antibody has been proven effective in vitro to prevent hemolysis of PNH erythrocytes. More intriguingly, a human fusion protein consisting of the iC3b/ C3d-binding region of complement receptor 2 and of the inhibitory domain of the CAP regulator factor H has been recently shown effective in inhibiting, in vitro, both intravascular hemolysis of and surface C3-deposition on PNH erythrocytes, and is now under investigation in phase 1 clinical trials.