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TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca2+ signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC50s of 3–5 µM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 µM). Norgestimate blocked TRPC-mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC50s ranging from 6 to 18 µM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy.
Dieser größte mitteleuropäische Blauling besitzt eine Vorderflügellange bis 2,2 cm. Die Flügeloberseite ist leuchtend blau mit breiter schwarzbrauner Randbinde, die Fransen sind weiß. Auf den Vorderflügeln ist die Postdiskalreihe schwarzer, länglicher Flecke meist gut ausgebildet, aber sehr veränderlich. Auch auf den Hinterflügeln ist die Postdiskalreihe sehr veränderlich, die einzelnen Flecken sind verhältnismäßig klein. Die Unterseite der Flügel ist grau bis graubraun mit gut entwickelten schwarzen, weiß geringten Flecken, die Fransen sind gescheckt. Auf den Hinterflügeln ist eine meist kräftige, ausgedehnte blaugrüne Basalbestäubung.
Der Botanische Arbeitskreis Nordharz e.V. 1) führte vom 10.-11.8.1996 eine Kartierungsexkursion in das Gebiet um Sangerhausen durch2). Zum Zeitpunkt der Exkursionsvorbereitung war kein Kartierer im Rahmen der laufenden Sachsen-Anhalt-Kartierung in diesem Meßtischblatt tätig. Ziel war daher die Erfassung des Grundbestandes in den vier Quadranten. Die erste Augusthälfte wurde gewählt, um mit den Sommer- und Spätsommeraspekten ein möglichst breites Artenspektrum erschließen zu können. Allein der Frühjahrsaspekt blieb damit unberücksichtigt. Im nachfolgenden wird über bemerkenswerte Pflanzenfunde berichtet, sowohl Neufunde gegenüber dem Kenntnisstand, der die Grundlage für den Florenatlas der neuen Bundesländer bildete3), als auch Bestätigungen seltener und überregional bedeutsamer Artenvorkommen. Alle Funde beziehen sich, wenn nicht anders angegeben, auf das Meßtischblatt 4533, so daß den Fundorten nur die Quadrantennummer vorangestellt wird.
Simple Summary: The incidence of brain metastases from breast cancer is increasing and the treatment is still a major challenge. Several scores have been developed in order to estimate the prognosis of patients with brain metastases by objective criteria. Here, we validated all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer patients with brain metastases in the Brain Metastases in the German Breast Cancer (BMBC) registry. Although all three available GPA-scores were associated with OS, they all show limitations mainly in predicting short-term (below 3 months) survival but also in long-term (above 12 months) survival. We discuss the test performances of all scores in our work and provide evidence how physicians should use them as a tool to select patients for different treatment options.
Abstract: Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.
Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases
(2020)
Simple Summary: The prognosis for patients with breast cancer that has spread to the brain is poor, and survival for these women hasn’t improved over the last few decades. We do not currently test for asymptomatic brain metastases in breast cancer patients, although this does happen in some other types of cancer. In this study we wanted to find out more about breast cancer that has spread to the brain and in particular to see whether there might be any advantage to spotting brain metastases before the development of neurological symptoms. Overall, our results suggest that women could be better off if their brain metastases are diagnosed before they begin to cause symptoms. We now need to carry out a clinical trial to see what happens if we screen high-risk breast cancer patients for brain metastases. This will verify whether doing so could increase survival, symptom control or quality of life.
