Assoziation von Herpes Simplex Virus Typ 1 Glykoprotein B und MHC Klasse II-Molekülen

Das menschliche Immunsystem wird ständig durch virale Infektionen herausgefordert und setzt verschiedene Effektorreaktionen zur Abwehr ein. Obwohl die humanpathogenen Viren untereinander sehr verschieden sind, haben sie ähnliche Mechanismen entwickelt, um diesen Effektorreaktionen zu entgehen. Bei den humanpathogenen Herpesviren sind verschiedene Strategien bekannt, die die Antigenpräsentation gegenüber CD8+T-Zellen hemmen. Dagegen wurden bisher nur wenige virale Mechanismen beschrieben, die die Antigenpräsentation gegenüber CD4+T-Zellen beeinflussen. Dennoch verhindern neutralisierende Antikörper nach einer Reaktivierung von persistierenden Herpesviren deren Ausbreitung im Körper. Wir haben in dem Glykoprotein B (gB) des Herpes Simplex Virus Typ1 (HSV-1) eine Sequenz von 6 Aminosäuren entdeckt, die identisch zu einer Sequenz innerhalb der humanen Invarianten Kette (Ii) ist. Über diese Sequenz bindet die Invariante Kette promiskuitiv an verschiedene MHC Klasse II-Allotypen. An die Sequenz im Glykoprotein B grenzt C-terminal ein HLA-DR1 Bindungsmotiv, wodurch die Virussequenz der MHC Klasse II-Bindungsstelle der Invarianten Kette ähnelt. Zwischen dem viralen Glykoprotein B und MHC Klasse II-Molekülen verschiedenen Allotyps und unterschiedlicher Spezies konnte eine Interaktion gezeigt werden. In Chimären der Invarianten Kette mit gB-Sequenzen kann die potentielle MHC Klasse II-Bindungsstelle von Glykoprotein B die Klasse II-Bindungsstelle der Invarianten Kette ersetzen. Eine Assoziation zwischen MHC Klasse II-Molekülen und gB-Deletionskonstrukten weist auf zusätzliche MHC Klasse II-Bindungsstellen innerhalb des Glykoproteins B hin. Sowohl Glykoprotein B als auch MHC Klasse II-Moleküle verlassen das ER und werden posttranslational modifiziert. Die MHC Klasse II-Moleküle gelangen zur Zelloberfläche, wo auch ein Teil von Glykoprotein B exprimiert wird. Das intrazellulär verbleibende Glykoprotein B kann die Invariante Kette bei der Ii-abhängigen Antigenpräsentation nicht ersetzen. Die hoch konservierten Glykoproteine B verschiedener HSV-1 Stämme, die für deren unterschiedliche Pathogenität in Mäusen mitverantwortlich sind, zeigen weder Unterschiede in der Assoziation zu MHC Klasse II-Molekülen noch in der Ii-abhängigen Antigenpräsentation. Das für die Infektiösität und Virusausbreitung wichtige Glykoprotein B liefert dem Immunsystem dominante CD4+-Epitope. Möglicherweise kann Glykoprotein B über die Assoziation mit Klasse II-Molekülen in die MHC II-Prozessierungskompartimente gelangen und die Prozessierung innerhalb dieser Kompartimente beeinflussen. Denkbar ist auch ein veränderter intrazellulärer Transport, bei dem das Glykoprotein B dem MHC II-Prozessierungsweg entgeht

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction

Telomerase-pulsed dendritic cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma

Objective: Therapeutic vaccination with dendritic cells (DC) showed promising results in first clinical trials in cases of metastatic renal cell carcinoma (RCC). Human telomerase reverse transcriptase (hTERT) could be a potential target because it is detectable in more than 85% of human tumors including RCC

Control of mitogenic and motogenic pathways by miR-198, diminishing hepatoma cell growth and migration

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied. In hepatoma cell-types with low levels of liver-specific transcription factor HNF1α indicating a low differentiation grade, miR-198 expression was most downregulated. However, miR-198 treatment did not restore the expression of the liver-specific transcription factors HNF1α or HNF4α. Importantly, overexpression of miR-198 in Pop10 hepatoma cells markedly reduced cell growth. In agreement, comprehensive gene expression profiling by microarray hybridisation and real-time quantification revealed that central signal transducers of proliferation pathways were downregulated by miR-198. In contrast, genes mediating cellular adherence were highly upregulated by miR-198. Thus, the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, was abolished in hepatoma cells after miR-198 overexpression. This definite induction of both proteins by miR-198 was shown to be accompanied by a significantly impaired migration activity of hepatoma Pop10 cells. In conclusion, miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration

Death and organization: Heidegger’s thought on death and life in organizations

Mortality has not been given the attention it deserves within organization studies. Even when it has been considered, it is not usually in terms of its implications for own lives and ethical choices. In particular, Heidegger’s writing on death has been almost entirely ignored both in writing on death and writing on organizational ethics, despite his insights into how our mortality and the ethics of existence are linked. In this paper, we seek to address this omission by arguing that a consideration of death may yield important insights about the ethics of organizational life. Most important of these is that a Heideggerian approach to death brings us up against fundamental ethical questions such as what our lives are for, how they should be lived and how we relate to others. Heideggerarian thought also reconnects ethics and politics, as it is closely concerned with how we can collectively make institutions that support our life projects rather than thwart or diminish them

Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease

Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02

Standards of care for meningioma include surgical resection and radiotherapy whereas pharmacotherapy plays almost no role in this disease. We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign (ben)-1, 2, 3, intermediate (int)-A, B, and malignant (mal). Four tumors assigned to the methylation class ben-2 showed the same class in culture whereas cultures from five non-ben-2 tumors showed a more malignant class in four patients. Cell cultures were uniformly sensitive to TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation class appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors. Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase (CDK) inhibitor, warrants further exploration