The relapse risk of AML patients undergoing autologous transplantation correlates with the stem cell mobilizing potential

Autologous stem cell transplantation (ASCT) is widely used to consolidate first remission in AML. We determined the significance of circulating CD34+ cells at the day of blood stem cell collection in 78 AML patients. Patients mobilizing more than 60,000 CD34+ cells/ml had shorter overall survival (OS; P=0.0274), shorter time to progression (TTP; P=0.0014), and a higher relapse rate (P=0.0177). High levels of CD34+ cells were an independent marker for shorter OS and TTP in a multivariate analysis. These data suggest that ASCT is associated with unfavorable outcome in AML patients with high levels of mobilized peripheral CD34+ cells.

Prion removal capacity of plasma protein manufacturing processes

BACKGROUND The variant Creutzfeldt-Jakob disease incidence peaked a decade ago and has since declined. Based on epidemiologic evidence, the causative agent, pathogenic prion, has not constituted a tangible contamination threat to large-scale manufacturing of human plasma-derived proteins. Nonetheless, manufacturers have studied the prion removal capabilities of various manufacturing steps to better understand product safety. Collectively analyzing the results could reveal experimental reproducibility and detect trends and mechanisms driving prion removal. STUDY DESIGN AND METHODS Plasma Protein Therapeutics Association member companies collected more than 200 prion removal studies on plasma protein manufacturing steps, including precipitation, adsorption, chromatography, and filtration, as well as combined steps. The studies used a range of model spiking agents and bench-scale process replicas. The results were grouped based on key manufacturing variables to identify factors impacting removal. The log reduction values of a group are presented for comparison. RESULTS Overall prion removal capacities evaluated by independent groups were in good agreement. The removal capacity evaluated using biochemical assays was consistent with prion infectivity removal measured by animal bioassays. Similar reduction values were observed for a given step using various spiking agents, except highly purified prion protein in some circumstances. Comparison between combined and single-step studies revealed complementary or overlapping removal mechanisms. Steps with high removal capacities represent the conditions where the physiochemical differences between prions and therapeutic proteins are most significant. CONCLUSION The results support the intrinsic ability of certain plasma protein manufacturing steps to remove prions in case of an unlikely contamination, providing a safeguard to products.

Dephosphorylation of p-ERK1/2 in relation to tumor remission after HER-2 and Raf1 blocking therapy in a conditional mouse tumor model

Several studies have shown that HER-2/neu (erbB-2) blocking therapy strategies can cause tumor remission. However, the responsible molecular mechanisms are not yet known. Both ERK1/2 and Akt/PKB are critical for HER-2-mediated signal transduction. Therefore, we used a mouse tumor model that allows downregulation of HER-2 in tumor tissue by administration of anhydrotetracycline (ATc). Switching-off HER-2 caused a rapid tumor remission by more than 95% within 7 d of ATc administration compared to the volume before switching-off HER-2. Interestingly, HER-2 downregulation caused a dephosphorylation of p-ERK1/2 by more than 80% already before tumor remission occurred. Levels of total ERK protein were not influenced. In contrast, dephosphorylation of p-Akt occurred later, when the tumor was already in remission. These data suggest that in our HER-2 tumor model dephosphorylation of p-ERK1/2 may be more critical for tumor remission than dephosphorylation of p-Akt. To test this hypothesis we used a second mouse tumor model that allows ATc controlled expression of BXB-Raf1 because the latter constitutively signals to ERK1/2, but cannot activate Akt/PKB. As expected, downregulation of BXB-Raf1 in tumor tissue caused a strong dephosphorylation of p-ERK1/2, but did not decrease levels of p-Akt. Interestingly, tumor remission after switching-off BXB-Raf1 was similarly efficient as the effect of HER-2 downregulation, despite the lack of p-Akt dephosphorylation. In conclusion, two lines of evidence strongly suggest that dephosphorylation of p-ERK1/2 and not that of p-Akt is critical for the rapid tumor remission after downregulation of HER-2 or BXB-Raf1 in our tumor model: (i) dephosphorylation of p-ERK1/2 but not that of p-Akt precedes tumor remission after switching-off HER-2 and (ii) downregulation of BXB-Raf1 leads to a similarly efficient tumor remission as downregulation of HER-2, although no p-Akt dephosphorylation was observed after switching-off BXB-Raf1.

