Drug resistance in pancreatic cancer: Impact of altered energy metabolism

Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer

Rationale immunhämatologische Diagnostik und Komplikationen der Hämotherapie bei anti-erythrozytär autoimmunisierten Patienten:Eine statistische Auswertung der Hämotherapiedaten des Universitätsklinikums Münster der Jahre 2001-2003

Anti-erythrozytär autoimmunisierte Patienten sind an einem Klinikum der Maximalversorgung häufig hämotherapeutisch zu betreuen. Wir zeigen, dass (1) das Risiko der Alloimmunisierung gegenüber erythrozytären Antigenen im untersuchten Kollektiv bisher unterschätzt wurde, (2) Alloimmunisierung einen Indikator für die Notwendigkeit der Hämotherapie darstellt, (3) die Wahrscheinlichkeit, klinisch bedeutende Transfusionsreaktionen zu erleiden, bei autoimmunisierten Patienten im Vergleich zum nicht selektionierten Patientenkollektiv erhöht ist, (4) die transfusions-assoziierte Autoimmunisierung eine bedeutende Komplikation der Hämotherapie ist und (5) Patienten mit einer Kombination von anti-erythrozytären Wärme- und Kälteautoantikörpern ein ganz eigenes Kollektiv darstellen, in dem sowohl die prä-transfusionelle Diagnostik als auch die Hämotherapie beiden Antikörpertypen gerecht werden muss

Monte-Carlo Simulation Based on Patient-Individual Distributions for Supporting Intensive Care Occupancy Management

Managing Intensive Care Units (ICUs) in hospitals is a highly challenging endeavor. In particular, decisions such as admitting elective patients and discharging patients from the ICU have to be taken under a high level of uncertainty since the occupancy of ICUs does not only depend on these decisions but also on unknown parameters such emergency patient arrivals and lengths of stay of the patients in the ICU. In this paper, we develop a framework for supporting ICU occupation management by quantifying the impact of admission and discharge decisions on the probability of reaching critical ICU occupancy levels in a given planning horizon. A key component of this framework is the use of data-driven approaches for obtaining probability distributions for the parameters affected by uncertainty. In particular, we use standardized treatment and patient health state data to create patient-specific length-of-stay distributions with a Machine Learning approach. These patient-individual distributions are then validated and/or adjusted by medical experts. The validated distributions form the input to a Monte-Carlo Simulation that is used to approximate the probability distributions of the daily ICU occupancy levels resulting from ICU admission and discharge decisions. We experimentally evaluate our framework in a counterfactual simulation based on one year of historical data from 2019 from a medium-sized ICU in a German hospital. In that evaluation, we use a simple ICU management policy based on the probabilistic occupancy forecasts aiming at reducing the risk of running out of ICU capacity. The results show that following this policy would have avoided hitting critical occupancy levels by around 70% and would have had a smoothing effect on ICU occupancy levels

FitTetra 2.0-improved genotype calling for tetraploids with multiple population and parental data support

BackgroundGenetic studies in tetraploids are lagging behind in comparison with studies of diploids as the complex genetics of tetraploids require much more elaborated computational methodologies. Recent advancements in development of molecular techniques and computational tools facilitate new methods for automated, high-throughput genotype calling in tetraploid species. We report on the upgrade of the widely-used fitTetra software aiming to improve its accuracy, which to date is hampered by technical artefacts in the data.ResultsOur upgrade of the fitTetra package is designed for a more accurate modelling of complex collections of samples. The package fits a mixture model where some parameters of the model are estimated separately for each sub-collection. When a full-sib family is analyzed, we use parental genotypes to predict the expected segregation in terms of allele dosages in the offspring. More accurate modelling and use of parental data increases the accuracy of dosage calling. We tested the package on data obtained with an Affymetrix Axiom 60k array and compared its performance with the original version and the recently published ClusterCall tool, showing that at least 20% more SNPs could be called with our updated.ConclusionOur updated software package shows clearly improved performance in genotype calling accuracy. Estimation of mixing proportions of the underlying dosage distributions is separated for full-sib families (where mixture proportions can be estimated from the parental dosages and inheritance model) and unstructured populations (where they are based on the assumption of Hardy-Weinberg equilibrium). Additionally, as the distributions of signal ratios of the dosage classes can be assumed to be the same for all populations, including parental data for some subpopulations helps to improve fitting other populations as well. The R package fitTetra 2.0 is freely available under the GNU Public License as Additional file with this article.</p

