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This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.
BACKGROUND: Evaluation of latest generation automated attenuation-based tube potential selection (ATPS) impact on image quality and radiation dose in contrast-enhanced chest-abdomen-pelvis computed tomography examinations for gynaecologic cancer staging.
METHODS: This IRB approved single-centre, observer-blinded retrospective study with a waiver for informed consent included a total of 100 patients with contrast-enhanced chest-abdomen-pelvis CT for gynaecologic cancer staging. All patients were examined with activated ATPS for adaption of tube voltage to body habitus. 50 patients were scanned on a third-generation dual-source CT (DSCT), and another 50 patients on a second-generation DSCT. Predefined image quality setting remained stable between both groups at 120 kV and a current of 210 Reference mAs. Subjective image quality assessment was performed by two blinded readers independently. Attenuation and image noise were measured in several anatomic structures. Signal-to-noise ratio (SNR) was calculated. For the evaluation of radiation exposure, CT dose index (CTDIvol) values were compared.
RESULTS: Diagnostic image quality was obtained in all patients. The median CTDIvol (6.1 mGy, range 3.9-22 mGy) was 40 % lower when using the algorithm compared with the previous ATCM protocol (median 10.2 mGy · cm, range 5.8-22.8 mGy). A reduction in potential to 90 kV occurred in 19 cases, a reduction to 100 kV in 23 patients and a reduction to 110 kV in 3 patients of our experimental cohort. These patients received significantly lower radiation exposure compared to the former used protocol.
CONCLUSION: Latest generation automated ATPS on third-generation DSCT provides good diagnostic image quality in chest-abdomen-pelvis CT while average radiation dose is reduced by 40 % compared to former ATPS protocol on second-generation DSCT.
Paul Klees 'Angelus Novus' setzt bei Benjamin eine Reflexion in Gang, die unter der Ziffer 9 in seiner Schrift "Über den Begriff der Geschichte" (1940) ihre letzte sprachliche Gestalt findet. Das Denkbild setzt sich zur Zeichnung abseits 'objektiver' Beschreibungen und gängiger Bildkritik ins Verhältnis. Benjamins methodologisches Plädoyer für die Verwandlung von "Dinge[n] und Werke[n] in erregende Schrift" führt zu einer Betrachtungsweise, der es gelingt, das materielle Bild in sinnlicher Präsenz zur Darstellung zu bringen, und zwar wiederum als - dialektisches - Bild, welches den Augenblick, in dem die aktuelle Lektüre mit dem Abstand der Zeit zusammentritt, stillstellt. Diese Kunst der Darstellung soll hier Anlass dafür sein, das Verhältnis von Benjamins Sprache zur Malerei als einem zweiten Medium zu beleuchten.
Im Folgenden werden einige Facetten dieses weiten Feldes [der Synästhesie] herausgegriffen, nämlich das der Farblichtmusik und der Verbindung von Ton und Bild zwischen 1920 und 1930 mittels apparativer Verschaltungen. Hierzu werden zwei technische Anordnungen gegenübergestellt, die eine Ton-Bild-Wandlung auf eine Weise vornahmen, die radikaler als die damals weit verbreiteten Lichtorgeln vorging, indem sie nicht nur metaphorisch mit der gleichschwingenden Kraft von Tönen und Bildern agierten, sondern diese zum Gegenstand medientechnischer Anordnungen machten. Die eine dieser Apparaturen wurde im Kontext der Kunst entwickelt und stammt von Raoul Hausmann, während die andere von dem Fernmeldetechniker Fritz Winckel realisiert wurde. Indem Hausmann und Winckel die Zuordnung von Tönen und Bildern nicht assoziativ realisierten wie die meisten Lichtorgeln dieser Zeit, sondern die Ton- und Bildquellen mit analoger Technik direkt verschalteten, riefen sie umso mehr den Vergleich mit der durch Menschen wahrgenommenen Synästhesie auf, weshalb zu Beginn auf diese etwas breiter eingegangen werden muss. Hier ist zu fragen, was geschieht, wenn Synästhesie zu einem künstlerischen Konzept wird und welche Rhetoriken von Kunstschaffen in den 1920er Jahren daran gebunden waren. Es soll deutlich werden, dass die vom Menschen wahrgenommene Synästhesie in ihrer körperlichen Grundlage sowie in ihrem ästhetischen Empfinden nicht mehr als eine Metapher für ihr medientechnisches Pendant sein konnte. Synästhetische Wahrnehmung und verschaltete Medien bringen jeweils ihre eigenen ästhetischen Reiche hervor. Andererseits boten die unscharfen und vielschichtigen Konzepte der Synästhesie zahlreiche Anregungen für Künstler, schufen Raum für eine Synthese der Künste und waren der Anstoß für neue künstlerische Ausdrucksformen mittels Medientechnik und damit eine frühe Form der Medienkunst.
Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.
FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.
A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.
Background: Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment.
Methods: To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach.
Discussion: Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care.
Systematic review registration: PROSPERO: CRD42016037932.
To accommodate the growth of the software industry, programming languages are getting increasingly easy to use. The latest trend in the simplification of the software development process is the usage of visual programming environments. To make visual programming effective, the graph-like representation of the source code must be clearly arranged. This thesis details some of the difficulties in automatic layout generation and proposes an interface as well as two different implementations of automatic layout generators to integrate into the VWorkflows visual programming framework.
Polo-like kinase 1 inhibition sensitizes neuroblastoma cells for vinca alkaloid-induced apoptosis
(2015)
High polo-like kinase 1 (PLK1) expression has been linked to poor outcome in neuroblastoma (NB), indicating that it represents a relevant therapeutic target in this malignancy. Here, we identify a synergistic induction of apoptosis by the PLK1 inhibitor BI 2536 and vinca alkaloids in NB cells. Synergistic drug interaction of BI 2536 together with vincristine (VCR), vinblastine (VBL) or vinorelbine (VNR) is confirmed by calculation of combination index (CI). Also, BI 2536 and VCR act in concert to reduce long-term clonogenic survival. Importantly, BI 2536 significantly enhances the antitumor activity of VCR in an in vivo model of NB. Mechanistically, BI 2536/VCR co-treatment triggers prolonged mitotic arrest, which is necessary for BI 2536/VCR-mediated apoptosis, since pharmacological inhibition of mitotic arrest by the CDK1 inhibitor RO-3306 significantly reduces cell death. Prolonged mitotic arrest leads to phosphorylation-mediated inactivation of BCL-2 and BCL-XL as well as downregulation of MCL-1, since inhibition of mitotic arrest by RO-3306 also prevents phosphorylation of BCL-2 and BCL-XL and MCL-1 downregulation. This inactivation of antiapoptotic BCL-2 proteins promotes activation of BAX and BAK, cleavage of caspase-9 and -3 and caspase-dependent apoptosis. Engagement of the mitochondrial pathway of apoptosis is critically required for BI 2536/VCR-induced apoptosis, since ectopic expression of a non-degradable MCL-1 phospho-mutant, BCL-2 overexpression or BAK knockdown significantly reduce BI 2536/VCR-mediated apoptosis. Thus, PLK1 inhibitors may open new perspectives for chemosensitization of NB.
Chromosomal translocations of the human mixed-lineage leukemia (MLL) gene have been analyzed for more than 20 yr at the molecular level. So far, we have collected about 80 direct MLL fusions (MLL-X alleles) and about 120 reciprocal MLL fusions (X-MLL alleles). The reason for the higher amount of reciprocal MLL fusions is that the excess is caused by 3-way translocations with known direct fusion partners. This review is aiming to propose a solution for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL). This review is aiming to explain the molecular consequences of MLL translocations, and secondly, the contribution of the different fusion partners. A new hypothesis will be posed that can be used for future research, aiming to find new avenues for the treatment of this particular leukemia entity.