Abstract: Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
Plant community biomass production is co-dependent on climatic and edaphic factors that are often covarying and non-independent. Disentangling how these factors act in isolation is challenging, especially along large climatic gradients that can mask soil effects. As anthropogenic pressure increasingly alters local climate and soil resource supply unevenly across landscapes, our ability to predict concurrent changes in plant community processes requires clearer understandings of independent and interactive effects of climate and soil. To address this, we developed a multispecies phytometer (i.e., standardized plant community) for separating key drivers underlying plant productivity across gradients. Phytometers were composed of three globally cosmopolitan herbaceous perennials, Dactylis glomerata, Plantago lanceolata, and Trifolium pratense. In 2017, we grew phytometer communities in 18 sites across a pan-European aridity gradient in local site soils and a standardized substrate and compared biomass production. Standard substrate phytometers succeeded in providing a standardized climate biomass response independent of local soil effects. This allowed us to factor out climate effects in local soil phytometers, establishing that nitrogen availability did not predict biomass production, while phosphorus availability exerted a strong, positive effect independent of climate. Additionally, we identified a negative relationship between biomass production and potassium and magnesium availability. Species-specific biomass responses to the environment in the climate-corrected biomass were asynchronous, demonstrating the importance of species interactions in vegetation responses to global change. Biomass production was co-limited by climatic and soil drivers, with each species experiencing its own unique set of co-limitations. Our study demonstrates the potential of phytometers for disentangling effects of climate and soil on plant biomass production and suggests an increasing role of P limitation in the temperate regions of Europe.
Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol
(2010)
Aims: Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data. Methods and Results: In 25 control subjects, 65 patients with coronary artery disease (CAD; 40 stable CAD, 25 acute coronary syndrome/acute myocardial infarction (ACS)), EPC were quantified using the following approach: Whole blood was incubated with CD45, KDR, and CD34. The ISHAGE sequential strategy was used, and finally, CD45dimCD34+ cells were quantified for KDR. A minimum of 100 CD34+ events were collected. For comparison, CD45+CD34+ and CD45-CD34+ were analysed simultaneously. The number of CD45dimCD34+KDR+ cells only were significantly higher in healthy controls compared to patients with CAD or ACS (p = 0.005 each, p<0.001 for trend). An inverse correlation of CD45dimCD34+KDR+ with disease activity (r = -0.475, p<0.001) was confirmed. Only CD45dimCD34+KDR+ correlated inversely with the number of diseased coronaries (r = -0.344; p<0.005). In a second study, a 4-week de-novo treatment of atorvastatin in stable CAD evoked an increase only of CD45dimCD34+KDR+ EPC (p<0.05). CD45+CD34+KDR+ and CD45-CD34+KDR+ were indifferent between the three groups. Conclusion: Our newly established protocol adopted from the standardised ISHAGE protocol achieved higher accuracy in EPC enumeration confirming previous findings with respect to the correlation of EPC with disease activity and the increase of EPC during statin therapy. The data of this study show the CD45dim fraction to harbour EPC.
Copper perchlorophthalocyanine (CuPcCl16, CuC32N8Cl16, Pigment Green 7) is one of the commercially most important green pigments. The compound is a nanocrystalline fully insoluble powder. Its crystal structure was first addressed by electron diffraction in 1972 [Uyeda et al. (1972). J. Appl. Phys. 43, 5181–5189]. Despite the commercial importance of the compound, the crystal structure remained undetermined until now. Using a special vacuum sublimation technique, micron-sized crystals could be obtained. Three-dimensional electron diffraction (3D ED) data were collected in two ways: (i) in static geometry using a combined stage-tilt/beam-tilt collection scheme and (ii) in continuous rotation mode. Both types of data allowed the crystal structure to be solved by direct methods. The structure was refined kinematically with anisotropic displacement parameters for all atoms. Due to the pronounced crystal mosaicity, a dynamic refinement was not feasible. The unit-cell parameters were verified by Rietveld refinement from powder X-ray diffraction data. The crystal structure was validated by many-body dispersion density functional theory (DFT) calculations. CuPcCl16 crystallizes in the space group C2/m (Z = 2), with the molecules arranged in layers. The structure agrees with that proposed in 1972.
Measurements of the π±, K±, and proton double differential yields emitted from the surface of the 90-cm-long carbon target (T2K replica) were performed for the incoming 31 GeV/c protons with the NA61/SHINE spectrometer at the CERN SPS using data collected during 2010 run. The double differential π± yields were measured with increased precision compared to the previously published NA61/SHINE results, while the K± and proton yields were obtained for the first time. A strategy for dealing with the dependence of the results on the incoming proton beam profile is proposed. The purpose of these measurements is to reduce significantly the (anti)neutrino flux uncertainty in the T2K long-baseline neutrino experiment by constraining the production of (anti)neutrino ancestors coming from the T2K target.
