Die Ergänzung von halbierenden GlcNAcs an dem IFNgRa Protein stellt die IFN-g Antwort in kolorektalen Karzinomzellen wieder her.

In Germany, every fourth death is caused by cancer and with around 25,000 deaths annually, colorectal carcinoma (CRC) is one of the third most common forms of cancer. CRC occurs sporadically in 50-60%, while 30-40% of patients have a hereditary disposition. The presence of an active TH1 immune response has been shown to be positive for the cancer-related 5-year survival rate of CRC patients. A marker for the detection of an active TH1 immune response is the expression of the guanylate binding protein 1 (GBP-1), which is induced to a high degree by the cytokine interferon-g (IFN-g), which is characteristic of the TH1 immune response. A study on tumor tissue from CRC patients showed that in 50 % of the cases only the stromal cells, but not the tumor cells, expressed GBP-1. This suggests that the tumor cells in these cases were resistant to IFN-g signaling. In vitro analyses of eleven CRC cell lines confirmed this. In six cell lines it was not possible to induce the GBP-1 expression or the apoptosis which is associated with IFN-g treatment. Investigations into the cause of the IFN-g resistance showed that the expression of the interferon-gamma receptor alpha chain (IFNgRa) was greatly reduced in the IFN-g-resistant CRC cell lines. Analysis of CRC patient data showed that reduced IFNgRa expression is associated with a reduced disease-free survival. The present work investigated the molecular mechanisms of potential regulatory mechanisms for the decreased expression of the IFNgRa in IFN-g-resistant tumor cells. IFN-g-resistant CRC cell lines showed intracellular accumulation of the IFNgRa in the Golgi apparatus, accompanied by a reduced molecular weight of the receptor. The latter indicated defects in N-glycosylation of the receptor in IFN-g-resistant CRC cell lines. It was not possible to restore the IFN-g response in IFN-g-resistant CRC cell lines by re-expression of the IFNgRa. The recombinant expressed receptor protein also showed a reduced molecular weight and incomplete N-glycosylation. Further investigations showed that the incompletely glycosylated IFNgRa cannot transmit the signals of the bound IFN-g. In addition, the incomplete glycosylation of the IFNgRa led to a proteasome-mediated degradation of the receptor protein in IFN-g-resistant CRC cell lines. These results showed that an incorrect glycosylation of the IFNgRa leads to the destabilization of the protein, which could explain the reduced receptor expression in IFN-g-resistant CRC cell lines. A comparative analysis of the gene expression of N-glycosylation enzymes in IFN-g-sensitive and –resistant CRC cell lines was then carried out. It was found that the enzyme beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) was absent in all IFN-g-resistant CRC cell lines or was present in significantly reduced amounts. The re-expression of this enzyme led to an increased expression of the IFNgRa with the same molecular weight as in IFN-g-sensitive CRC cells. In accordance with this, a cellular IFN-g response could be reinstated again after the treatment with IFN-g. This study showed that the functionality and stability of the IFNgRa are decisively influenced by the activity of the MGAT3 glycosylation enzyme. In CRC cell lines, it was possible to restore the susceptibility of previously resistant cells to IFN-g in one-step by reconstituting the MGAT3 expression. This finding could open new approaches for the treatment of CRC.In Deutschland wird jeder vierte Todesfall durch eine Krebserkrankung verursacht und mit ca. 25.000 Sterbefällen jährlich gehört das Kolorektale Karzinom (KRK) zu den dritthäufigsten Krebserkrankungen. Zu 50-60% tritt das KRK sporadisch auf, während 30-40% der Patienten eine erbliche Disposition aufweisen. Das Vorhandensein einer aktiven TH1-Immunantwort hat sich als positiv für das krebsbezogene 5-Jahres Überlebensrate von KRK-Patienten gezeigt. Ein Marker zum Nachweis einer aktiven Wirkung dieser Immunantwort in Geweben ist die Expression des Guanylat-Bindungs-Protein 1 (GBP-1), welche in hohem Maße durch das charakteristisch mit der TH1-Immunantwort assoziierte Zytokin Interferon-g (IFN-g) induziert wird. Eine Studie an Tumorgeweben von KRK-Patienten zeigte, dass in 50% ausschließlich die Stromazellen, nicht jedoch die Tumorzellen GBP-1 exprimieren. Dies liegt nahe, dass die Tumorzellen in diesen Fällen resistent gegen eine IFN-g Wirkung waren. In vitro-Analysen von elf KRK-Zelllinien bestätigten dies. In sechs Zelllinien gelang es nicht durch eine IFN-g Behandlung die GBP-1 Expression bzw. die sonst mit dieser Behandlung verbundene Apoptose zu induzieren. Untersuchungen zur Ursache der IFN-g-Resistenz zeigten, dass in den entsprechenden Zellen die Expression der Interferon-gamma Rezeptor Alpha Kette (IFNgRa) stark erniedrigt war. Die Analyse von KRK-Patientendaten zeigte, dass die reduzierte IFNgRa-Expression mit einem reduzierten Krankheits-freien-Überleben assoziiert ist. Die vorliegende Arbeit untersuchte die molekularen Mechanismen möglicher Regulationsmechanismen für die erniedrigte Expression des IFNgRa in IFN-g-resistenten Tumorzellen. IFN-g-resistente KRK-Zelllinien zeigten eine intrazelluläre Akkumulation des IFNgRa im Golgi Apparat einhergehend mit einem erniedrigten Molekulargewichts des Rezeptors. Letzteres deutete auf Defekte in der N-glykoslierung des Rezeptors in IFN-g-resistenten Zelllinien hin. Es war nicht möglich die fehlende IFN-g-Antwort in IFN-g-resistenten KRK-Zelllinien mittels Re-expression des IFNgRa wiederherzustellen. Auch das rekombinant exprimierte Rezeptormolekül zeigte ein erniedrigtes Molekulargewicht und eine unvollständige N-glykosylierung. Weitere Untersuchungen zeigten, dass der unvollständig glykosylierte IFNgRa die Signale der IFN-g-Bindung nicht weiterleiten kann. Zudem führte die unvollständige Glykosylierung des IFNgRa zu einem proteasom-vermittelten Abbau des Rezeptorproteins in IFN-g-resistenten KRK-Zelllinien. Diese Ergebnisse zeigten, dass eine fehlerhafte Glykosylierung des IFNgRa zur Destabiliesierung des Proteins führt, wodurch die verringerte Expression in IFNg-resistenten KRK-Zelllinien erklärt werden könnte. Anschließend wurde eine vergleichende Analyse der Genexpression von N-glykosylierungsenzymen in IFN-g-sensitiven und –resistenten KRK Zelllinien durchgeführt. Es zeigte sich, dass das Enzym Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) in allen IFN-g-resistenten KRK Zelllinien fehlte oder in deutlich erniedrigten Mengen vorlag. Die Re-expression dieses Enzymes führte zu einer verstärkten Bildung des IFNgRa mit identischem Molekulargewicht wie in IFN-g-sensitiven Zellen. Im Einklang hierzu konnte nach der Behandlung entsprechender Zellen mit IFN-g wieder eine zelluläre IFN-g-Antwort ausgelöst werden konnte. Diese Studie zeigte, dass die Funktionalität und Stabilität des IFNgRa entscheidend von der Aktivität des MGAT3 Glykosylierungsenzyms beeinflusst werden. In KRK-Zellinien gelang es durch Rekonstitution der MGAT3-Expression in einem Schritt die Suszeptibilität vormals resistenter Zellen auf IFN-g wiederherzustellen. Dieser Befund könnte neue Ansätze für die Behandlung des KRK eröffnen

