Effect of the reaction mixture on the structure and permeability of macroporous SiO[2], obtained by sol gel by method

In this paper, a number of porous silicone monoliths were synthesized under various conditions and their composition, structure, permeability coefficients k, and porosity were studied. The effect of the introduction of ethyl alcohol in the reaction mixture on the properties of the obtained silica was revealed

Анализ методов увеличения нефтеотдачи на терригенных коллекторах месторождений Западной Сибири

В данной выпускной работе были рассмотрены и проанализированы особенности строения терригенных коллекторов, а также методы увеличения нефтеотдачи, применяемые на месторождениях Западной Сибири, имеющих терригенный тип коллекторов.In the final work, the structural features of terrigenous reservoirs, as well as oil recovery enhancement methods used in fields of Western Siberia having a terrigenous reservoir type, were considered and analyzed

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130[superscript F/F] GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori–infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130[superscript F/F] mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression

Predicting Outcomes in Pediatric Crohn’s Disease for Management Optimization: Systematic Review and Consensus Statements from PIBD-Ahead Program

A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk

Life-threatening hypersplenism due to idiopathic portal hypertension in early childhood: case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings.</p> <p>Case Presentation</p> <p>We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy.</p> <p>Conclusions</p> <p>Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.</p

Genetically engineered Mouse Models reveal a tumourigenic collaboration between Sdhb deficiency and oncogenic Hras

The mitochondrial tumour suppressor succinate dehydrogenase is found inactivated in several tumour entities, amongst them SDH–deficient renal cell carcinoma (RCC) and pheochromocytoma/paraganglioma (Pheo/PGL). An in-depth understanding of cooperating events that enable malignant transformation of SDH-deficient tissues and preclinical model systems of SDH-deficient malignancies are still lacking. The first major goal of this thesis project was to generate a genetically engineered model of SDH-deficient RCC as an easy-to-monitor pathology in mice. In addition, we set out to study tissue-specific phenotypes resulting from stochastic Sdhb loss in peripheral organs. Driven by a Cadherin 16 promoter (KspCre) and thus in the distal renal tubular system, a fatal cystic degeneration of Sdhbfl/fl kidneys resulted from Cre expression. Ongoing untargeted metabolomics analyses of kidney, plasma and urine specimens obtained from this model hold potential for discovery of new biomarkers of SDH-deficient tumours. In a RosaCreERT2-based model, dramatic weight loss within the first weeks after transgene induction correlated with succinate accumulation in peripheral organs of Sdhbfl/fl, Hraswt/wt animals. Less intense transgene induction schemes resulted in long-term survival irrespective of Sdhb status. To the best of my knowledge, this work describes the first, albeit not perfect, genetically engineered mouse model of SDH-deficient RCC. Ongoing experimental efforts focus on reliable identification of systemic metabolic biomarkers that could improve monitoring of patients who are at (relapse) risk of SDH-deficient tumours

Lymphoma cell senescence as a mechanism of action of the therapeutic antibody rituximab