Development and validation of an alternative parameter for quantification of signals emitted by fluorescently labelled bacteria in microscopic images

In this study, an alternative parameter for quantifying the signals of fluorescently labelled bacteria (e.g. propidium iodide, Cyanine 3, etc.) in microscopic images was investigated. Three common parameters (mean grey value (MGV), mean grey value which is corrected for the background (MGVcwB) and the signal to background ratio (SBR) per bacterial cell) are used as reference parameters. As an alternative, the coefficient of variation (CV) is defined as the ratio of the logarithm of the standard deviation and the logarithm of the mean grey value of a bacterial cell in a microscopic image. The actual fluorescence value was safeguarded by measuring commercially available fluorescence latex microspheres at regular time intervals within our study. The precision and the correlation of the respective values of MGV, MGVcwB, SBR and CV taken from identical images were measured and subsequently normalized in order to enhance the inter-parameter comparability. The average precision of CV was the highest (89% +/- 14) with decreasing numbers for MGVcwB, SBR, and MGV (78% +/- 25, 71% +/- 32, and, 52% +/- 22, respectively). Changes in operational parameters, e.g., microscope settings, protocol steps, etc., yielded good results for the CV but less precise results for MGV, MGVcwB, and SBR in the analyses of identical images. In conclusion, using the alternative parameter CV, changes in the composition of microbial ecosystems may thus be investigated at the highest precision level

Capture of CO2 from medium-scale emission sources

AbstractUntil now, the work done on capture and storage of CO2 has mainly focused on capture and storage of CO2 from fossil fuel fired power plants and other large point sources. Although medium-scale sources of CO2 account for a smaller proportion, their contribution to global CO2 emissions is still substantial and in the range of 10–15% of total global energy related CO2 emissions. The study identifies possible combinations of capture technologies and medium scale combustion installations and assesses these in terms of potential and costs. Although medium-scale capture of CO2 is expected to be more expensive than large-scale capture, it may nevertheless be competitive with alternative methods of abating CO2 from medium-scale sources in some circumstances

Opportunities for CO2 capture through oxygen conducting membranes at medium-scale oxyfuel coal boilers

AbstractEcofys and ECN conducted a study commissioned by the IEA Greenhouse Gas R&D Programme to identify the most suitable combinations of medium-scale CO2 sources (1–100 MWth) and capture technologies, with respect to potential and costs (see parallel paper by Hendriks et al.). An industrial coal-fired Circulating Fluidized Bed (CFB) boiler with oxyfuel combustion and Oxygen Conducting Membranes (OCM) appeared to be an economically attractive combination to capture CO2. This paper describes the principle and economic evaluation of this combination in comparison with a reference coal boiler without CO2 capture, as well as a coal boiler with CO2 capture based on amine scrubbing

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/ MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing aYnities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = ¡0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding aYnity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deWcient chow. Dietary folate depletion signiWcantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor eVects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deWcient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic eVects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding aYnity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic eVect of antifolates may be further improved

Culture (and Religion) in Constitutional Adjudication

The faculty of law of the Potchefstroom University for Christian Higher Education in corroboration with the Konrad-Adenauer-Stifttung embarked on a study on Politics, Socio-Economic Issues and Culture in Constitutional Adjudication. The aim of the project is twofold. The first aim is to analyse the influence of political, socio-economic and cultural considerations on the constitutional court’s interpretation and application of the Bill of Rights. The second aim is to develop practical guidelines (based on the findings during the analysing process) for South African courts confronted with issues of a political, socio-economic and cultural nature. This article is concerned with initiating discussions of the decisions of the constitutional court with regard to cultural and religious rights. Before we can explore the role of political, socio-economic and cultural (and religious) rights in the decisions of the constitutional court it is important to discuss a few preliminary issues. In this article the meaning of culture and religion within the South African context receives some attention. Secondly, some preliminary comments regarding constitutional protection of culturally and religiously based rights will be made. We are well aware that this is a daunting task, not only in view of the seemingly abysmal gap between the applicable constitutional rights and values enshrined in the 1996 Constitution that, in some instances over centuries, brought about customs and practices within “traditional” communities which, seemingly, infringe on certain constitutional values and rights. &nbsp; &nbsp;&nbsp;&nbsp

Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia

We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL