Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review

[EN] Purpose: To systematically review evidence regarding the association of multi-parametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th , 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and high-risk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, alpha=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.This work was supported by the Spanish Ministry for Investigation, Development and Innovation project with identification number DPI2016-80054-R.Oltra-Sastre, M.; Fuster García, E.; Juan -Albarracín, J.; Sáez Silvestre, C.; Perez-Girbes, A.; Sanz-Requena, R.; Revert-Ventura, A.... (2019). Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review. Current Medical Imaging Reviews. 15(10):933-947. https://doi.org/10.2174/1573405615666190109100503S9339471510Louis D.N.; Perry A.; Reifenberger G.; The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016,131(6),803-820Ostrom Q.T.; Gittleman H.; Fulop J.; CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 2015,17(Suppl. 4),iv1-iv62Yachida S.; Jones S.; Bozic I.; Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010,467(7319),1114-1117Gerlinger M.; Rowan A.J.; Horswell S.; Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012,366(10),883-892Sottoriva A.; Spiteri I.; Piccirillo S.G.M.; Intratumor heterogeneityin human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 2013,110(10),4009-4014Whiting P.F.; Rutjes A.W.; Westwood M.E.; QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011,155(8),529-536Stupp R.; Mason W.P.; van den Bent M.J.; Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005,352(10),987-996Ponte K.F.; Berro D.H.; Collet S.; In vivo relationship between hypoxia and angiogenesis in human glioblastoma: a multimodal imaging study. J Nucl Med 2017,58(10),1574-1579Pope W.B.; Kim H.J.; Huo J.; Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 2009,252(1),182-189Mörén L.; Bergenheim A.T.; Ghasimi S.; Brännström T.; Johansson M.; Antti H.; Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites 2015,5(3),502-520Prager A.J.; Martinez N.; Beal K.; Omuro A.; Zhang Z.; Young R.J.; Diffusion and perfusion MRI to differentiate treatment-related changes including pseudoprogression from recurrent tumors in high-grade gliomas with histopathologic evidence. AJNR Am J Neuroradiol 2015,36(5),877-885Kickingereder P.; Burth S.; Wick A.; Radiomic profiling of glioblastoma: identifying an imaging predictor of patient survival with improved performance over established clinical and radiologic risk models. Radiology 2016,280(3),880-889Yoo R-E.; Choi S.H.; Cho H.R.; Tumor blood flow from arterial spin labeling perfusion MRI: a key parameter in distinguishing high-grade gliomas from primary cerebral lymphomas, and in predicting genetic biomarkers in high-grade gliomas. J Magn Reson Imaging 2013,38(4),852-860Liberman G.; Louzoun Y.; Aizenstein O.; Automatic multi-modal MR tissue classification for the assessment of response to bevacizumab in patients with glioblastoma. Eur J Radiol 2013,82(2),e87-e94Ramadan S.; Andronesi O.C.; Stanwell P.; Lin A.P.; Sorensen A.G.; Mountford C.E.; Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma. Radiology 2011,259(2),540-549Xintao H.; Wong K.K.; Young G.S.; Guo L.; Wong S.T.; Support vector machine multi-parametric MRI identification of pseudoprogression from tumor recurrence in patients with resected glioblastoma. J Magn Reson Imaging 2011,33(2),296Ingrisch M.; Schneider M.J.; Nörenberg D.; Radiomic Analysis reveals prognostic information in T1-weighted baseline magnetic resonance imaging in patients with glioblastoma. Invest Radiol 2017,52(6),360-366Ulyte A.; Katsaros V.K.; Liouta E.; Prognostic value of preoperative dynamic contrast-enhanced MRI perfusion parameters for high-grade glioma patients. Neuroradiology 2016,58(12),1197-1208O’Neill A.F.; Qin L.; Wen P.Y.; de Groot J.F.; Van den Abbeele A.D.; Yap J.T.; Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma. J Neurooncol 2016,130(3),495-503Kickingereder P.; Bonekamp D.; Nowosielski M.; Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional mr imaging features. Radiology 2016,281(3),907-918Roberto S-R.; Antonio R-V.; Luis M-B.; Angel A-B.; Gracián G-M.; Quantitative mr perfusion parameters related to survival time in high-grade gliomas. European Radiology 2013,23(12),3456-3465Jain R.; Poisson L.; Narang J.; Genomic mapping and survival prediction in glioblastoma: molecular subclassification strengthened by hemodynamic imaging biomarkers. Radiology 2013,267(1),212-220Fathi K.A.; Mohseni M.; Rezaei S.; Bakhshandehpour G.; Saligheh R.H.; Multi-parametric (ADC/PWI/T2-W) image fusion approach for accurate semi-automatic segmentation of tumorous regions in glioblastoma multiforme. MAGMA 2015,28(1),13-22Caulo M.; Panara V.; Tortora D.; Data-driven grading of brain gliomas: a multiparametric MR imaging study. Radiology 2014,272(2),494-503Alexiou G.A.; Zikou A.; Tsiouris S.; Comparison of diffusion tensor, dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma. Magn Reson Imaging 2014,32(7),854-859Van Cauter S.; De Keyzer F.; Sima D.M.; Integrating diffusion kurtosis imaging, dynamic susceptibility-weighted contrast-enhanced MRI, and short echo time chemical shift imaging for grading gliomas. Neuro-oncol 2014,16(7),1010-1021Seeger A.; Braun C.; Skardelly M.; Comparison of three different MR perfusion techniques and MR spectroscopy for multiparametric assessment in distinguishing recurrent high-grade gliomas from stable disease. Acad Radiol 2013,20(12),1557-1565Chawalparit O.; Sangruchi T.; Witthiwej T.; Diagnostic performance of advanced mri in differentiating high-grade from low-grade gliomas in a setting of routine service. J Med Assoc Thai 