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The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
During January/February 2013, at the High Alpine Research Station Jungfraujoch a measurement campaign was carried out, which was centered on atmospheric ice-nucleating particles (INP) and ice particle residuals (IPR). Three different techniques for separation of INP and IPR from the non-ice-active particles are compared. The Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI) sample ice particles from mixed phase clouds and allow for the analysis of the residuals. The combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Counterflow Virtual Impactor (IN-PCVI) provides ice-activating conditions to aerosol particles and extracts the activated INP for analysis.Collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine size, chemical composition and mixing state. All INP/IPR-separating techniques had considerable abundances (median 20 – 70 %) of instrumental contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH+IN-PCVI: steel particles). Also, potential sampling artifacts (e.g., pure soluble material) occurred with a median abundance of < 20 %. While these could be explained as IPR by ice break-up, for INP their IN-ability pathway is less clear. After removal of the contamination artifacts, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Soot was a minor contributor. Lead was detected in less than 10 % of the particles, of which the majority were internal mixtures with other particle types. Sea-salt and sulfates were identified by all three methods as INP/IPR. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also separated many submicron IPR. As strictly parallel sampling could not be performed, a part of the discrepancies between the different techniques may result from variations in meteorological conditions and subsequent INP/IPR composition. The observed differences in the particle group abundances as well as in the mixing state of INP/IPR express the need for further studies to better understand the influence of the separating techniques on the INP/IPR chemical
composition.
In the present work, three different techniques are used to separate ice-nucleating particles (INP) and ice particle residuals (IPR) from non-ice-active particles: the Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI), which sample ice particles from mixed phase clouds and allow for the analysis of the residuals, as well as the combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Virtual Impactor (IN-PCVI), which provides ice-activating conditions to aerosol particles and extracts the activated ones for analysis. The collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine their size, chemical composition and mixing state. Samples were taken during January/February 2013 at the High Alpine Research Station Jungfraujoch. All INP/IPR-separating techniques had considerable abundances (median 20–70%) of contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH + IN-PCVI: steel particles). Also, potential measurement artifacts (soluble material) occurred (median abundance < 20%). After removal of the contamination particles, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Minor types include soot and Pb-bearing particles. Sea-salt and sulfates were identified by all three methods as INP/IPR. Lead was identified in less than 10% of the INP/IPR. It was mainly present as an internal mixture with other particle types, but also external lead-rich particles were found. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also sampled many submicron particles. Probably owing to the different meteorological conditions, the INP/IPR composition was highly variable on a sample to sample basis. Thus, some part of the discrepancies between the different techniques may result from the (unavoidable) non-parallel sampling. The observed differences of the particles group abundances as well as the mixing state of INP/IPR point to the need of further studies to better understand the influence of the separating techniques on the INP/IPR chemical composition.
Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis
(2020)
Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
Background: Obesity and depression are both associated with changes in sleep/wake regulation, with potential implications for individualized treatment especially in comorbid individuals suffering from both. However, the associations between obesity, depression, and subjective, questionnaire-based and objective, EEG-based measurements of sleepiness used to assess disturbed sleep/wake regulation in clinical practice are not well known.
Objectives: The study investigates associations between sleep/wake regulation measures based on self-reported subjective questionnaires and EEG-derived measurements of sleep/wake regulation patterns with depression and obesity and how/whether depression and/or obesity affect associations between such self-reported subjective questionnaires and EEG-derived measurements.
Methods: Healthy controls (HC, NHC = 66), normal-weighted depressed (DEP, NDEP = 16), non-depressed obese (OB, NOB = 68), and obese depressed patients (OBDEP, NOBDEP = 43) were included from the OBDEP (Obesity and Depression, University Leipzig, Germany) study. All subjects completed standardized questionnaires related to daytime sleepiness (ESS), sleep quality and sleep duration once as well as questionnaires related to situational sleepiness (KSS, SSS, VAS) before and after a 20 min resting state EEG in eyes-closed condition. EEG-based measurements of objective sleepiness were extracted by the VIGALL algorithm. Associations of subjective sleepiness with objective sleepiness and moderating effects of obesity, depression, and additional confounders were investigated by correlation analyses and regression analyses.
Results: Depressed and non-depressed subgroups differed significantly in most subjective sleepiness measures, while obese and non-obese subgroups only differed significantly in few. Objective sleepiness measures did not differ significantly between the subgroups. Moderating effects of obesity and/or depression on the associations between subjective and objective measures of sleepiness were rarely significant, but associations between subjective and objective measures of sleepiness in the depressed subgroup were systematically weaker when patients comorbidly suffered from obesity than when they did not.
Conclusion: This study provides some evidence that both depression and obesity can affect the association between objective and subjective sleepiness. If confirmed, this insight may have implications for individualized diagnosis and treatment approaches in comorbid depression and obesity.
Post‐traumatic stress disorder (PTSD) is associated with a hypersensitivity to potential threat. This hypersensitivity manifests through differential patterns of emotional information processing and has been demonstrated in behavioral and neurophysiological experimental paradigms. However, the majority of research has been focused on adult patients with PTSD. To examine possible differences in underlying neurophysiological patterns for adolescent patients with PTSD after childhood sexual and/or physical abuse (CSA/CPA), ERP correlates of emotional word processing in 38 healthy participants and 40 adolescent participants with PTSD after experiencing CSA/CPA were studied. The experimental paradigm consisted of a passive reading task with neutral, positive (e.g., paradise), physically threatening (e.g., torment), and socially threatening (i.e., swearing, e.g., son of a bitch) words. A modulation of P3 amplitudes by emotional valence was found, with positive words inducing less elevated amplitudes over both groups. Interestingly, in later processing, the PTSD group showed augmented early late positive potential (LPP) amplitudes for socially threatening stimuli, while there were no modulations within the healthy control group. Also, region‐specific emotional modulations for anterior and posterior electrode clusters were found. For the anterior LPP, highest activations have been found for positive words, while socially and physically threatening words led to strongest modulations in the posterior LPP cluster. There were no modulations by group or emotional valence at the P1 and EPN stage. The findings suggest an enhanced conscious processing of socially threatening words in adolescent patients with PTSD after CSA/CPA, pointing to the importance of a disjoined examination of threat words in emotional processing research.
Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib’s safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit–risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib’s efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.
Objective: Skin and soft tissue infections (SSTI) are a commonly known entity of diseases associated with difficult treatment procedures. The current gold standard when there is a rapidly progressing infection of soft tissues with a risk of sepsis is radical surgical debridement accompanied by systemic antibiotic therapy. In clinical settings, local antibiotics alone or formulated within carrier material are commonly used alongside this therapy regimen. One possibility of local antibiotic application is the fixation of colistin with fibrin glue spray. It is not yet sufficiently researched how the local antibiotic concentrations remain as high as possible over time.
Methods: We conducted an animal study including 29 male Wistar rats inducing sterile back sores reaching the muscle fascia. We sprayed only colistin, simultaneously or consecutively, with fibrin glue in different groups in order to measure the tissue concentration of the antibiotic applied locally.
Results: After liquid chromatography and quadrupole mass spectrometry analysis, it could be demonstrated that in comparison to the colistin group, tissue concentrations of colistin stayed significantly higher in the wound tissue when it was fixed with fibrin glue. This was observed in both groups, the simultaneous as well as in the consecutively fibrin glue sprayed groups after colistin application.
Conclusion: The fixation of colistin with the fibrin-glue-spray technique as a carrier for local antibiotic therapy is an easy and inexpensive method and shows promising potential for the treatment of SSTI.