Positive affect through interactions in meetings: The role of proactive and supportive statements

Meetings often dominate software projects. Despite frequent dissatisfaction within meetings, many software engineers are not aware of the crucial importance about their behavior. This can set the tone for the entire project and influence the success. In a study based on 32 student development teams with 155 participants, we observed the participants' interactions during the first internal team meeting. Analyzing the observations showed that constructive remarks had a positive impact on positive group affect tone. However, this effect can only be observed when supportive utterances followed constructive remarks. In the article, we show a complete mediation of this statistically significant effect, e.g., about seemingly subtle interaction patterns that influence group affect tone. We also propose practical interventions on how software projects could benefit from supportive meeting behavior. This summary refers to the article "Positive affect through interactions in meetings: The role of proactive and supportive statements" [Scl8] published in the Journal of Systems & Software in 2018 (vol. 143). © 2019 Gesellschaft fur Informatik (GI). All rights reserved

Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis

Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion-evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2)-antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala

Le Gâvre – Alignement du Pilier

Le site dit alignement du Pilier (également Breuil de la Herse et allée du Pilier) s’étale dans le nord de la forêt domaniale du Gâvre (ancienne tenue 39), sur la commune du même nom. Il est constitué, au dernier décompte, d’une file de 85 blocs de quartz et quartzite orientée nord-ouest – sud-est, sur près d’1 km, de chaque côté de l’allée forestière du Breuil de la Herse jusqu’à toucher l’allée du Pilier, au sud du carrefour du Pilier ; 9 blocs supplémentaires sont détachés de cet alignemen..

