Recognition of Virus Infection and Innate Host Responses to Viral Gene Therapy Vectors

The innate immune and inflammatory response represents one of the key stumbling blocks limiting the efficacy of viral-based therapies. Numerous human diseases could be corrected or ameliorated if viruses were harnessed to safely and effectively deliver therapeutic genes to diseased cells and tissues in vivo. Recent studies have shown that host cells recognize viruses using an elaborate network of sensor proteins localized at the plasma membrane, in endosomes, or in the cytosol. Three classes of sensors have been implicated in sensing viruses in mammalian cells—Toll-like receptors (TLRs), retinoid acid-inducible gene (RIG)-I-like receptors (RLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs). The interaction of virus-associated nucleic acids with these sensor molecules triggers a signaling cascade that activates the principal host defense program aimed to limit or eliminate virus infection and restore tissue homeostasis. In addition, recent data strongly suggest that host cells can mount innate immune responses to viruses without prior recognition of their nucleic acids. To deliver therapeutic genes into the nuclei of diseased cells, viral gene therapy vectors must be efficient at penetrating either the plasma or endosomal membrane. The therapeutic use of high numbers of virus particles disturbs cellular homeostasis, triggering cell damage and stress pathways, or “sensing of modified self”. Accumulating data indicate that the sensing of modified self might represent a powerful framework explaining the innate immune response activation by viral gene therapy vectors.     

Risk score for predicting abdominal complications after coronary artery bypass grafting

BACKGROUND Although early abdominal complications after coronary artery bypass grafting(CABG) with cardiopulmonary bypass(CPB) are rare, the associated mortality remains high.AIM To develop a risk score for the prediction of early abdominal complications after CABG with CPB.METHODS This retrospective study was performed in the Federal State Budgetary Establishment "Federal Center of Cardiovascular Surgery" of the Ministry of Health of Russia(the city of Chelyabinsk) and included data of 6586 patients who underwent CABG with CPB during 2011-2017. The risk factors taken for evaluation were compared between patients with early abdominal complications(n = 73) and without them(n = 6513). We identified the most important risk factors and their influence on the development of early abdominal complications after CABG with CPB.RESULTS Gender and the presence of postinfarction cardiosclerosis, chronic kidney disease, or diabetes in the anamnesis did not affect the occurrence of abdominal complications. The leading risk factors of the early abdominal complications after CABG with CPB were multifocal atherosclerosis, extracorporeal membrane oxygenation, intra-aortic balloon pump, atrial fibrillation, perioperative myocardial infarction, and the need for resternotomy in the postoperative period. The average value of the predicted probability was 0.087 ± 0.015 in patients with early abdominal complications after CABG with CPB and 0.0094 ± 0.0003 in patients without these complications. The percentage of correct classification turned out to be 98.9%. After calculating a score for each of the leading risk factors, we counted a total score for each particular patient. The highest risk was noted in patients with a total score of 7 or more.CONCLUSION The developed score predicts the risk of early abdominal complications after CABG with CPB and makes it possible to stratify patients by risk groups.     

Features of adult neurogenesis and neurochemical signaling in the Cherry salmon Oncorhynchus masou brain

We investigated the distribution of gamma aminobutyric acid, tyrosine hydroxylase and nitric oxide-producing elements in a cherry salmon Oncorhynchus masou brain at various stages of postnatal ontogenesis by immunohistochemical staining and histochemical staining. The periventricular region cells exhibited the morphology of neurons and glia including radial glia-like cells and contained several neurochemical substances. Heterogeneous populations of tyrosine hydroxylase-, gamma aminobutyric acid-immunoreactive, аs well as nicotinamide adenine dinucleotide phosphate diaphorase-positive cells were observed in proliferating cell nuclear antigen-immunoreactive proliferative zones in periventricular area of diencephalon, central grey layer of dorsomedial tegmentum, medulla and spinal cord. Immunolocalization of Pax6 in the cherry salmon brain revealed a neuromeric construction of the brain at various stages of postnatal ontogenesis, and this was confirmed by tyrosine hydroxylase and gamma aminobutyric acid labeling.     

Diffusion-weighted MRI of renal cell carcinoma, upper tract urothelial carcinoma, and renal infection: a pictorial review

Diffusion-weighted (DW) magnetic resonance imaging (MRI) is a functional imaging technique that derives image contrast from differences in water molecule diffusion within tissues. DW MRI helps detect and characterize renal and urothelial malignancies, may help in differentiating some benign from malignant renal masses, and can also recognize renal and upper urinary tract infections. Patients precluded from receiving intravenous contrast agents may particularly benefit from this technique.     

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.     

Wip1, an oncogene targeting tumor suppressors expressed in intestinal stem cells

Wip1 phosphatase (PPM1D) has oncogenic properties and is implicated in a variety of cancer types, including gastrointestinal. Like Mdm2, Wip1 normally functions to resolve stress responses, such as after DNA damage, and return the cell to its normal, unstressed state. It is expressed in somatic as well as stem cells, with relatively high expression in intestinal stem cells. Loss of normal APC function and other events early in the carcinogenic process trigger a stress-like state often referred to as oncogenic stress. Wip1 can dampen protective responses to such stress through dephosphorylation of key activating sites in important tumor suppressors, such as p53. Even normal levels of Wip1 affect tumor suppression, because Wip1-deficient mice are markedly tumor resistant in a variety of tumor-prone models, including APC^min. Unlike Mdm2-null mice, Wip1-null mice have a relatively mild phenotype, so development of Wip1 inhibitors may be well tolerated in vivo.