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Background and Aim: The main disadvantage of plastic stents is the high rate of stent occlusion. The usual replacement interval of biliary plastic stents is 3 months. This study aimed to investigate if a shorter interval of 6–8 weeks impacts the median premature exchange rate (mPER) in benign and malignant biliary strictures.
Methods: All cases with endoscopic retrograde cholangiopancreatography (ERCP) and plastic stent placement were retrospectively analyzed since establishing an elective replacement interval of every 6–8 weeks at our institution and mPER was determined.
Results: A total of 3979 ERCPs (1199 patients) were analyzed, including 1262 (31.7%) malignant and 2717 (68.3%) benign cases, respectively. The median stent patency (mSP) was 41 days (range 14–120) for scheduled stent exchanges, whereas it was 17 days (1–75) for prematurely exchanged stents. The mPER was significantly higher for malignant (28.1%, 35–50%) compared with benign strictures (15.2%, 10–28%), P < 0.0001, respectively. mSP was significantly shorter in cases with only one stent (34 days [1–87] vs 41 days [1–120]) and in cases with only a 7-Fr stent (28 days [2–79]) compared with a larger stent (34 days [1–87], P = 0.001). Correspondingly, mPER was significantly higher in cases with only one stent (23% vs 16.2%, P < 0.0001) and only a 7-Fr stent (31.3% vs 22.4%, P = 0.03).
Conclusion: A shorter replacement interval does not seem to lead to a clinically meaningful reduction of mPER in benign and malignant strictures. Large stents and multiple stenting should be favored as possible.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
(2021)
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
Sozial- und politikromantische Einbildungen haben eine lange, vielleicht sogar unendliche Lebensdauer, vor allem - aber nicht nur - in den Massenmedien. Zu solchen Vorstellungen gehört, dass die Oper vor allem im 19. Jahrhundert eine revolutionäre und systemkritische Wirksamkeit entfaltete oder die Komponisten dies zumindest beabsichtigten. [...] Die Opernzensur, so wird umgekehrt geschlossen, sei dazu dagewesen, all dies zu unterdrücken. Und die freiheitsliebenden und aufgeklärten Komponisten hätten einen steten Kampf gegen die Zensoren zu führen gehabt. Das hier skizzierte Bild der Operngeschichte darf man, auch wenn es immer noch in wissenschaftlichen Kontexten erscheint, als groben Unfug bezeichnen. [...] Viel wichtiger als das politische Argument war sowohl im 18. wie im 19. Jahrhundert das moralische Argument von Zensoren gegen einzelne Opern.
Warum interessiert sich der Opernforscher für das Opernpublikum? Opernkomponisten und Librettisten des 19. Jahrhunderts verfaßten oder bearbeiteten ihre Werke im Hinblick auf bestimmte Opernhäuser, auf deren Usancen, finanzielle und technische Möglichkeiten (z.B. die zur Verfügung stehende Orchesterbesetzung und - vor allem - die verfügbaren Sänger und Sängerinnen) sowie Rahmenbedingungen, auf die sie ebenso Rücksicht nehmen mußten wie auf die Zensur. Eine der dominanten Rahmenbedingungen war das Publikum. Ästhetische Präferenzen, Bildungsgrad, Erwartungshorizont, aber auch ganz banale Erwartungen an die maximale Länge einer Oper konnten den Erfolg einer Oper erheblich beeinflussen. [...] Will man also die Bedingungen untersuchen, denen die Opern in ästhetischer und institutioneller Hinsicht unterlagen, kommt man um eine Analyse des Opernpublikums nicht herum. [...] Die folgenden Ausführungen sollen einige methodische Hinweise zur Möglichkeit der Analyse des Opernpublikums im 19. Jahrhundert anhand konkreter Beispiele geben, die aber ausdrücklich nur auf dieses Jahrhundert (im Sinne des "langen" 19. Jahrhunderts) beschränkt sind.