Einleitung: Trotz seines in der Behandlung maligner B-Zell-Lymphome weit verbreiteten klinischen Einsatzes sind die antineoplastischen Wirkmechanismen des Antikörpers Rituximab bisher nicht hinreichend aufgeklärt. Zelluläre Seneszenz tritt als langfristiger Wachstumsarrest vitaler Malignom-Zellen nach zytostatischer Therapie auf und hat weitreichende Einflüsse auf die Tumorbiologie sowie -prognose. Ob Rituximab nach Ligation seines Zielantigens CD20 neben Immun-Effektor-Kaskaden und programmiertem Zelltod auch Lymphomzell-Seneszenz auslösen kann, war bisher unbekannt. Methodik: Ausgewählte B-Zell-Lymphom-Linien, in denen nach zytostatischer Behandlung wesentliche Charakteristika zellulärer Seneszenz nachweisbar waren, wurden, z.T. unter zusätzlichem Einsatz pharmakologischer Inhibitoren, in vitro mit Rituximab-basierter Immuntherapie oder Immunchemotherapie behandelt. Dabei wurden das Wachstumsverhalten, das Auftreten Seneszenz-typischer morphologischer und sekretorischer Veränderungen sowie der Aktivierungszustand ausgewählter, zelluläre Seneszenz regulierender Signalwege untersucht. Ergebnisse: Nach Rituximab-basierter Immuntherapie trat in den analysierten Zelllinien-Modellen – wenn auch in geringerem Ausmaß als durch Behandlung mit dem Anthrazyklin Adriamycin erreichbar – ein seneszenter Phänotyp auf. Dieser wurde intrazellulär offenbar vor allem durch reaktive Sauerstoff-Radikale vermittelt. In kombinierten Ansätzen zeigte sich eine deutliche Erhöhung der Fraktion seneszenter Zellen nach moderater Adriamycin-Behandlung durch zusätzliche gegen CD20 gerichtete Immuntherapie. Passend dazu wurden nach Immunchemotherapie eine im Vergleich zu alleiniger Adriamycin-Behandlung stärkere Aktivierung der DNA-Schadensantwort-Signalkaskade sowie die vermehrte Sekretion der Seneszenz-assoziierten Zytokine Interleukin 6 und Interleukin 8 beobachtet. Diskussion: Langfristig an Zellkulturbedingungen adaptierte Zelllinien stellen keine idealen Modellsysteme für die mechanistische Dissektion zellulärer Seneszenz dar und die Übertragbarkeit der in ihnen gewonnenen Experimentalergebnisse auf primäre humane B-Zell-Lymphome muss daher noch kritisch geprüft werden. Dennoch weisen die dargelegten Beobachtungen auf Lymphomzell-Seneszenz als bisher nicht bekannte zellbiologische Wirkung des im klinischen Alltag häufig eingesetzten Antikörpers Rituximab hin und legen – in Übereinstimmung mit anderen Forschungsberichten – eine Erhöhung der Empfindlichkeit maligner Lymphomzellen für durch Zytostatika vermittelte DNA-Schadenssignale als einen wesentlichen Wirkmechanismus gegen CD20 gerichteter Immuntherapien nahe. Aufgrund der weitreichenden tumorbiologischen und klinischen Implikationen in malignen Lymphomen nach Rituximab-Behandlung auftretender Seneszenz sollten weiterführende wissenschaftliche Untersuchungen zu deren besseren Verständnis durchgeführt werden.Introduction: Despite its broad clinical application in lymphoma therapy, the mechanisms by which the antibody rituximab exerts its antineoplastic activity have not been fully elucidated. Malignant cells may enter cellular senescence, a permanent growth arrest with strong impact on tumor biology and prognostic relevance, in response to cytostatic agents. Whether ligation of its target antigen CD20 by rituximab, besides recruiting classical immune effector functions and triggering apoptotic cell death, may result in lymphoma cell senescence as well was not known. Methods: B-cell lymphoma cell lines, that had been selected based on their capability to display characteristic features of senescence after cytostatic treatment, were exposed to rituximab-based immunotherapy or immunochemotherapy in vitro, with additional application of pharmacological inhibitors in some experiments. Growth characteristics, morphological and secretory changes associated with cellular senescence as wells as activation of selected senescence-regulating signaling pathways were monitored. Results: Rituximab-based immunotherapy induced a senescent phenotype in cell lines derived from human B-cell lymphomas, albeit to a lower extent than the anthracycline adriamycin at optimal concentration. Rituximab- induced senescence seemed to be mediated by intracellular reactive oxygen species. When applied together with a moderate concentration of adriamycin, additional anti-CD20 treatment strongly enhanced the fraction of lymphoma cells entering cellular senescence. In line with this, after combined immunochemotherapy, stronger activation of the DNA damage response signaling cascade as well as enhanced secretion of senescence-associated cytokines interleukin 6 and interleukin 8 in comparison to single agent adriamycin treatment were detected. Discussion: Mechanistic dissection of cellular senescence in established multi-passage cell lines has fundamental limitations. Therefore, the findings of this work need to be critically reassessed in primary human B-cell lymphomas. However, the observations point towards cellular senescence as a hitherto unrecognized consequence of CD20-directed immunotherapy and underscore enhancement of lymphoma cell susceptibility to chemotherapy-induced DNA damage signaling as an essential antineoplastic mechanism of the standard anti-lymphoma compound rituximab. With regard to the broad implications of rituximab-mediated lymphoma cell senescence in tumor biology and clinical settings, further scientific analyses are needed in order to gain a better understanding of this antineoplastic principle