•Quinoa is an underutilized food with potential to contribute to food security.•Nutrient content variations between quinoa varieties are considerable.•Protein content: 9.1–15.7g per 100g edible ...portion (fresh weight).•Total fat content: 4.0–7.6g per 100g edible portion (fresh weight).•More high quality compositional data on quinoa are needed.
Quinoa (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. A limited number of data were found that met the dataset quality criteria. In general, high variations in nutrient contents of quinoa were observed per 100g edible portion on fresh weight basis, for example: protein (9.1–15.7g), total fat (4.0–7.6g) and dietary fiber (8.8–14.1g). The variations of nutrient values among different varieties and among different data sources were considerable. The results show the nutritional potential of quinoa but they also demonstrate that more high-quality analytical data of quinoa are needed, especially for minerals and vitamins.
•FAO/INFOODS BioFoodComp2.1 contains compositional data on edible insects.•Collection of evaluated and standardised analytical data on edible insects.•The mealworm (Tenebrio molitor) contains ...significant amounts of essential nutrients.•The compiled data will assist to improve nutrient intake estimations.
Edible 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). Data were compiled for 456 food entries on insects in different developmental stages. A total of 5734 data points were entered, most on minerals and trace elements (34.8%), proximates (24.5%), amino acids (15.3%) and (pro)vitamins (9.1%). Data analysis of Tenebrio molitor confirms its nutritive quality that can help to combat malnutrition. The collection of data will assist compilers to incorporate more insects into tables and databases, and to further improve nutrient intake estimations.
The 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. However, validation experiments in serial culture passages, chronological BM aspirations and backtracking of high confidence mutations by re-sequencing primary sorted MDS MSCs indicate that the discovered mutations are secondary to in vitro expansion but not present in primary BM. Thus, we here report that there is no evidence for clonal mutations in the BM stroma of MDS patients.
We 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). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (P = .023), disease-free survival (P = .012), and remission duration (P = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.
•Genomic deletions of CDKN2A/2B are a new independent prognostic risk factor in adult Ph+ ALL.
Aims
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. This paper aims to determine the actual amount of IgG4+ plasma cells in nodular‐sclerosing Hodgkin lymphoma (NSHL) and its potential to be misdiagnosed in routine clinical practice.
Methods and results
IgG4+ plasma cells per high‐power field (HPF) and the ratio of IgG4+ versus IgG+ plasma cells (IgG4/IgG ratio) in lymph node biopsies of 24 patients with nodular‐sclerosing Hodgkin lymphoma (NSHL) were determined using immunohistochemistry and consensus scoring criteria as used for IgG4‐RD. Ten lymph node biopsies with reactive follicular hyperplasia were assessed for comparison. Higher numbers of IgG4+ plasma cells (P < 0.001) were observed in NSHL versus follicular hyperplasia (mean 34 versus 8 per HPF) with a mean IgG4/IgG ratio of 0.38 versus 0.18. Five cases (21%) fulfilled the consensus criteria of IgG4‐RD, with >50 IgG4+ plasma cells per HPF and an IgG4/IgG ratio of >0.4. The mean count of IgG4+ plasma cells per HPF in NSHL varied greatly (3–88) with increased numbers of IgG4+ plasma cells seen near areas of fibrosclerosis.
Conclusions
Significantly higher levels of IgG4+ plasma cells are common in NSHL, emphasising the need to exclude Reed–Sternberg cells by morphology and immunohistochemistry in biopsies where IgG4‐RD is suspected.
Clonal 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). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS.
•Mutational trajectories are defined by complex patterns of molecular heterogeneity in MDS, including lower-risk cases.•Therapeutic intervention dynamically reshapes mutational patterns often resulting in branched or independent evolution of MDS clones.
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 the low-dose splicing modulatory compound Pladienolide B. We further confirm the direct association between R-loops and ATR sensitivity and 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.
Preclinical 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. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient-individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients' clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.
The erythroferrone gene (
), also termed
, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE ...in cancer progression is largely unknown. We previously found that
was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the
mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma,
overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of
is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover,
expression influences intratumoral immune cell infiltration. Conclusively,
is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development.
Limited 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. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.