Wer ist Margherita Salicola? Man erfährt über sie in den einschlägigen Lexika nur, sie sei die Schwester der Sängerin Angiola (oder Angela) Salicola und die berühmtere der beiden gewesen, daß aber sich kaum Nachrichten über sie erhalten hätten, außer jener daß sie, wie ihre Schwester, in den Diensten des Herzogs Ferdinando Carlo (IV.) Gonzaga von Mantua gestanden habe und dann mit Johann Georg III. nach Dresden gegangen sei. Schon Lorenzo Bianconi und Thomas Walker hatten in einem langen Artikel, der noch heute die Grundlage aller sozialgeschichtlichen Arbeiten zur Operngeschichte des 17. Jahrhunderts ist, herausgearbeitet, daß die ca. 1660 geborene Sängerin in den 1680er Jahren zu den international berühmtesten italienischen Sängerinnen gehörte und ihr Ruhm auch jenseits der Alpen noch am Anfang des 18. Jahrhunderts nicht verblaßt war. 1682 begegnet Salicola zum erstenmal als Sängerin am Teatro San Salvatore in Venedig in einer Oper Giovanni Legrenzis und trat im folgenden Jahr in Pietro Andrea Zianis "Il talamo preservato dalla fedeltà d’Eudossa" in Reggio Emilia auf. Kurz darauf sang sie in Venedig, wo ihr der sächsische Kurfürst begegnete, der sie - davon handelt der folgende Text - mit nach Dresden nahm, wo sie, die erste Primadonna jenseits der Alpen wurde. 1693, nachdem sie Dresden verlassen hatte, trat sie in Wien auf und ist ab 1696 erneut in Italien nachweisbar. [...] War Salicola bei den Zeitgenossen berühmt wegen ihres Gesangs, so wurde sie musikhistorisch vor allem bekannt durch ihre angebliche Entführung aus Venedig, die noch im 19. Jahrhundert und bis heute immer wieder erzählt wurde. Aber auch außerhalb der musikwissenschaftlichen Literatur werden die im folgenden dargestellten Ereignisse anekdotisch erzählt und mit der "Theaterbegeisterung der höfischen Gesellschaft" erklärt. Im folgenden soll dem, im Detail gelegentlich verwirrenden, "Salicola incident" erneut nachgegangen werden, um ihn dann innerhalb des politisch-kulturellen Rahmens zu erklären.
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2−/−) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2−/− mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.
Complexin-1 and foxp1 expression changes are novel brain effects of
alpha-synuclein pathology
(2014)
As the second most frequent neurodegenerative disorder of the aging population, Parkinson’s disease (PD) is characterized by progressive deficits in spontaneous movement, atrophy of dopaminergic midbrain neurons and aggregation of the protein alpha-synuclein (SNCA). To elucidate molecular events before irreversible cell death, we studied synucleinopathy-induced expression changes in mouse brain and identified 49 midbrain/brainstem-specific transcriptional dysregulations. In particular complexin-1 (Cplx1), Rabl2a and 14-3-3epsilon (Ywhae) downregulation, as well as upregulation of the midbrain-specific factor forkhead box P1 (Foxp1) and of Rabgef1, were interesting as early mRNA level effects of alpha-synuclein triggered pathology. The protein levels of complexin-1 were elevated in midbrain/brainstem tissue of mice with A53T-SNCA overexpression and of mice with SNCA-knockout. The response of CPLX1 and Foxp1 levels to SNCA deficiency supports the notion that these factors are regulated by altered physiological function of alpha-synuclein. Thus, their analysis might be useful in PD stages before the advent of Lewy pathology. Because both alpha-synuclein and complexin-1 modulate vesicle release, our findings support presynaptic dysfunction as an early event in PD pathology.
Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation and to affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript and soluble and insoluble protein levels were increased. In the more vulnerable cerebellum, the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated a selective induction of Fbxw8 in the old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissuespecific effects, which may be partially alleviated by the induction of FBXW8.
Compactness is introduced as a new method to search for the onset of the quark matter transition in relativistic heavy ion collisions. That transition supposedly leads to stronger compression and higher compactness of the source in coordinate space. That effect could be observed via pion interferometry. We propose to measure the compactness of the source in the appropriate principal axis frame of the compactness tensor in coordinate space.