In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response.
View Article and Find Full Text PDFInhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMA) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5-azacytidine (5-AZA) could also extend the rationale of this treatment concept to high-risk MDS.
View Article and Find Full Text PDFBackground: Robust and reliable in vitro and in vivo models of primary cells are necessary to study the pathomechanisms of Myelodysplastic Neoplasms (MDS) and identify novel therapeutic strategies. MDS-derived hematopoietic stem and progenitor cells (HSPCs) are reliant on the support of bone marrow (BM) derived mesenchymal stroma cells (MSCs). Therefore, isolation and expansion of MCSs are essential for successfully modeling this disease.
View Article and Find Full Text PDFLimited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling.
View Article and Find Full Text PDFPatient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis.
View Article and Find Full Text PDFThe bone marrow (BM) stroma in myeloid neoplasms is altered and it is hypothesized that this cell compartment may also harbor clonal somatically acquired mutations. By exome sequencing of in vitro expanded mesenchymal stromal cells (MSCs) from n = 98 patients with myelodysplastic syndrome (MDS) and n = 28 healthy controls we show that these cells accumulate recurrent mutations in genes such as ZFX (n = 8/98), RANK (n = 5/98), and others. MDS derived MSCs display higher mutational burdens, increased replicative stress, senescence, inflammatory gene expression, and distinct mutational signatures as compared to healthy MSCs.
View Article and Find Full Text PDFPreclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag.
View Article and Find Full Text PDFMyelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide.
View Article and Find Full Text PDFIneffective erythropoiesis and iron overload are common in myelodysplastic syndromes (MDS). Erythroferrone (ERFE) and growth/differentiation factor 15 (GDF15) are two regulators of iron homeostasis produced by erythroid progenitors. Elevated systemic levels of ERFE and GDF15 in MDS are associated with dysregulated iron metabolism and iron overload, which is especially pronounced in MDS with SF3B1 gene mutations.
View Article and Find Full Text PDFSomatic 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).
View Article and Find Full Text PDFAlthough acute promyelocytic leukemia (APL) has evolved to the AML entity with the best prognosis, typical 'early death' (ED) events still account for mortality rates of ∼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis of = 7 APL ED cases compared to = 7 APL cases with long term remission. We discovered the proteins S100A8/S100A9 and EFEMP1 as the most differentially expressed factors.
View Article and Find Full Text PDFAims: Despite increasing interest in the recently established immunoglobulin 4-related disease (IgG4-RD), its pathogenesis and aetiology remain largely unclear. Characteristic histopathological features are one of the key elements of diagnosis, including 'storiform' fibrosis, obliterative phlebitis, increased lymphoplasmacytic infiltration and increased levels of IgG4 in serum and tissue. Histopathological features of IgG4-RD are striking but not specific, and can pose a pitfall for surgical pathologists.
View Article and Find Full Text PDFObjectives Food composition data are key for many nutrition related activities in research, planning and policy. Combatting micronutrient malnutrition among women and young children using sustainable food based approaches, as aimed at in the SMILING project, requires high quality food composition data. Methods In order to develop capacity and to align procedures for establishing, updating and assessing the quality of key nutrient data in the food composition tables in Southeast Asia, a detailed roadmap was developed to identify and propose steps for this.
View Article and Find Full Text PDFWe investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1).
View Article and Find Full Text PDFBackground: Cytogenetic aberrations such as deletion of chromosome 5q (del(5q)) represent key elements in routine clinical diagnostics of haematological malignancies. Currently established methods such as metaphase cytogenetics, FISH or array-based approaches have limitations due to their dependency on viable cells, high costs or semi-quantitative nature. Importantly, they cannot be used on low abundance DNA.
View Article and Find Full Text PDFClonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2).
View Article and Find Full Text PDFReliable food composition data are required for virtually all nutrition-related programs and policies. In many food composition tables, fish are included to a limited extent. Therefore, FAO/INFOODS decided to compile and publish a user databases for fish and shellfish (uFiSh), considering the following main objectives: to develop a global database for fish, crustaceans and molluscs with raw, cooked and processed foods; to base the database preferable on analytical data; to include major as well as minor species consumed; and to capture intra-species variation due to habitat, edible part, season or region.
View Article and Find Full Text PDFFood composition data play a key role in many sectors and the availability of quality data is critically important. Since 1984, the International Network of Food Data Systems (INFOODS) has been working towards improving food composition data quality and availability, including the development and updating of standards, guidelines and tools for food composition. FAO/INFOODS has recently published three comprehensive guidelines to improve and harmonise the compilation of data: (1) Guidelines for Food Matching, (2) Guidelines for Checking Food Composition Data prior to Publication of a User Table/Database, and (3) Guidelines for Converting Units, Denominators and Expressions.
View Article and Find Full Text PDFQuinoa (Chenopodium quinoa Willd.) is an ancient crop which can play an important role for worldwide food security. The current review aimed at evaluating existing compositional data which were compiled according to international standards.
View Article and Find Full Text PDFEdible insects are considered rich in protein and a variety of micronutrients, and are therefore seen as potential contributors to food security. However, the estimation of the insects' contribution to the nutrient intake is limited since data are absent in food composition tables and databases. Therefore, FAO/INFOODS collected and published analytical data from primary sources with sufficient quality in the Food Composition Database for Biodiversity (BioFoodComp).
View Article and Find Full Text PDFThe FAO/INFOODS e-Learning Course on Food Composition Data was developed to close existing knowledge gaps on food composition of professionals working with those data. It covers the important aspects of food composition, is based on instructional design, is highly interactive and comprises 14 lessons of approximate 10h duration. It was developed primarily for usage in universities, but also suits self-paced learning and blended learning programmes.
View Article and Find Full Text PDFTo date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC, ERG and WT1. Hereby, the main focus was on prediction of relapse.
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