We present measurements of ρ0, ω and K∗0 spectra in π−+ C production interactions at 158 GeV / c and ρ0 spectra at 350 GeV / c using the NA61/SHINE spectrometer at the CERN SPS. Spectra are presented as a function of the Feynman’s variable xF in the range 0<xF<1 and 0<xF<0.5 for 158 and 350 GeV / c respectively. Furthermore, we show comparisons with previous measurements and predictions of several hadronic interaction models. These measurements are essential for a better understanding of hadronic shower development and for improving the modeling of cosmic ray air showers.
his Erratum replaces incorrect plots shown in Fig. 7 with the corrected ones. In the publication, the NA57 [1] ratios of Ξ− and Ξ¯¯¯¯+ to the number of wounded nucleons at ⟨NW⟩=349 by mistake were plotted at the wrong values. The ratios were calculated and plotted by mistake using ⟨NW⟩=249.
The correct normalization does not change the conclusions of the paper. The correctly normalized results are presented in Fig. 7.
The production of Ξ(1321)− and Ξ¯¯¯¯(1321)+ hyperons in inelastic p+p interactions is studied in a fixed target experiment at a beam momentum of 158 GeV/c. Double differential distributions in rapidity y and transverse momentum pT are obtained from a sample of 33M inelastic events. They allow to extrapolate the spectra to full phase space and to determine the mean multiplicity of both Ξ− and Ξ¯¯¯¯+. The rapidity and transverse momentum spectra are compared to transport model predictions. The Ξ− mean multiplicity in inelastic p+p interactions at 158 GeV/c is used to quantify the strangeness enhancement in A+A collisions at the same centre-of-mass energy per nucleon pair.
The physics goal of the strong interaction program of the NA61/SHINE experiment at the CERN Super Proton Synchrotron (SPS) is to study the phase diagram of hadronic matter by a scan of particle production in collisions of nuclei with various sizes at a set of energies covering the SPS energy range. This paper presents differential inclusive spectra of transverse momentum, transverse mass and rapidity of π− mesons produced in central 40Ar+45Sc collisions at beam momenta of 13A, 19A, 30A, 40A, 75A and 150A Ge V /c. Energy and system size dependence of parameters of these distributions – mean transverse mass, the inverse slope parameter of transverse mass spectra, width of the rapidity distribution and mean multiplicity – are presented and discussed. Furthermore, the dependence of the ratio of the mean number of produced pions to the mean number of wounded nucleons on the collision energy was derived. The results are compared to predictions of several models.
A measurement of charged hadron pair correlations in two-dimensional ηφ space is presented. The analysis is based on total 30 million central Be + Be collisions observed in the NA61/SHINE detector at the CERN SPS for incident beam momenta of 19A, 30A, 40A, 75A, and 150A GeV/c. Measurements were carried out for unlike-sign and like-sign charge hadron pairs independently. The C(η, φ) correlation functions were compared with results from a similar analysis on p + p interactions at similar beam momenta per nucleon. General trends of the backto-back correlations are similar in central Be + Be collisions and p + p interactions, but are suppressed in magnitude due to the increased combinatorial background. Predictions from the Epos and UrQMD models are compared to the measurements. Evolution of an enhancement around (η, φ) = (0, 0) with incident energy is observed in central Be + Be collisions. It is not predicted by both models and almost non-existing in proton–proton collisions at the same momentum per nucleon.
