KIT , PDGFRα and EGFR analysis in nephroblastoma

Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRα and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRα exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRα or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRα mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRα or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRα or EGFR mutation

Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the CommunityThe Gutenberg Health Study

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 +/- 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 +/- 8.6 years-old compared to a mean age of 55.3 +/- 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 mol/L (interquartile range (IQR) 1.5-2.5) and 2.0 mol/L (IQR 1.5-2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was -0.12 (95% confidence interval (CI) -0.23-(-0.02);p = 0.024) for left atrial area and -0.01 (95% CI -0.02-(-0.003);p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70-1.16;p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function

Myocardial Infarction Accelerates Atherosclerosis

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE$^{−/−}$ mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression

Identifying drivers of non-stationary climate-growth relationships of European beech.

The future performance of the widely abundant European beech (Fagus sylvatica L.) across its ecological amplitude is uncertain. Although beech is considered drought-sensitive and thus negatively affected by drought events, scientific evidence indicating increasing drought vulnerability under climate change on a cross-regional scale remains elusive. While evaluating changes in climate sensitivity of secondary growth offers a promising avenue, studies from productive, closed-canopy forests suffer from knowledge gaps, especially regarding the natural variability of climate sensitivity and how it relates to radial growth as an indicator of tree vitality. Since beech is sensitive to drought, we in this study use a drought index as a climate variable to account for the combined effects of temperature and water availability and explore how the drought sensitivity of secondary growth varies temporally in dependence on growth variability, growth trends, and climatic water availability across the species' ecological amplitude. Our results show that drought sensitivity is highly variable and non-stationary, though consistently higher at dry sites compared to moist sites. Increasing drought sensitivity can largely be explained by increasing climatic aridity, especially as it is exacerbated by climate change and trees' rank progression within forest communities, as (co-)dominant trees are more sensitive to extra-canopy climatic conditions than trees embedded in understories. However, during the driest periods of the 20th century, growth showed clear signs of being decoupled from climate. This may indicate fundamental changes in system behavior and be early-warning signals of decreasing drought tolerance. The multiple significant interaction terms in our model elucidate the complexity of European beech's drought sensitivity, which needs to be taken into consideration when assessing this species' response to climate change

Climate warming-induced replacement of mesic beech by thermophilic oak forests will reduce the carbon storage potential in aboveground biomass and soil

International audienceContext: Climate warming may change the carbon (C) storage in forest biomass and soil through future shifts in tree species composition. With a projected warming by 2–3 K over the twenty-first century, silvicultural adaptation measures and natural succession might lead to the replacement of European beech forests by thermophilic oak forests in drought- and heat-affected regions of central and south-eastern Europe, but the consequences for ecosystem C storage of this species shift are not clear.Aims: To quantify the change in C storage in biomass and soil with a shift from beech (Fagus sylvatica) to oak forest (Quercus petraea, Q. frainetto, Q. cerris), we measured the aboveground biomass (AGC) and soil C pools (SOC).MethodsAGC pools and SOC stocks to − 100 cm depth were calculated from forest inventory and volume-related SOC content data for beech, mixed beech-oak and oak forests in three transects in the natural beech-oak ecotone of western Romania, where beech occurs at its heat- and drought-induced distribution limit.Results: From the cooler, more humid beech forests to the warmer, more xeric oak forests, which are 1–2 K warmer, AGC and SOC pools decreased by about 22% (40 Mg C ha−1) and 20% (17 Mg C ha−1), respectively. The likely main drivers are indirect temperature effects acting through tree species and management in the case of AGC, but direct temperature effects for SOC.Conclusion: If drought- and heat-affected beech forests in Central Europe are replaced by thermophilic oak forests in future, this will lead to carbon losses of ~ 50–60 Mg ha−1, thus reducing ecosystem carbon storage substantially