Increased circulating placental growth factor during percutaneous coronary intervention is associated with applied radiocontrast agent

BACKGROUND AND AIM OF THE STUDY: Recent studies have suggested placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) as promising new biomarkers for risk stratification in acute coronary syndromes (ACS). However, little is known about the influence of percutaneous coronary intervention (PCI) on circulating PlGF and VEGF levels. METHODS: Thirty-five patients with ACS, 27 patients with stable coronary artery disease (sCAD), and nine healthy controls were enrolled in the study. Although all patients with ACS and 14 patients with stable angina pectoris underwent PCI, 13 patients with coronary artery disease required no revascularization (sCAD). PlGF and VEGF plasma concentrations were measured by immunoassay during and at the end of PCI and coronary angiography. RESULTS: Plasma PlGF levels were comparable in patients with ACS and sCAD on admission. Although coronary angiography or heparin alone did not alter PlGF and VEGF levels, immediately after PCI a dramatic increase was seen in circulating PlGF and a decrease in VEGF, which was independent of the clinical presentation of the patients, heparin administration, or the angiographic procedure itself, but was associated with the extent of coronary artery disease and the amount of the injected contrast media. In-vitro experiments revealed that radiocontrast agents induced the release of PlGF from endothelial cells without altering PlGF mRNA expression. CONCLUSION: Patients undergoing PCI exhibit an increase in circulating PlGF, probably caused by posttranslational modifications of radiocontrast agents in endothelial cells. Therefore, analysis of plasma PlGF and VEGF levels may consider the timing of blood sampling with respect to PCI and contrast media exposure.

Health-related quality of life in rural children living in four European countries: the GABRIEL study

OBJECTIVE Measuring children's health-related quality of life (HRQOL) is of growing importance given increasing chronic diseases. By integrating HRQOL questions into the European GABRIEL study, we assessed differences in HRQOL between rural farm and non-farm children from Germany, Austria, Switzerland and Poland to relate it to common childhood health problems and to compare it to a representative, mostly urban German population sample (KIGGS). METHODS The parents of 10,400 school-aged children answered comprehensive questionnaires including health-related questions and the KINDL-R questions assessing HRQOL. RESULTS Austrian children reported highest KINDL-R scores (mean: 80.9; 95 % CI [80.4, 81.4]) and Polish children the lowest (74.5; [73.9, 75.0]). Farm children reported higher KINDL-R scores than non-farm children (p = 0.002). Significantly lower scores were observed in children with allergic diseases (p < 0.001), with sleeping difficulties (p < 0.001) and in overweight children (p = 0.04). The German GABRIEL sample reported higher mean scores (age 7-10 years: 80.1, [79.9, 80.4]; age 11-13 years: 77.1, [74.9, 79.2]) compared to the urban KIGGS study (age 7-10 years: 79.0, [78.7-79.3]; age 11-13 years: 75.1 [74.6-75.6]). Socio-demographic or health-related factors could not explain differences in HRQOL between countries. CONCLUSIONS Future increases in chronic diseases may negatively impact children's HRQOL.

Dating polygenetic metamorphic assemblages along a transect across the Western Alps

Multichronometric analyses were performed on samples from a transect in the French-Italian Western Alps crossing nappes derived from the Briançonnais terrane and the Piemonte-Liguria Ocean, in an endeavour to constrain the high-pressure (HP) metamorphism and the retrogression history. 12 samples of white mica were analysed by 39Ar-40Ar stepwise heating, complemented by 2 samples from the Monte Rosa 100 km to the NE and also attributed to the Briançonnais terrane. One Sm-Nd and three Lu-Hf garnet ages from eclogites were also obtained. White mica ages decrease from ca. 300 Ma in the westernmost samples (Zone Houillère), reaching ca. 300 °C during Alpine metamorphism, to < 48 Ma in the internal units to the East, which reached ca. 500 °C during Alpine orogeny. The conventional “thermochronological” interpretation postulates Cretaceous Eo-Alpine HP metamorphism and younger “cooling ages” in the higher-temperature samples. However, Eocene Lu-Hf and Sm-Nd ages from the same samples cannot be interpreted as post-metamorphic cooling ages, which makes a Cretaceous eclogitization untenable. The age date from this transect require instead to replace conventional “thermochronology” by an approach combining age dating with detailed geochemical, petrological and microstructural investigations. Petrology reveals important mineralogical differences along the transect. Samples from the Zone Houillère mostly contain detrital mica. White mica with Si > 6.45 atoms per formula unit becomes more abundant eastward. Across the whole traverse, HP phengitic mica forms the D1 foliation. Syn-D2 mica is Si-poorer and associated with nappe stacking, exhumation, and hydrous retrogression under greenschist facies conditions. D1 phengite is very often corroded, overgrown or intergrown by syn-D2 muscovite. Most importantly, syn-D2 recrystallization is not limited to S2 schistosity domains; microchemical fingerprinting shows that it also can form pseudomorphs after crystals that could be mistaken to have formed during D1 based on microstructural arguments alone. Thereby the Cl concentration in white mica is a useful discriminator, since D2 retrogression was associated with a less saline fluid than eclogitization. Once the petrological stage is set, geochronology is straightforward. All samples contain mixtures of detrital, syn-D1 and syn-D2 mica, and retrogression phases (D3) in greatly varying proportions according to local pressure-temperature-fluid activity-deformation conditions. The correlation of age vs. Cl/K clearly identifies 47 ± 1 Ma as the age of formation of syn-D1 mica along the entire transect, including the Monte Rosa nappe samples. The inferred age of the greenschist-facies low-Si syn-D2 mica generation ranges within 39-43 Ma, with local variations. Coexistence of D1 and D2 ages, and the constancy of non-reset D1 ages along the entire transect, are strong evidence that the D1 white mica ages are very close to formation ages. Volume diffusion of Ar in white mica (activation energy E = 250 kJ/mol; pressure-adjusted diffusion coefficient D’0 < 0.03 cm2 s-1) has a subordinate effect on mineral ages compared to both prograde and retrograde recrystallization in most samples. Eocene Lu-Hf and Sm-Nd garnet ages are prograde and predate the HP peak.