Cytokine-induced killer (CIK) cells are an immunotherapeutic approach to combat relapse following allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia or myelodysplastic syndrome (MDS) patients. Prompt and sequential administration of escalating cell doses improves the efficacy of CIK cell therapy without exacerbating graft vs. host disease (GVHD). This study addresses manufacturing-related issues and aimed to develop a time-, personal- and cost-saving good manufacturing process (GMP)-compliant protocol for the generation of ready-for-use therapeutic CIK cell doses starting from one unstimulated donor-derived peripheral blood (PB) or leukocytapheresis (LP) products. Culture medium with or without the addition of either AB serum, fresh frozen plasma (FFP) or platelet lysate (PL) was used for culture. Fresh and cryopreserved CIK cells were compared regarding expansion rate, viability, phenotype, and ability to inhibit leukemia growth. Cell numbers increased by a median factor of 10-fold in the presence of FFP, PL, or AB serum, whereas cultivation in FFP/PL-free or AB serum-free medium failed to promote adequate CIK cell proliferation (p < 0.01) needed to provide clinical doses of 1 × 106 T cells/kG, 5 × 106 T cells/kG, 1 × 107 T cells/kG, and 1 × 108 T cells/kG recipient body weight. CIK cells consisting of T cells, T- natural killer (T-NK) cells and a minor fraction of NK cells were not significantly modified by different medium supplements. Moreover, neither cytotoxic potential against leukemic THP-1 cells nor cell activation shown by CD25 expression were significantly influenced. Moreover, overnight and long-term cryopreservation had no significant effect on the composition of CIK cells, their phenotype or cytotoxic potential. A viability of almost 93% (range: 89–96) and 89.3% (range: 84–94) was obtained after freeze-thawing procedure and long-term storage, respectively, whereas viability was 96% (range: 90-97) in fresh CIK cells. Altogether, GMP-complaint CIK cell generation from an unstimulated donor-derived PB or LP products was feasible. Introducing FFP, which is easily accessible, into CIK cell cultures was time- and cost-saving without loss of viability and potency in a 10-12 day batch culture. The feasibility of cryopreservation enabled storage and delivery of sequential highly effective ready-for-use CIK cell doses and therefore reduced the number of manufacturing cycles.
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)
On the observation of mesospheric air inside the arctic stratospheric polar vortex in early 2003
(2005)
During several balloon flights inside the Arctic polar vortex in early 2003, unusual trace gas distributions were observed, which indicate a strong influence of mesospheric air in the stratosphere. The tuneable diode laser (TDL) instrument SPIRALE (Spectroscopie InFrarouge par Absorption de Lasers Embarqués) measured unusually high CO values (up to 600 ppb) on 27 January at about 30 km altitude. The cryosampler BONBON sampled air masses with very high molecular Hydrogen, extremely low SF6 and enhanced CO values on 6 March at about 25 km altitude. Finally, the MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) Fourier Transform Infra-Red (FTIR) spectrometer showed NOy values which are significantly higher than NOy* (the NOy derived from a correlation between N2O and NOy under undisturbed conditions), on 21 and 22 March in a layer centred at 22 km altitude. Thus, the mesospheric air seems to have been present in a layer descending from about 30 km in late January to 25 km altitude in early March and about 22 km altitude on 20 March. We present corroborating evidence from a model study using the KASIMA (KArlsruhe Simulation model of the Middle Atmosphere) model that also shows a layer of mesospheric air, which descended into the stratosphere in November and early December 2002, before the minor warming which occurred in late December 2002 lead to a descent of upper stratospheric air, cutting of a layer in which mesospheric air is present. This layer then descended inside the vortex over the course of the winter. The same feature is found in trajectory calculations, based on a large number of trajectories started in the vicinity of the observations on 6 March. Based on the difference between the mean age derived from SF6 (which has an irreversible mesospheric loss) and from CO2 (whose mesospheric loss is much smaller and reversible) we estimate that the fraction of mesospheric air in the layer observed on 6 March, must have been somewhere between 35% and 100%.
The radiative capture cross section of 238U is very important for the developing of new reactor technologies and the safety of existing ones. Here the preliminary results of the 238U(n,γ) cross section measurement performed at n_TOF with C6D6 scintillation detectors are presented, paying particular attention to data reduction and background subtraction.
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.