Vertical partitioning of CO2 production in a forest soil

Large amounts of total organic carbon are temporarily stored in soils, which makes soil respiration one of the major sources of terrestrial CO2 fluxes within the global carbon cycle. More than half of global soil organic carbon (SOC) is stored in subsoils (below 30 cm), which represent a significant carbon (C) pool. Although several studies and models have investigated soil respiration, little is known about the quantitative contribution of subsoils to total soil respiration or about the sources of CO2 production in subsoils. In a 2-year field study in a European beech forest in northern Germany, vertical CO2 concentration profiles were continuously measured at three locations, and CO2 production was quantified in the topsoil and the subsoil. To determine the contribution of fresh litter-derived C to CO2 production in the three soil profiles, an isotopic labelling experiment, using C-13-enriched leaf litter, was performed. Additionally, radiocarbon measurements of CO2 in the soil atmosphere were used to obtain information about the age of the C source in the CO2 production. At the study site, it was found that 90% of total soil respiration was produced in the first 30 cm of the soil profile, where 53% of the SOC stock is stored. Freshly labelled litter inputs in the form of dissolved organic matter were only a minor source for CO2 production below a depth of 10 cm. In the first 2 months after litter application, fresh litter-derived C contributed, on average, 1% at 10 cm depth and 0.1% at 150 cm depth to CO2 in the soil profile. Thereafter, its contribution was less than 0.3% and 0.05% at 10 and 150 cm depths, respectively. Furthermore CO2 in the soil profile had the same modern radiocarbon signature at all depths, indicating that CO2 in the subsoil originated from young C sources despite a radiocarbon age bulk SOC in the subsoil. This suggests that fresh C inputs in subsoils, in the form of roots and root exudates, are rapidly respired, and that other subsoil SOC seems to be relatively stable. The field labelling experiment also revealed a downward diffusion of (CO2)-C-13 in the soil profile against the total CO2 gradient. This isotopic dependency should be taken into account when using labelled C-13 and C-14 isotope data as an age proxy for CO2 sources in the soil

Methoden zur Sofortpreiskalkulation von CNC-Drehteilen: Entwicklung und Bewertung der Anwendbarkeit von Algorithmen und prädiktiven Machine-Learning-Modellen

For the development of an immediate price calculation for CNC turned parts, machine learning frameworks as well as a deterministic algorithm are developed. The deterministic algorithm works exclusively for simple CNC turned parts. The machine learning models in contrary are significantly more promising, since the first results already achieve small deviation values related to the defined reference prices. With increasing data volume, both models can be further improved without great effort

Scientific Reports / Toxicological testing of allogeneic secretome derived from peripheral mononuclear cells (APOSEC): a novel cell-free therapeutic agent in skin disease

A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies. Regulatory authorities classify these secretomes as biological medicinal products, and non- clinical safety assessment thus falls under the scope of ICH S6. A secretome of stressed peripheral blood mononuclear cells (APOSEC) was successfully tested in a toxicology program, supporting clinical use of the new drug candidate. Here, to allow for topical, dermal treatment of patients with diabetic foot ulcer, several non-clinical safety studies were performed. Acute toxicity (single dose) and neuropharmacological screening were tested intravenously in a rat model. Risk for skin sensitisation was tested in mice. A 4-week intravenous toxicity study in mice and a 4-week subcutaneous toxicity study in minipigs were conducted to cover the clinical setting and application in a rodent and a non-rodent model. Acute and repeated-dose toxicity studies show that APOSEC administered intravenously and subcutaneously does not involve major toxicities or signs of local intolerance at levels above the intended total human maximal dose of 3.3U/kg/treatment, 200U/wound/treatment, and 100U/cm/treatment. The non-clinical data support the safe topical use of APOSEC in skin diseases related to deficient wound healing.(VLID)493189

PET/MRI of inflammation in myocardial infarction

ObjectivesThe aim of this study was to explore post–myocardial infarction (MI) myocardial inflammation.BackgroundInnate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes.MethodsAcute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose (18FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology.ResultsGd-DTPA–enhanced infarcts showed high 18FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher 18FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 104/mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation.ConclusionsThis study shed light on the innate inflammatory response in remote myocardium after MI

Cardiovascular profiling in the diabetic continuum: results from the population-based Gutenberg Health Study

Aims!#!To assess the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in the general population and to investigate the associated cardiovascular burden and clinical outcome.!##!Methods and results!#!The study sample comprised 15,010 individuals aged 35-74 years of the population-based Gutenberg Health Study. Subjects were classified into euglycaemia, prediabetes and T2DM according to clinical and metabolic (HbA1c) information. The prevalence of prediabetes was 9.5% (n = 1415) and of T2DM 8.9% (n = 1316). Prediabetes and T2DM showed a significantly increased prevalence ratio (PR) for age, obesity, active smoking, dyslipidemia, and arterial hypertension compared to euglycaemia (for all, P &amp;lt; 0.0001). In a robust Poisson regression analysis, prediabetes was established as an independent predictor of clinically-prevalent cardiovascular disease (PR!##!Conclusion!#!Besides T2DM, also prediabetes inherits a significant cardiovascular burden, which translates into poor clinical outcome and indicates the need for new concepts regarding the prevention of cardiometabolic disorders