Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis

There is strong evidence that stromal cells promote drug resistance of cancer. Here, we show that mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs) desensitize ERa-positive breast cancer cells to the anti-estrogen fulvestrant. In search for the mechanism, we found that MSCs and CAFs similarly increased the activity of the PI3K/AKT and the JAK/STAT3 pathways and upregulated the expression of integrin ß1, IGF1R, HIF1α, CAIX and Bcl-3 in MCF-7 cells. Further analyses revealed that MSCs and CAFs coordinately induce these changes by triggering the downregulation of IGFBP5. Loss of IGFBP5 in MCF-7 cells was an early and long-lasting event in response to MSCs and CAFs and was accompanied by growth stimulation both in the absence and presence of fulvestrant. The growth-stimulatory effect in the absence of fulvestrant could be attributed to PI3K/AKT pathway activation and could be mimicked by insulin. The growth-promoting effect in the presence of fulvestrant depended upon the upregulation of Bcl-3. By cRNA microarray analysis we identified additional IGFBP5 targets, of which two (KLHL4 and SEPP1) were inversely regulated by IGFBP5 and Bcl-3. BT474 cells also responded to stromal cells by downregulating IGFBP5 and upregulating the P-AKT, Bcl-3 and IGF1R levels, whereas T47D cells did not show any of these responses. In conclusion, our data suggest that, by targeting IGFBP5 expression in ERa-positive breast cancer cells, such as MCF-7 cells, MSCs and CAFs are able to orchestrate a variety of events, particularly activation of the PI3K/AKT pathway, upregulation of Bcl-3 expression and desensitization to anti-estrogen

Nanotube Action between Human Mesothelial Cells Reveals Novel Aspects of Inflammatory Responses

A well-known role of human peritoneal mesothelial cells (HPMCs), the resident cells of the peritoneal cavity, is the generation of an immune response during peritonitis by activation of T-cells via antigen presentation. Recent findings have shown that intercellular nanotubes (NTs) mediate functional connectivity between various cell types including immune cells - such as T-cells, natural killer (NK) cells or macrophages - by facilitating a spectrum of long range cell-cell interactions. Although of medical interest, the relevance of NT-related findings for human medical conditions and treatment, e.g. in relation to inflammatory processes, remains elusive, particularly due to a lack of appropriate in vivo data. Here, we show for the first time that primary cultures of patient derived HPMCs are functionally connected via membranous nanotubes. NT formation appears to be actin cytoskeleton dependent, mediated by the action of filopodia. Importantly, significant variances in NT numbers between different donors as a consequence of pathophysiological alterations were observable. Furthermore, we show that TNF-α induces nanotube formation and demonstrate a strong correlation of NT connectivity in accordance with the cellular cholesterol level and distribution, pointing to a complex involvement of NTs in inflammatory processes with potential impact for clinical treatment

Predictors of packed red cell transfusion after isolated primary coronary artery bypass grafting – The experience of a single cardiac center: A prospective observational study

<p>Abstract</p> <p>Background</p> <p>Preoperative patients' characteristics can predict the need for perioperative blood component transfusion in cardiac surgical operations. The aim of this prospective observational study is to identify perioperative patient characteristics predicting the need for allogeneic packed red blood cell (PRBC) transfusion in isolated primary coronary artery bypass grafting (CABG) operations.</p> <p>Patients and Methods</p> <p>105 patients undergoing isolated, first-time CABG were reviewed for their preoperative variables and followed for intraoperative and postoperative data. Patients were 97 males and 8 females, with mean age 58.28 ± 10.97 years. Regression logistic analysis was used for identifying the strongest perioperative predictors of PRBC transfusion.</p> <p>Results</p> <p>PRBC transfusion was used in 71 patients (67.6%); 35 patients (33.3%) needed > 2 units and 14 (13.3%) of these needed > 4 units. Univariate analysis identified female gender, age > 65 years, body weight ≤ 70 Kg, BSA ≤ 1.75 m², BMI ≤ 25, preoperative hemoglobin ≤ 13 gm/dL, preoperative hematocrit ≤ 40%, serum creatinine > 100 μmol/L, Euro SCORE (standard/logistic) > 2, use of CPB, radial artery use, higher number of distal anastomoses, and postoperative chest tube drainage > 1000 mL as significant predictors. The strongest predictors using multivariate analysis were CPB use, hematocrit, body weight, and serum creatinine.</p> <p>Conclusion</p> <p>The predictors of PRBC transfusion after primary isolated CABG are use of CPB, hematocrit ≤ 40%, weight ≤ 70 Kg, and serum creatinine > 100 μmol/L. This leads to better utilization of blood bank resources and cost-efficient targeted use of expensive blood conservation modalities.</p