Recovery of large carnivores in Europe's modern human-dominated landscapes.

The conservation of large carnivores is a formidable challenge for biodiversity conservation. Using a data set on the past and current status of brown bears (Ursus arctos), Eurasian lynx (Lynx lynx), gray wolves (Canis lupus), and wolverines (Gulo gulo) in European countries, we show that roughly one-third of mainland Europe hosts at least one large carnivore species, with stable or increasing abundance in most cases in 21st-century records. The reasons for this overall conservation success include protective legislation, supportive public opinion, and a variety of practices making coexistence between large carnivores and people possible. The European situation reveals that large carnivores and people can share the same landscape.

Der Einfluss des Geschlechtsrollen-Selbstkonzepts und der Einstellung gegenüber Geschlechtsrollen zu Schulbeginn auf das Interesse an feminin und maskulin konnotierten Schulfächern

Bereits in der ersten Grundschulklasse bekunden Mädchen ein stärkeres Interesse am Lesen als Jungen, die ihrerseits vergleichsweise mehr Interesse an der Mathematik angeben. In einer Stichprobe von 65 Jungen und 70 Mädchen wurde längsschnittlich geprüft, inwieweit die Geschlechtstypisierung in schulischen Interessen auf das Ausmaß zurückgeführt werden kann, in dem das Geschlechtsrollen-Selbstkonzept und die Einstellungen gegenüber Geschlechtsrollen (traditionell vs. egalitär) des Kindes in Übereinstimmung mit Geschlechtsstereotypen ausgeprägt sind. Erwartungsgemäß wiesen die Kinder bereits in der ersten Schulklasse geschlechtstypisierte Selbstkonzepte auf: Jungen schrieben sich mehr maskulin typisierte Merkmale zu als Mädchen, die ihrerseits mehr feminin-typisierte Merkmale für selbstbeschreibend hielten. Mädchen waren egalitärer gegenüber Geschlechtsrollen eingestellt als Jungen. Die Geschlechtsrollen-Selbstkonzepte beeinflussten moderiert durch die Einstellungen gegenüber Geschlechtsrollen das Interesse am Lesen und der Mathematik in der zweiten Grundschulklasse. Das Zusammenspiel zwischen kognitiver Entwicklung und geschlechtstypisierten Sozialisationseinflüssen wird diskutiert.

Phytoplakton pigment concentrations during POLARSTERN cruise ANT-XXVIII/3 and SONNE cruise SO218

Diatoms are the major marine primary producers on the global scale and, recently, several methods have been developed to retrieve their abundance or dominance from satellite remote sensing data. In this work, we highlight the importance of the Southern Ocean (SO) in developing a global algorithm for diatom using an Abundance Based Approach (ABA). A large global in situ data set of phytoplankton pigments was compiled, particularly with more samples collected in the SO. We revised the ABA to take account of the information on the penetration depth (Zpd) and to improve the relationship between diatoms and total chlorophyll-a (TChla). The results showed that there is a distinct relationship between diatoms and TChla in the SO, and a new global model (ABAZpd) improved the estimation of diatoms abundance by 28% in the SO compared with the original ABA model. In addition, we developed a regional model for the SO which further improved the retrieval of diatoms by 17% compared with the global ABAZpd model. As a result, we found that diatom may be more abundant in the SO than previously thought. Linear trend analysis of diatom abundance using the regional model for the SO showed that there are statistically significant trends, both increasing and decreasing, in diatom abundance over the past eleven years in the region.