Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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Rare conditions are sometimes ignored in biomedical research because of difficulties in obtaining specimens and limited interest from fund raisers. However, the study of rare diseases such as unusual cancers has again and again led to breakthroughs in our understanding of more common diseases. It is therefore unsurprising that with the development and accessibility of next-generation sequencing, much has been learnt from studying cancers that are rare and in particular those with uniform biological and clinical behavior. Herein, we describe how shotgun sequencing of cancers such as granulosa cell tumor, endometrial stromal sarcoma, epithelioid hemangioendothelioma, ameloblastoma, small-cell carcinoma of the ovary, clear-cell carcinoma of the ovary, nonepithelial ovarian tumors, chondroblastoma, and giant cell tumor of the bone has led to rapidly translatable discoveries in diagnostics and tumor taxonomies, as well as providing insights into cancer biology.
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Despite improvements in cardiopulmonary resuscitation (CPR) quality, defibrillation technologies, and implementation of therapeutic hypothermia, less than 10 % of out-of-hospital cardiac arrest (OHCA) victims survive to hospital discharge. New resuscitation therapies have been slow to develop, in part, because the pathophysiologic mechanisms critical for resuscitation are not understood. During cardiac arrest, systemic cessation of blood flow results in whole body ischemia. ⋯ New insights into mitochondrial dynamics and the role of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) in apoptosis have made targeting these mechanisms attractive for IR therapy. In animal models, inhibiting Drp1 following IR injury or cardiac arrest confers protection to both the heart and brain. In this review, the relationship of the major mitochondrial fission protein Drp1 to ischemic changes in the heart and its targeting as a new therapeutic target following cardiac arrest are discussed.
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MicroRNAs (miRNAs) are about 20-22 nucleotide conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3'-untranslated region of specific messenger RNAs (mRNAs) for degradation or translational repression. During the last two decades, miRNAs have emerged as critical regulators of a range of biological processes including immune cell lineage commitment, differentiation, maturation, and immune signaling pathways. The endoribonucleases such as Dicer, which is required for miRNA biogenesis, has also been shown to play an important role in inflammatory response and autoimmunity. ⋯ In this review, we will discuss recent advances in miRNAs mediated regulation of inflammatory responses and autoimmune pathogenesis. Specifically, we will discuss how miRNAs regulate autoimmunity through affecting the development, differentiation, and function of various cell types such as innate immune cells, adaptive immune cells and local resident cells. The identification of distinct miRNA expression patterns, and a comprehensive understanding of the roles of those dysregulated miRNAs in inflammatory autoimmune pathogenesis offers inspirations of not only potential molecular diagnostic markers but also novel therapeutic strategies for treating inflammatory autoimmune diseases.
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Glioblastoma multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs, such as bevacizumab (Avastin), an anti-VEGF antibody. ⋯ Enhanced invasiveness is one such resistance mechanism and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.
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Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by constricted and remodeled pulmonary arteries. This phenomenon is associated with enhanced pulmonary artery smooth muscle cells proliferation and suppressed apoptosis, metabolism shift, inflammation, and several other features that are considered as hallmarks of cancer. Since oncogenes, tumor suppressors, and miRNAs are the major regulators of signaling in the cancer phenotype, we studied if the same type of regulation is operative in PAH. ⋯ Taken together, targeting oncoproteins or miRNAs appear as new therapeutic strategies for PAH. Several oncoprotein inhibitors are already in trials for cancer and could be soon available for PAH. Concerning miRNAs, the youth of this area makes therapies less achievable soon but not less interesting.