2013,96(10),1365-1373Li Y.; Lupo J.M.; Parvataneni R.; Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging. Neuro-oncol 2013,15(5),607-617Shankar J.J.S.; Woulfe J.; Silva V.D.; Nguyen T.B.; Evaluation of perfusion CT in grading and prognostication of high-grade gliomas at diagnosis: a pilot study. AJR Am J Roentgenol 2013,200(5)Zinn P.O.; Mahajan B.; Sathyan P.; Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 2011,6(10)Matsusue E.; Fink J.R.; Rockhill J.K.; Ogawa T.; Maravilla K.R.; Distinction between glioma progression and post-radiation change by combined physiologic MR imaging. Neuroradiology 2010,52(4),297-306Juan-Albarracín J.; Fuster-Garcia E.; Manjón J.V.; Automated glioblastoma segmentation based on a multiparametric structured unsupervised classification. PLoS One 2015,10(5)Itakura H.; Achrol A.S.; Mitchell L.A.; Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities. Sci Transl Med 2015,7(303)Ion-Margineanu A.; Van Cauter S.; Sima D.M.; Tumour relapse prediction using multiparametric MR data recorded during follow-up of GBM patients. BioMed Res Int 2015,2015Durst C.R.; Raghavan P.; Shaffrey M.E.; Multimodal MR imaging model to predict tumor infiltration in patients with gliomas. Neuroradiology 2014,56(2),107-115Yoon J.H.; Kim J.H.; Kang W.J.; Grading of cerebral glioma with multi-parametric MR Imaging and 18F-FDG-PET: concordance and accuracy. European Radiol 2014,24(2),380-389Demerath T.; Simon-Gabriel C.P.; Kellner E.; Mesoscopic imaging of glioblastomas: are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype? Neuroradiol J 2017,30(1),36-47Qin L.; Li X.; Stroiney A.; Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma. Neuroradiology 2017,59(2),135-145Boult J.K.R.; Borri M.; Jury A.; Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging. NMR Biomed 2016,29(11),1608-1617Server A.; Kulle B.; Gadmar Ø.B.; Josefsen R.; Kumar T.; Nakstad P.H.; Measurements of diagnostic examination performance using quantitative apparent diffusion coefficient and proton MR spectroscopic imaging in the preoperative evaluation of tumor grade in cerebral gliomas. Eur J Radiol 2011,80(2),462-470Chang P.D.; Chow D.S.; Yang P.H.; Filippi C.G.; Lignelli A.; Predicting glioblastoma recurrence by early changes in the apparent diffusion coefficient value and signal intensity on FLAIR images. AJR Am J Roentgenol 2017,208(1),57-65Yi C.; Shangjie R.; Volume of high-risk intratumoralsubregions at multi-parametric MR imaging predicts overall survival and complements molecular analysis of glioblastoma. Eur Radiol 2017,27,3583-3592Khalifa J.; Tensaouti F.; Chaltiel L.; Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation. Eur Radiol 2016,26(11),4194-4203Prateek P.; Jay P.; Partovi S.; Madabhushi A.; Tiwari P.; Radiomic features from the peritumoral brain parenchyma on treatment-naïve multi-parametric MR imaging predict long versus short-term survival in glioblastomamultiforme: preliminary findings. Eur Radiol 2017,27(10),4188-4197Lemasson B.; Chenevert T.L.; Lawrence T.S.; Impact of perfusion map analysis on early survival prediction accuracy in glioma patients. Transl Oncol 2013,6(6),766-774Inano R.; Oishi N.; Kunieda T.; Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images. Sci Rep 2016,6,30344Delgado-Goñi T.; Ortega-Martorell S.; Ciezka M.; MRSI-based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis. NMR Biomed 2016,29(6),732-743Cui Y.; Tha K.K.; Terasaka S.; Prognostic imaging biomarkers in glioblastoma: development and independent validation on the basis of multiregion and quantitative analysis of MR images. Radiology 2016,278(2),546-553Price S.J.; Young A.M.H.; Scotton W.J.; Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas. J Magn Reson Imaging 2016,43(2),487-494Sauwen N.; Acou M.; Van Cauter S.; Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI. Neuroimage Clin 2016,12,753-764Jena A.; Taneja S.; Gambhir A.; Glioma recurrence versus radiation necrosis: single-session multiparametric approach using simultaneous O-(2-18F-Fluoroethyl)-L-Tyrosine PET/MRI. Clin Nucl Med 2016,41(5),e228-e236Kim H.S.; Goh M.J.; Kim N.; Choi C.G.; Kim S.J.; Kim J.H.; Which combination of MR imaging modalities is best for predicting recurrent glioblastoma? Study of diagnostic accuracy and reproducibility. Radiology 2014,273(3),831-843Christoforidis G.A.; Yang M.; Abduljalil A.; “Tumoral pseudoblush” identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy. Radiology 2012,264(1),210-217Wang S.; Kim S.; Chawla S.; Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2011,32(3),507-514Hanahan D.; Weinberg R.A.; Hallmarks of cancer: the next generation. Cell 2011,144(5),646-674Macdonald D.R.; Cascino T.L.; Schold S.C.; Cairncross J.G.; Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990,8(7),1277-1280Wen P.Y.; Macdonald D.R.; Reardon D.A.; Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010,28(11),1963-1972Sorensen A.G.; Batchelor T.T.; Wen P.Y.; Zhang W-T.; Jain R.K.; Response criteria for glioma. Nat Clin Pract Oncol 2008,5(11),634-644Rosenkrantz A.B.; Friedman K.; Chandarana H.; Current status of hybrid PET/MRI in oncologic imaging. AJR Am J Roentgenol 2016,206(1),162-172Castiglioni I.; Gallivanone F.; Canevari C.; Hybrid PET/MRI for In vivo imaging of cancer: current clinical experiences and recent advances. Curr Med Imaging 2016,12,106Mainta I.C.; Perani D.; Delattre B.M.A.; FDG PET/MR imaging in major neurocognitive disorders. Curr Alzheimer Res 2017,14,186-197Marner L.; Henriksen O.M.; Lundemann M.; Larsen V.A.; Law I.; Clinical PET/MRI in neurooncology: opportunities and challenges from a single-institution perspective. Clin Transl Imaging 2017,5(2),135-149R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2015. Available from: https://www.R-project.org

