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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)
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.
The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
The integrated luminosities of data samples collected in the BESIII experiment in 2016–2017 at center-of-mass energies between 4.19 and 4.28 GeV are measured with a precision better than 1% by analyzing large-angle Bhabha scattering events. The integrated luminosities of old datasets collected in 2010–2014 are updated by considering corrections related to detector performance, offsetting the effect of newly discovered readout errors in the electromagnetic calorimeter, which can haphazardly occur.
Vorwort : Hansjakob Seiler
Deskriptive und metaphorische Benennung im Bereich der deutschen Nominalformen : Rita Becker
Die Anwendung des Prinzips der deskriptiven und etikettierenden Benennung auf Instrumentausdrücke im Deutschen und Ungarischen : Elisabeth Katz
Etikettierende und deskriptive Benennung in Prä- und Postpositionalsystemen : Heribert Walter
Das deskriptive Prinzip im Hebräischen : Edna Habel
Anwendung der Prinzipien der deskriptiven und der etikettierenden Benennung auf Farbbezeichnungen im Deutschen : Charlotte Schwendy
Deskriptiv vs. Etikettierend in der Fachsprache der EDV : Wolfgang Kirsch
Relativkonstruktionen : Bernhard Clasen und Claudia Seip
Die […] Arbeiten entstanden im Rahmen eines vom Unterzeichneten geleiteten Forschungsseminars über sprachliche Universalien im Wintersemester 1974/75. Das Interesse konzentrierte sich auf den als "deskriptive und etikettierende Benennung" bezeichneten Problembereich; die Relativkonstruktionen, hier durch eine Arbeit vertreten, hängen letztlich mit dem genannten Problembereich zusammen. Eine weitere Studie über Relativkonstruktionen sowie sonstige zur Zeit noch in Arbeit befindliche Aufsätze dieses Seminars werden vielleicht, in einem späteren Arbeitspapier Aufnahme finden.
Based on (10087±44)×106 J/ψ events collected with the BESIII detector, the process J/ψ→γπ+π−η′ is studied using two dominant decay channels of the η′ meson, η′→γπ+π− and η′→ηπ+π−,η→γγ. The X(2600) is observed with a statistical significance larger than 20σ in the π+π−η′ invariant mass spectrum, and it has a strong correlation to a structure around 1.5 GeV/{\it c}2 in the π+π− invariant mass spectrum. A simultaneous fit on the π+π−η′ and π+π− invariant mass spectra with the two η′ decay modes indicates that the mass and width of the X(2600) state are 2617.8±2.1+18.2−1.9 MeV/{\it c}2 and 200±8+20−17 MeV, respectively. The corresponding branching fractions are measured to be B(J/ψ→γX(2600))⋅B(X(2600)→f0(1500)η′)⋅B(f0(1500)→π+π−) = (3.39±0.18+0.91−0.66)×10−5 and B(J/ψ→γX(2600))⋅B(X(2600)→f′2(1525)η′)⋅B(f′2(1525)→π+π−) = (2.43±0.13+0.31−1.11)×10−5, where the first uncertainties are statistical, and the second systematic.
Using a sample of (10.09±0.04)×109 J/ψ events collected with the BESIII detector operating at the BEPCII storage ring, a partial wave analysis of the decay J/ψ→γηη′ is performed. The first observation of an isoscalar state with exotic quantum numbers JPC=1−+, denoted as η1(1855), is reported in the process J/ψ→γη1(1855) with η1(1855)→ηη′. Its mass and width are measured to be (1855±9+6−1)MeV/c2 and (188±18+3−8)MeV, respectively, where the first uncertainties are statistical and the second are systematic, and its statistical significance is estimated to be larger than 19σ.
Based on a sample of (10.09±0.04)×109 J/ψ events collected with the BESIII detector operating at the BEPCII storage ring, a partial wave analysis of the decay J/ψ→γηη′ is performed. An isoscalar state with exotic quantum numbers JPC=1−+, denoted as η1(1855), has been observed for the first time with statistical significance larger than 19σ. Its mass and width are measured to be (1855±9+6−1)~MeV/c2 and (188±18+3−8)~MeV, respectively. The product branching fraction B(J/ψ→γη1(1855)→γηη′) is measured to be (2.70±0.41+0.16−0.35)×10−6. The first uncertainties are statistical and the second are systematic. In addition, an upper limit on the branching ratio B(f0(1710)→ηη′)/B(f0(1710)→ππ) is determined to be 1.61×10−3 at 90\% confidence level, which lends support to the hypothesis that the f0(1710) has a large glueball component.
Analyzing (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector at the BEPCII collider, the ψ(3686)→ωK0SK0S decay is observed for the first time. The branching fraction for this decay is determined to be Bψ(3686)→ωK0SK0S=(7.04±0.39±0.36)×10−5, where the first uncertainty is statistical and the second is systematic.
Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.