Funktionelle Charakterisierung eines rekombinanten IgA2 Antikörpers gegen CD20

Die funktionelle Charakterisierung eines CD20-gerichteten IgA2-Antikörpers stellt den thematischen Schwerpunkt dieser Arbeit dar und hatte zum Ziel, dessen therapeutisches Potential zu erfassen sowie die zugrundeliegenden Effektormechanismen darzulegen. Mit Rituximab steht seit 1997 für die Klinik ein chimärer, monoklonaler Antikörper gegen CD20 zur Verfügung. Alle aktuell therapeutisch eingesetzten sowie in der Entwicklung befindlichen CD20-Antikörper sind Antikörper des IgG-Isotyp. Interessanterweise sind 1F5-IgG1 und –IgA2 in der Vermittlung von Zytotoxizität gegen verschiedene Lymphom-Zelllinien mit dem peripheren Vollblut gesunder Spender als Effektorquelle gleichermaßen effektiv. Weiterhin sind 1F5-IgA2 und 1F5-IgG1 gleichermaßen effektiv in der Depletion von hCD20-positiven B-Zellen in Mäusen. Der untersuchte IgA2 Antikörper gegen CD20 ist in der Lage, signifikant CDC gegen unterschiedliche Lymphom-Zelllinien und frisch isolierte humane CLL Zellen zu vermitteln. Diese Daten legten in vitro eine unerwartet prominente Rolle komplementvermittelter Zytotoxizität nahe, welche sich in komplementdefizienten Mäusen nicht bestätigen ließ. 1F5-IgA2 war in vitro in der Lage, effektiv PMN Zellen zur Tumorzelllyse auf verschiedenen Lymphom-Zelllinien und primäreren CLL-Proben zu aktivieren. Die Untersuchung der in vivo Effektivität des CD20-gerichteten IgA-Antikörpers in FcαRI transgenen Mäusen konnte jedoch keinen Beitrag FcαRI-abhängiger Mechanismen an der gemessenen Zytotoxizität feststellen und stehen damit nicht in Einklang mit vorhergehenden Studien. Zusammenfassend demonstrieren die Daten die Effektivität eines CD20-gerichteten IgA2 Antikörpers in der Abtötung CD20-positiver Lymphomzellen in vitro und in vivo. IgA Antikörper könnten somit das Immuntherapeutische Repertoire gegen lymphatische Neoplasien wirksam ergänzen

Accessing the entire overdoped regime in pristine YBa2Cu3O6 + x by application of pressure

We uncover the previously inaccessible overdoped regime to attain the complete superconducting dome in a pristine high temperature cuprate superconductor, by applying pressures up to 280 kbar to single crystals near stoichiometric YBa[subscript 2]Cu[subscript3]O[subscript 7]. The obtained superconducting phase boundary as a function of hole doping closely follows the form of the superconducting dome in La[subscript 2−x]Sr[subscript x]CuO[subscript 4]. Measurements are now enabled to trace the evolution of various entangled phases and the Fermi surface from the underdoped to overdoped regime in a single high purity cuprate superconducting family of materials.Royal Society (Great Britain)Winton Programme for the Physics of SustainabilityCambridge-MIT InstituteSeventh Framework Programme (European Commission) (Grants FP/2007-2013, ERC 337425 and EPSRC EP/M000524/1

Unconventional quantum vortex matter state hosts quantum oscillations in the underdoped high-temperature cuprate superconductors.

A central question in the underdoped cuprates pertains to the nature of the pseudogap ground state. A conventional metallic ground state of the pseudogap region has been argued to host quantum oscillations upon destruction of the superconducting order parameter by modest magnetic fields. Here, we use low applied measurement currents and millikelvin temperatures on ultrapure single crystals of underdoped [Formula: see text] to unearth an unconventional quantum vortex matter ground state characterized by vanishing electrical resistivity, magnetic hysteresis, and nonohmic electrical transport characteristics beyond the highest laboratory-accessible static fields. A model of the pseudogap ground state is now required to explain quantum oscillations that are hosted by the bulk quantum vortex matter state without experiencing sizable additional damping in the presence of a large maximum superconducting gap; possibilities include a pair density wave.Royal Society Winton Programme for the Physics of Sustainability Engineering and Physical Sciences Research Council (EPSRC; studentship and grant numbers EP/R513180/1, EP/M506485/1 and EP/P024947/1) European Research Council under the European Unions Seventh Framework Programme (Grant Agreement numbers 337425 and 772891). EPSRC Strategic Equipment Grant EP/M000524/1 Leverhulme Trust by way of the award of a Philip Leverhulme Prize. National Key Research and Development Program of China (grant no. 2016YFA0401704). Work performed at the National High Magnetic Field Laboratory (NHMFL) supported by NSF Cooperative Agreement DMR-1157490, the State of Florida, and the Department of Energy (DOE) DOE Basic Energy Sciences project: ‘Science of 100 tesla’

Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer

Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non-small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8+ T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC

Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer

In vitro measurement of temperature changes during implantation of cemented glenoid components

Background and purpose It is unclear whether the increase in temperature during cement curing may cause osteonecrosis, leading to loosening of the glenoid component in shoulder arthroplasty. We therefore analyzed the temperature during implantation of cemented glenoid implants

The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size

LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Bulletin der deutschen Slavistik 24.2018

Jahrbuch der Deutschen Slavistik mit Forumsbeiträgen zu Digital Humanities, Rubriken zu Personen, Publikationen, Preisen, Wirkungsorten, wissenschaftlichen Abhandlungen