Metabolic reconstruction of sulfur assimilation in the extremophile Acidithiobacillus ferrooxidans based on genome analysis

BACKGROUND: Acidithiobacillus ferrooxidans is a gamma-proteobacterium that lives at pH2 and obtains energy by the oxidation of sulfur and iron. It is used in the biomining industry for the recovery of metals and is one of the causative agents of acid mine drainage. Effective tools for the study of its genetics and physiology are not in widespread use and, despite considerable effort, an understanding of its unusual physiology remains at a rudimentary level. Nearly complete genome sequences of A. ferrooxidans are available from two public sources and we have exploited this information to reconstruct aspects of its sulfur metabolism. RESULTS: Two candidate mechanisms for sulfate uptake from the environment were detected but both belong to large paralogous families of membrane transporters and their identification remains tentative. Prospective genes, pathways and regulatory mechanisms were identified that are likely to be involved in the assimilation of sulfate into cysteine and in the formation of Fe-S centers. Genes and regulatory networks were also uncovered that may link sulfur assimilation with nitrogen fixation, hydrogen utilization and sulfur reduction. Potential pathways were identified for sulfation of extracellular metabolites that may possibly be involved in cellular attachment to pyrite, sulfur and other solid substrates. CONCLUSIONS: A bioinformatic analysis of the genome sequence of A. ferrooxidans has revealed candidate genes, metabolic process and control mechanisms potentially involved in aspects of sulfur metabolism. Metabolic modeling provides an important preliminary step in understanding the unusual physiology of this extremophile especially given the severe difficulties involved in its genetic manipulation and biochemical analysis

Numerical tools for burning plasmas

The software stack under development within a European coordinated effort on tools for burning plasma modelling is presented. The project is organised as a Task (TSVV Task 10) under the new E-TASC initiative (Litaudon et al 2022 Plasma Phys. Control. Fusion 64 034005). This is a continued effort within the EUROfusion inheriting from the earlier European coordination projects as well as research projects based at various European laboratories. The ongoing work of the TSVV Tasks is supported by the Advanced Computing Hubs. Major projects requiring the high performance computing (HPC) resources are global gyrokinetic codes and global hybrid particle-magnetohydrodynamics (MHD) codes. Also applications using the integrated modelling tools, such as the Energetic-Particle Workflow, based on the ITER Integrated Modelling & Analysis Suite (IMAS), or the code package for modelling radio-frequency heating and fast-ion generation may require intensive computation and a substantial memory footprint. The continual development of these codes both on the physics side and on the HPC side allows us to tackle frontier problems, such as the interaction of turbulence with MHD-type modes in the presence of fast particles. One of the important mandated outcomes of the E-TASC project is the IMAS-enabling of EUROfusion codes and release of the software stack to the EUROfusion community

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for

Self-assembly of poly(ethylene oxide)-b-poly(e-caprolactone) copolymers in aqueous solution

The associative behavior of monodisperse diblock copolymers consisting of a hydrophilic poly(ethylene oxide) block and a hydrophobic poly(epsilon-caprolactone) or poly(gamma-methyl-epsilon-caprolactone) block has been studied in aqueous solution. Copolymers have been directly dissolved in water. The solution properties have been studied by surface tension, in relation to mesoscopic analyses by NMR (self-diffusion coefficients), transmission electron microscopy, and small-angle neutron and X-ray scattering. The experimental results suggest that micellization occurs at low concentration (approximately 0.002 wt %) and results in a mixture of unimers and spherical micelles that exchange slowly. The radius of the micelles has been measured (ca. 11 nm), and the micellar substructure has been extracted from the fitting of the SANS data with two analytical models. The core radius and the aggregation number change with the hydrophobic block length according to scaling laws as reported in the scientific literature. The poly(ethylene oxide) blocks are in a moderately extended conformation in the corona, which corresponds to about 25% of the completely extended chain. No significant modification is observed when poly(gamma-methyl-epsilon-caprolactone) replaces poly(epsilon-caprolactone) in the diblocks