German Red Cross

About: German Red Cross is a healthcare organization based out in Berlin, Germany. It is known for research contribution in the topics: Transplantation & Mesenchymal stem cell. The organization has 653 authors who have published 1146 publications receiving 40111 citations. The organization is also known as: Deutsches Rotes Kreuz & DRK.

Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations.

Abstract: Somatic mutations in genes coding for splicing factors, e.g. SF3B1, U2AF1, SRSF2, and others are found in approximately 50% of patients with Myelodysplastic Syndromes (MDS). These mutations have been predicted to frequently occur early in the mutational hierarchy of the disease therefore making them particularly attractive potential therapeutic targets. Recent studies in cell lines engineered to carry splicing factor mutations have revealed a strong association with elevated levels of DNA:RNA intermediates (R-loops) and a dependency on proper ATR function. However, data confirming this hypothesis in a representative cohort of primary MDS patient samples have so far been missing. Using CD34+ cells isolated from MDS patients with and without splicing factor mutations as well as healthy controls we show that splicing factor mutation-associated R-loops lead to elevated levels of replication stress and ATR pathway activation. Moreover, splicing factor mutated CD34+ cells are more susceptible to pharmacological inhibition of ATR resulting in elevated levels of DNA damage, cell cycle blockade, and cell death. This can be enhanced by combination treatment with low-dose splicing modulatory compound Pladienolide B. We further confirm the direct association of R-loops and ATR sensitivity with the presence of a splicing factor mutation using lentiviral overexpression of wild-type and mutant SRSF2 P95H in cord blood CD34+ cells. Collectively, our results from n=53 MDS patients identify replication stress and associated ATR signaling to be critical pathophysiological mechanisms in primary MDS CD34+ cells carrying splicing factor mutations, and provide a preclinical rationale for targeting ATR signaling in these patients.

Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype

Abstract: The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.

Determination of Low Wear Rates in Metal-On-Metal Hip Joint Replacements Based on Ultra Trace Element Analysis in Simulator Studies

Abstract: Metal-on-metal joint bearings are being increasingly used for total hip arthroplasty. Previous results from simulator tests to determine wear of metal-on-metal bearings exhibited high fluctuations. Consequently, wear tests had to be performed for a long period of time to achieve stable values. The aim of this study was to establish a method for the precise measurement of wear of metal-on-metal bearings. Wear was determined by analyzing the concentrations of particles and selected elements in the test medium (serum) using high resolution-inductively coupled plasma-mass spectrometry (HR-ICP-MS). The procedure was first validated and compared to gravimetric measurements on two different implant designs and then applied in wear tests on four total hip resurfacing implants. The validation showed a significant reliability of the HR-ICP-MS method (p ≤ 0.02). The final wear test revealed that the HR-ICP-MS method can precisely detect very low wear rates and accurately characterize alterations in wear progression. The duration of simulation can be reduced due to the high detection power and low fluctuation in HR-ICP-MS wear determination analyses. This approach is suitable for test implants with extremely low wear rates.

Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium.

Abstract: Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0*0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.