Оценка воздействия производственной деятельности теплогенерирующего предприятия на атмосферный воздух

Объектом исследования теоретической части работы является исследование котельных установок и газоочистных установок для очистки промышленных газов. Объектом исследования практической части работы является анализ воздействия выбросов загрязняющих веществ от объектов ООО «Бакчартепло».The object of study the theoretical part of the work is to study the boiler plants and gas-cleaning unit for cleaning industrial gases. The object of study of the practical work is to analyze the impact of emissions from the facilities of OOO "Bakcharteplo"

Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation

© 2015, Nature Publishing Group. All rights reserved. Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible

Chemotherapy-induced intestinal injury promotes Galectin-9-driven modulation of T cell function

The intestine is vulnerable to chemotherapy-induced toxicity due to its high epithelial proliferative rate, making gut toxicity an off-target effect in several cancer treatments, including conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). In allo-HCT, intestinal damage is an important factor in the development of Graft-versus-Host Disease (GVHD), an immune complication in which donor immune cells attack the recipient's tissues. Here, we developed a novel human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced intestinal epithelial damage on T cell behavior. Chemotherapy treatment using busulfan, fludarabine, and clofarabine led to damage responses in organoids resulting in increased T cell migration, activation, and proliferation in ex- vivo co-culture assays. We identified galectin-9 (Gal-9), a beta-galactoside-binding lectin released by damaged organoids, as a key molecule mediating T cell responses to damage. Increased levels of Gal-9 were also found in the plasma of allo-HCT patients who later developed acute GVHD, supporting the predictive value of the model system in the clinical setting. This study highlights the potential contribution of chemotherapy-induced epithelial damage to the pathogenesis of intestinal GVHD through direct effects on T cell activation and trafficking promoted by galectin-9

Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease

Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32-Q87del mutations, respectively) and two patients with one mutated ANKZF1 allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD

Simulations in the development of the barrel muon chambers for the CMS detector at LHC

The development of the barrel drift chambers for the CMS muon detector at the CERN Large Hadron Collider is supported by a variety of simulation calculations, based on the GARFIELD drift chamber simulation program and the GEANT detector simulation package. This study surveys the results influencing the actual chamber design. The dependence of the drift cell performance on shape and position of the cell electrodes as well as on the mechanical tolerances is shown. The results obtained for space-time relation and spatial resolution are in good agreement to test beam measurements on prototypes. (C) 1998 Elsevier Science B.V. All rights reserved