Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients

A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation: Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis

BACKGROUND: In recent years, many immunoregulatory functions have been ascribed to soluble HLA-G (sHLA-G). Since chemotaxis is crucial for an efficient immune response, we have investigated for the first time the effects of sHLA-G on chemokine receptor expression and function in different human T cell populations. METHODOLOGY/PRINCIPAL FINDINGS: T cell populations isolated from peripheral blood were stimulated in the presence or absence of sHLA-G. Chemokine receptors expression was evaluated by flow cytometry. sHLA-G downregulated expression of i) CCR2, CXCR3 and CXCR5 in CD4(+) T cells, ii) CXCR3 in CD8(+) T cells, iii) CXCR3 in Th1 clones iv) CXCR3 in TCR Vdelta2gamma9 T cells, and upregulated CXCR4 expression in TCR Vdelta2gamma9 T cells. sHLA-G inhibited in vitro chemotaxis of i) CD4(+) T cells towards CCL2, CCL8, CXCL10 and CXCL11, ii) CD8(+) T cells towards CXCL10 and CXCL11, iii) Th1 clones towards CXCL10, and iv) TCR Vdelta2gamma9 T cells towards CXCL10 and CXCL11. Downregulation of CXCR3 expression on CD4+ T cells by sHLA-G was partially reverted by adding a blocking antibody against ILT2/CD85j, a receptor for sHLA-G, suggesting that sHLA-G downregulated chemokine receptor expression mainly through the interaction with ILT2/CD85j. Follicular helper T cells (T(FH)) were isolated from human tonsils and stimulated as described above. sHLA-G impaired CXCR5 expression in T(FH) and chemotaxis of the latter cells towards CXCL13. Moreover, sHLA-G expression was detected in tonsils by immunohistochemistry, suggesting a role of sHLA-G in local control of T(FH) cell chemotaxis. Intracellular pathways were investigated by Western Blot analysis on total extracts from CD4+ T cells. Phosphorylation of Stat5, p70 s6k, beta-arrestin and SHP2 was modulated by sHLA-G treatment. CONCLUSIONS/SIGNIFICANCE: Our data demonstrated that sHLA-G impairs expression and functionality of different chemokine receptors in T cells. These findings delineate a novel mechanism whereby sHLA-G modulates T cell recruitment in physiological and pathological conditions

Einfluss von anthropogenen Schadstoffen (PAK und PCB) auf terrestrische Invertebraten urbaner Oekosysteme Abschlussbericht

Das Projekt wurde von August 1993 bis Mai 1997 durchgefuehrt. Ziele waren die Erarbeitung (a) von Wirkschwellen fuer organische Schadstoffgruppen (PAK, PCB) und Schwermetalle im Boden fuer Destruenten urbaner Oekosysteme, (b) von Biotestsystemen zur Bewertung der Lebensraumfunktion belasteter Boeden und (c) von Hinweisen zur kontrollierten Nutzung belasteter Flaechen. Diese Fragestellungen wurden bearbeitet durch Freilanduntersuchungen auf stillgelegten Rieselfeldern der Stadt Berlin zur Abundanz, Artendiversitaet und Dominanzstruktur terrestrischer Anneliden (Lumbriciden, Enchytraeiden), durch Biotests unter Verwendung kontaminierter Rieselfeldboeden und aufdotierter Boeden (BaP, Fla, PCB 52, Cd, Cu) und durch Untersuchung zur Akkumulation, Elimination und Biotransformation bei Anneliden. Auf 12 der 17 untersuchten Rieselfeldstandorten wurden keine Regenwuermer gefunden, auf zwei keine Enchytraeiden. Die Enchytraeidenabundanz lag zwischen 500 und 12.500/m"2 und damit weit unter der von Kontrollflaechen (25.000 bis 280.000/m"2). Die Annelidenfeindlichkeit der Rieselfeldboeden wurde durch den Koederstreifen-Test und durch Biotests mit Enchytraeus crypticus, E. albidus, E. buchholzi und Eisenia f. fetida bestaetigt. Die Oekotoxizitaet der rieselfeldtypischen Schadstoffkombinationen wurde durch den sauren Boden-pH und Bodenumlagerungen verstaerkt. Die Toxizitaet der organischen und anorganischen Schadstoffe fuer Anneliden wurde durch Kurz- und Langzeituntersuchungen im Agar-Testsystem bestaetigt. Die Untersuchungsmethoden koennen zur Bewertung komtaminierter Boeden herangezogen werden. (orig.)The project was conducted from August 1993 until May 1997. The objectives were (a) an elaboration of effect concentrations and index values for organic contaminants (PAH, PCB) and heavy metals in soil of conurbations for the community of decomposers, (b) the improvement of a biotest system for the evaluation of the habitat function of contaminated soils and (c) to obtain informations concerning a controlled utilization of contaminated areas. For that purpose field investigations in former sewage water irrigation areas of Berlin, Germany, concerning the abundance, species composition and dominance structure of terrestrial annelids (Enchytraeids, Lumbricids) were performed, as well as bioassays using contaminated soils of these sites and soils spiked with bezo(a)pyrene, fluoranthene, PCB 52, Cd and Cu and experiments on accumulation, elimination and biotransformation in annelids. 12 of the 17 sites investigated lacked earthworms, while only 2 sites lacked enchytraeids. The abundance of enchytraeids was in the range of 500 to 12.500/m"2, compared to 25.000 to 280.000/m"2 on reference sites. The hostility of the soils of former irrigation fields to annelids was confirmed by lamina bait tests and by bioassays with Enchytraeus crypticus, E. albidus, E. buchholzi and Eisenia f. fetida. The ecotoxicity of the combined contaminants was enforced by the acidity and the degradation of the soils. The toxicity of organic and inorganic contaminants to terrestrial annelids was definitely proved by reproduction tests in the agar test system. The applied methods of investigation can be used for evaluation of contaminated soils. (orig.)Available from TIB Hannover: F98B1125+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman