Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising ...strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment.
To eliminate chronic hepatitis C virus (HCV) infection by 2030, 90% of those infected must be diagnosed and 80% treated. In Switzerland, >40% of the estimated 32,000 infected people are still ...undiagnosed. In the canton of St Gallen, HCV prevalence and cascade of care have only been studied in the centralised opioid agonist therapy (OAT) setting (institutions), although about 80% of OAT patients are treated decentrally (general practitioner GP or pharmacy).
To describe HCV prevalence and cascade of care among patients in the decentralised OAT programme of the canton of St Gallen, Switzerland, and compare it to contemporaneous data from the centralised setting.
For each patient receiving his/her OAT from a GP or pharmacy on 1 April 2021, the cantonal medical office sent a questionnaire to the prescribing GP. Patient characteristics, HCV antibody (Ab)/RNA screening uptake, HCV Ab/RNA prevalence and HCV treatment uptake were obtained and compared to those of patients of the Medizinisch-soziale Hilfsstelle 1 in St Gallen (centralised setting).
Of the 563 OAT patients under the care of 127 GPs, 107 patients from 41 GPs could be analysed (median age: 48 years IQR: 40-56; ongoing intravenous drug use: 25%; OAT provider: 66% GP, 34% pharmacy). HCV Ab screening uptake was 68% (73/107) with an HCV Ab prevalence of 68% (50/73) among those tested. Of the HCV Ab-positive patients, 84% (42/50) were HCV RNA-tested, among whom 57% (24/42) were viraemic. HCV treatment uptake was 83% (20/24), with 95% (19/20) achieving a sustained virological response. Non-uptake of HCV screening and treatment tended to be higher among patients receiving OAT at the pharmacy vs at the GP's office: 37% vs 26% (p = 0.245) for screening and 30% vs 7% (p = 0.139) for treatment. The proportion never HCV Ab-tested and the proportion of HCV Ab-positives never HCV RNA-tested was significantly higher in the decentralised compared to the centralised setting: 32% vs 3% (p <0.001) never Ab-tested and 16% vs 0% (p = 0.002) never RNA-tested. In contrast, HCV treatment uptake (83% vs 78%), sustained virological response rate (95% vs 100%) and residual HCV RNA prevalence among the HCV Ab-positive (12% vs 14%) were comparable for both settings.
In the decentralised OAT setting of the canton of St Gallen, HCV Ab prevalence is high. Since HCV Ab and RNA screening uptake are markedly lower than in the centralised setting, potentially >40% of patients with chronic HCV are not diagnosed yet. HCV screening in the decentralised setting needs improvement, e.g. by increasing awareness and simplifying testing. High HCV treatment uptake and cure rates are possible in centralised and decentralised settings.
This paper argues that effective cross-border cooperation (CBC) networks closely interrelate with the building of 'trust' between actors. The aim is to contribute to the CBC literature by ...investigating the different forms of trust, their spatial attributes and impact on actor relations in the context of the Finnish-Russian European Neighbourhood Instrument (ENI) of CBC. The paper applies a specific spatial approach by identifying the territorial and relational aspects of four different forms of trust: rational-personal decisions, social-cultural understanding, general-personal interactions and the historical-institutional environment. The analysis, based on policy documents and semi-structured interviews with relevant Finnish ENI CBC actors, shows that the study of transnational cooperation networks benefits from a conceptualization of trust recognizing its spatial characteristics. The study concludes that sub-national actors are key agents in the formation and maintenance of trust. These actors negotiate with socio-cultural differences through the development of personal relationships which increase social capital in the actor-network. However, the cooperation network is vulnerable towards geopolitical circumstances affecting foreign relations. The paper demonstrates that Finnish ENI CBC actors are operating in a transnational network in which their activities are challenged by territorial constraints such as national border-crossing regulations.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mixing alcohol (ethanol) with caffeinated beverages continues to be a common and risky practice. Energy drinks are one type of caffeinated beverage that may be especially problematic when used as ...mixers, due to their relatively high caffeine content in combination with their highly sweetened flavor profile. The present study used a mouse model of limited-access drinking and lickometer circuitry to examine the effects of an energy drink anid its caffeine content on ethanol consumption. Predictably, the highly sweetened energy drink significantly increased ethanol intake compared to a plain ethanol solution (6.34 ± 0.2 vs. 5.01 ± 0.3 g/kg; Cohen's d = 1.79). Interestingly, adulterating a plain ethanol solution with the same concentration of caffeine (without sweetener) found in the energy drink also increased ethanol intake (5.47 ± 0.3 vs. 4.11 ± 0.3 g/kg; Cohen's d = 1.4). A lower concentration of caffeine was without effect on ethanol drinking. Interestingly, plain caffeine solutions at both tested concentrations provoked high numbers of bottle contacts, indicating that the mice found the solution palatable. These findings suggest that altering the bitterness profile of an ethanol solution with the addition of caffeine can increase intake in a similar manner as sweetening the solution. Further, the findings underscore the importance of taste in motivating ethanol consumption and the potential role that caffeine can have in this process.
•Mixing ethanol (20%) with an energy drink increased ethanol consumption compared to a plain ethanol solution.•Adulterating 20% ethanol with 1.5 mM caffeine (the same concentration as the energy drink) increased ethanol intake.•A smaller concentration of caffeine (0.375 mM) added to ethanol did not change ethanol intake.
In which chronological, spatial, and social contexts is gender a relevant social category that is noticeable in the archaeological material? How can transformations in social gender relations and ...identity be recognized archaeologically? Is the identity of prehistoric people defined by gender? If so, what is the accompanying cultural context? What about gender equality among the scientists working in archaeology? In what degree are research teams, as well as their scientific approaches, biased today? These and other burning questions are intensively discussed in this volume, which comprises 25 contributions presented at the international workshop ‘Gender Transformations in Prehistoric and Archaic Societies’, organised by the Collaborative Research Centre 1266 of Kiel University funded by the German Research Foundation (DFG). The workshop offered a platform to discuss a broad range of approaches on the inter-dependencies between gender relations and socio-environmental transformation processes. Beyond a focus on the archaeology of women, gender archaeology offers a variety of possibilities to reconstruct the contribution of social groups differentiated e.g. by age, gender, and activities related to cultural transformation, based on the archaeological material. Thus, this volume includes papers dealing with different socio-economic units, from south-western Europe to Central Asia, between 15,000 and 1 BCE, paying particular attention to the scale of social reach. Since gender archaeology, and in particular feminist archaeology, also addresses the issue of scientific objectivity or bias, parts of this volume are dedicated to equal opportunity matters in archaeological academia across the globe. This is realised by bringing together feminist and female experiences from a range of countries, each with its own specific individual, cultural, and social perspectives and traditions. The papers are organised along three central topics: ‘Gendering fieldwork’, ‘Tracing gender transformations’, and ‘Gendering and shaping the environment’. By gendering the archaeological discussion on transformation processes, the contributions aim to more firmly embed gender-sensitive research in the archaeological agenda, not just in Europe, but world-wide.
Abstract
Aims
Pulmonary vein isolation (PVI) using radiofrequency ablation (RFA) in patients with paroxysmal atrial fibrillation (PAF) is effective but hampered by pulmonary vein reconnection due to ...insufficient ablation lesions. High-power delivery over a short period of time (HPSD) in RFA is stated to create more efficient lesions. The aim of this study was to compare intraprocedural safety and outcome of HPSD ablation to conventional power settings in patients undergoing PVI for PAF.
Methods and results
We included 197 patients with PAF that were scheduled for PVI. An ablation protocol with 70 W and a duration cut-off of 7 s at the anterior left atrium (LA) and 5 s at the posterior LA (HPSD group; n = 97) was compared to a conventional power protocol with 30–40 W for 20–40 s (standard group; n = 100) in terms of periprocedural complications and a 1-year outcome. The HPSD group showed significantly less arrhythmia recurrence during 1-year follow-up with 83.1% of patients free from atrial fibrillation compared to 65.1% in the standard group (P < 0.013). No pericardial tamponade, periprocedural thromboembolic complications, or atrio-oesophageal fistula occurred in either group. Mean radiofrequency time (12.4 ± 3.4 min vs. 35.6 ± 12.1 min) and procedural time (89.5 ± 23.9 min vs. 111.15 ± 27.9 min) were significantly shorter in the HPSD group compared to the standard group (both P < 0.001).
Conclusion
High-power short-duration ablation demonstrated a comparable safety profile to conventional ablation. High-power short-duration ablation using 70 W for 5–7 s leads to significantly less arrhythmia recurrences after 1 year. Radiofrequency and procedural time were significantly shortened.
Summary
The Siberian Laptev Sea shelf contains submarine permafrost, which was formed by flooding of terrestrial permafrost with ocean water during the Holocene sea level rise. This flooding resulted ...in a warming of the permafrost to temperatures close below 0°C. The impact of these environmental changes on methanogenic communities and carbon dynamics in the permafrost was studied in a submarine permafrost core of the Siberian Laptev Sea shelf. Total organic carbon (TOC) content varied between 0.03% and 8.7% with highest values between 53 and 62 m depth below sea floor. In the same depth, maximum methane concentrations (284 nmol CH4 g−1) and lowest carbon isotope values of methane (−72.2‰ VPDB) were measured, latter indicating microbial formation of methane under in situ conditions. The archaeal community structure was assessed by a nested polymerase chain reaction (PCR) amplification for DGGE, followed by sequencing of reamplified bands. Submarine permafrost samples showed a different archaeal community than the nearby terrestrial permafrost. Samples with high methane concentrations were dominated by sequences affiliated rather to the methylotrophic genera Methanosarcina and Methanococcoides as well as to uncultured archaea. The presented results give the first insights into the archaeal community in submarine permafrost and the first evidence for their activity at in situ conditions.
Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic ...dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (
H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/Glu
GSCs were found to be resistant to glutamine deprivation, whereas Gln/Glu
GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To ...overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100%
-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling.
Infrastructure development in Canada's northern regions remains a challenge. Although scholars and policy-makers recognize the significant socio-economic potential of northern infrastructure, the ...prevailing piecemeal approach does not respond to many of the challenges faced by Indigenous communities. A pan-Canadian approach, such as a Northern Corridor, can circumvent some of the disadvantages stemming from fractured and uncoordinated initiatives but it still underlies the diverse environmental and socio-economic conditions across the Canadian North. The Nordicity index, originally developed by Hamelin, reflects northern Canada's diversity and has been applied as a public policy tool, e.g. for determining northern living allowances or adapted for transportation development. However, these indices are spatio-temporally fixed which means they do not recognize changing spatial patterns of northern mobility. Thus, this paper argues that northern infrastructure development should be informed by Indigenous spatial practices of mobility. To this aim, the paper investigates the role of Nordicity in Canadian policy-making and analyses how northern Indigenous spatial practices of mobility have transformed throughout the last century. The Nordicity index recognizes the environmental and socio-economic conditions across Canada's diverse northern regions but it should be complemented with an analysis of the spatial practices of northern Indigenous Peoples to inform future infrastructure development.
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