25 years of endothelin research: the next generation

In the past three decades, endothelin and endothelin receptor antagonists have received great scientific and clinical interest, leading to the publication of more than 27,000 scientific articles since its discovery. The Thirteenth International Conference on Endothelin (ET-13) was held on September 8–11, 2013, at Tokyo Campus of the University of Tsukuba in Japan. Close to 300 scientists from 25 countries from around the world came to Tokyo to celebrate the anniversary of the discovery of the endothelin peptide discovered 25 years ago at the University of Tsukuba. This article summarizes some of the highlights of the conference, the anniversary celebration ceremony, and particularly the participation of next generation of endothelin researchers in endothelin science and the anniversary celebration. As a particular highlight, next generation endothelin researchers wrote a haiku (a traditional form of Japanese poetry originating from consisting of no more than three short verses and 27 on, or Japanese phonetic units) to describe the magic of endothelin science which they presented to the conference audience at the anniversary ceremony. The text of each haiku – both in its original language together with the English translation – is part of this article providing in an exemplary fashion how poetry can be bridged with science. Finally, we give an outlook towards the next 25 years of endothelin research

Retrospective Analysis of Radiological Recurrence Patterns in Glioblastoma, Their Prognostic Value And Association to Postoperative Infarct Volume

Recent studies suggested that postoperative hypoxia might trigger invasive tumor growth, resulting in diffuse/multifocal recurrence patterns. Aim of this study was to analyze distinct recurrence patterns and their association to postoperative infarct volume and outcome. 526 consecutive glioblastoma patients were analyzed, of which 129 met our inclusion criteria: initial tumor diagnosis, surgery, postoperative diffusion-weighted imaging and tumor recurrence during follow-up. Distinct patterns of contrast-enhancement at initial diagnosis and at first tumor recurrence (multifocal growth/progression, contact to dura/ventricle, ependymal spread, local/distant recurrence) were recorded by two blinded neuroradiologists. The association of radiological patterns to survival and postoperative infarct volume was analyzed by uni-/multivariate survival analyses and binary logistic regression analysis. With increasing postoperative infarct volume, patients were significantly more likely to develop multifocal recurrence, recurrence with contact to ventricle and contact to dura. Patients with multifocal recurrence (Hazard Ratio (HR) 1.99, P = 0.010) had significantly shorter OS, patients with recurrent tumor with contact to ventricle (HR 1.85, P = 0.036), ependymal spread (HR 2.97, P = 0.004) and distant recurrence (HR 1.75, P = 0.019) significantly shorter post-progression survival in multivariate analyses including well-established prognostic factors like age, Karnofsky Performance Score (KPS), therapy, extent of resection and patterns of primary tumors. Postoperative infarct volume might initiate hypoxia-mediated aggressive tumor growth resulting in multifocal and diffuse recurrence patterns and impaired survival

Biological roles of RNA m5C modification and its implications in Cancer immunotherapy

Epigenetics including DNA and RNA modifications have always been the hotspot field of life sciences in the post-genome era. Since the first mapping of N6-methyladenosine (m6A) and the discovery of its widespread presence in mRNA, there are at least 160-170 RNA modifications have been discovered. These methylations occur in different RNA types, and their distribution is species-specific. 5-methylcytosine (m5C) has been found in mRNA, rRNA and tRNA of representative organisms from all kinds of species. As reversible epigenetic modifications, m5C modifications of RNA affect the fate of the modified RNA molecules and play important roles in various biological processes including RNA stability control, protein synthesis, and transcriptional regulation. Furthermore, accumulative evidence also implicates the role of RNA m5C in tumorigenesis. Here, we review the latest progresses in the biological roles of m5C modifications and how it is regulated by corresponding “writers”, “readers” and “erasers” proteins, as well as the potential molecular mechanism in tumorigenesis and cancer immunotherapy

Innovative radiation oncology Together – Precise, Personalized, Human : Vision 2030 for radiotherapy & radiation oncology in Germany

Purpose Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany

Assessment of Brain Age in Posttraumatic Stress Disorder: Findings from the ENIGMA PTSD and Brain Age Working Groups

Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

ENIGMA-anxiety working group : Rationale for and organization of large-scale neuroimaging studies of anxiety disorders

Altres ajuts: Anxiety Disorders Research Network European College of Neuropsychopharmacology; Claude Leon Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 44541416-TRR58); EU7th Frame Work Marie Curie Actions International Staff Exchange Scheme grant 'European and South African Research Network in Anxiety Disorders' (EUSARNAD); Geestkracht programme of the Netherlands Organization for Health Research and Development (ZonMw, 10-000-1002); Intramural Research Training Award (IRTA) program within the National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, MH002781); National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, ZIA-MH-002782); SA Medical Research Council; U.S. National Institutes of Health grants (P01 AG026572, P01 AG055367, P41 EB015922, R01 AG060610, R56 AG058854, RF1 AG051710, U54 EB020403).Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders