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Background: Recent research highlights the potential role of sex-specific variations in cardiovascular disease. The gut microbiome has been shown to differ between the sexes in patients with cardiovascular risk factors. Objectives: The main objective of this study is to analyze the differences between women and men in the relationship between gut microbiota and measures of arterial stiffness. Methods: We conducted a cross-sectional study in Spain, selecting 180 subjects (122 women, 58 men) aged between 45 and 74. Subjects with arterial stiffness were identified by the presence of at least one of the following: carotid–femoral pulse wave velocity (cf-PWV) above 12 mm/s, cardio–ankle vascular index (CAVI) above nine, or brachial–ankle pulse wave velocity (ba-PWV) above 17.5 m/s. All other cases were considered subjects without arterial stiffness. The composition of the gut microbiome in fecal samples was determined by 16S rRNA sequencing. Results: We found that women have a more diverse microbiome than men (Shannon, p < 0.05). There is also a significant difference in gut microbiota composition between sexes (Bray–Curtis, p < 0.01). Dorea, Roseburia, and Agathobacter, all of them short-chain fatty-acid producers, were more abundant in women's microbiota (log values > 1, p-value and FDR < 0.05). Additionally, Blautia was more abundant in women when only the subjects with arterial stiffness were considered. According to logistic regression, Roseburia was negatively associated with arterial stiffness in men, while Bifidobacterium and Subdoligranulum were positively related to arterial stiffness. Conclusions: In the Spanish population under study, women had higher microbiome diversity and potentially protective genera. The host's gender determines the influence of the same bacteria on arterial stiffness. Trial Registration Number: NCT03900338. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota and its by‐products are increasingly recognized as having a decisive role in cardiovascular diseases. The aim is to study the relationship between gut microbiota and early vascular ageing (EVA). Methods: A cross‐sectional study was developed in Salamanca (Spain) in which 180 subjects aged 45–74 years were recruited. EVA was defined by the presence of at least one of the following: carotid‐femoral pulse wave velocity (cf‐PWV), cardio‐ankle vascular index (CAVI) or brachial‐ankle pulse wave velocity (ba‐PWV) above the 90th percentile of the reference population. All other cases were considered normal vascular ageing (NVA). Measurements: cf‐PWV was measured by SphygmoCor® System; CAVI and ba‐PWV were determined by Vasera 2000® device. Gut microbiome composition in faecal samples was determined by 16S rRNA Illumina sequencing. Results: Mean age was 64.4 ± 6.9 in EVA group and 60.4 ± 7.6 years in NVA (p <.01). Women in EVA group were 41% and 53% in NVA. There were no differences in the overall composition of gut microbiota between the two groups when evaluating Firmicutes/Bacteriodetes ratio, alfa diversity (Shannon Index) and beta diversity (Bray‐Curtis). Bilophila, Faecalibacterium sp.UBA1819 and Phocea, are increased in EVA group. While Cedecea, Lactococcus, Pseudomonas, Succiniclasticum and Dielma exist in lower abundance. In logistic regression analysis, Bilophila (OR: 1.71, 95% CI: 1.12–2.6, p =.013) remained significant. Conclusions: In the studied Spanish population, early vascular ageing is positively associated with gut microbiota abundance of the genus Bilophila. No relationship was found between phyla abundance and measures of diversity. [ABSTRACT FROM AUTHOR]

GALE gene encodes the uridine diphosphate [UDP]-galactose-4-epimerase, which catalyzes the bidirectional interconversion of UDP-glucose to UDP-galactose, and UDP-N-acetyl-glucosamine to UDPN-acetyl-galactosamine. In that way, GALE balances, through reversible epimerization, the pool of four sugars that are essential during the biosynthesis of glycoproteins and glycolipids. GALE-related disorder presents an autosomal recessive inheritance pattern, and it is commonly associated with galactosemia. Peripheral galactosemia generally associates with non-generalized forms or even asymptomatic presentations, while classical galactosemia may be related to complications such as learning difficulties, developmental delay, cardiac failure, or dysmorphic features. Recently, GALE variants have been related to severe thrombocytopenia, pancytopenia, and in one patient, to myelodysplastic syndrome. [ABSTRACT FROM AUTHOR]

Advances in bioinformatics have contributed towards a significant increase in available information. Information analysis requires the use of distributed computing systems to best engage the process of data analysis. This study proposes a multiagent system that incorporates grid technology to facilitate distributed data analysis by dynamically incorporating the roles associated to each specific case study. The system was applied to genetic sequencing data to extract relevant information about insertions, deletions or polymorphisms.

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications. [ABSTRACT FROM AUTHOR]

The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations. [ABSTRACT FROM AUTHOR]

22 Greinacher A, Pecci A, Kunishima S, Althaus K, Nurden P, Balduini CL, Bakchoul T. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. Keywords: bleeding; inherited platelet disorders; sitosterolemia; thrombocytopenia EN bleeding inherited platelet disorders sitosterolemia thrombocytopenia 573 577 5 08/03/21 20210601 NES 210601 Introduction Sitosterolemia (OMIM 210250) is a rare inherited autosomal recessive disorder of lipid metabolism, characterized by increased levels of plasma plant sterols (PS) such as stigmasterol, campesterol, and sitosterol [[1]]. Macrothrombocytopenia and stomatocytes are the typical findings in the peripheral blood smear (90%) and usually associate with other metabolic symptoms (70%) (Figure 1), indicating the presence of syndromic thrombocytopenia [[12]]. [Extracted from the article]

In total, 3 HG3 WT,3HG3 TP53 MUT, 3 HG3-del(11q), 5 HG3del(11q) TP53 MUT, and 5 HG3-del(11q) ATM MUT TP53 MUT clones were generated. Interestingly,HG3-del(11q) ATM MUT TP53 MUT cellsfailedtoengraftandcompetewith HG3-del(11q) and HG3-del(11q) TP53 MUT cells, almost disappearingfrombothspleenandbonemarrow2weeks aftercellinjection(Figure4B). Datawerefittedinanexponential growthequation,andtimepointvaluesarepresentedasthemean±SEM.(C)RepresentativeimmunoblotanalysesofHG3 WT,HG3TP53 MUT, HG3-del(11q),HG3-del(11q)TP53 MUT,andHG3-del(11q)ATM MUT TP53 MUT wholecelllysates.ATM,PARP1,andCaspase-3proteinexpression and/orcleavagewereanalyzed. -actinwasusedasloadingcontrol.(D)CellcyclephasedistributionofHG3-editedcelllinesuponexposureto irradiationattheindicatedtimepoints. In addition, HG3 TP53 MUT, and HG3-del(11q) TP53 MUT cells showed a G2/M cell cycle arrest in accordance with TP53-defective cell-cycle phenotype, 37 which was also overcame 48 hours post-IR. [Extracted from the article]

In the last years, the use of thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has improved the management of immune thrombocytopenia (ITP). Moreover, eltrombopag is also active in patients with aplastic anemia and myelodysplastic syndrome. However, their mechanisms of action and signaling pathways still remain controversial. In order to gain insight into the mechanisms underlying eltrombopag therapy, a gene expression profile (GEP) analysis in patients treated with this drug was carried out. Fourteen patients with chronic ITP were studied by means of microarrays before and during eltrombopag treatment. Median age was 78 years (range, 35–87 years); median baseline platelet count was 14 × 109/L (range, 2–68 × 109/L). Ten patients responded to the therapy, two cases relapsed after an initial response and the remaining two were refractory to the therapy. Eltrombopag induced relevant changes in the hematopoiesis, platelet activation and degranulation, as well as in megakaryocyte differentiation, with overexpression of some transcription factors and the genes PPBP, ITGB3, ITGA2B, F13A1, F13A1, MYL9 and ITGA2B. In addition, GP1BA, PF4, ITGA2B, MYL9, HIST1H4H and HIST1H2BH, genes regulated by RUNX1 were also significantly enriched after eltrombopag therapy. Furthermore, in non-responder patients, an overexpression of Bcl-X gene and genes involved in erythropoiesis, such as SLC4A1 and SLC25A39, was also observed. To conclude, overexpression in genes involved in megakaryopoiesis, platelet adhesion, degranulation and aggregation was observed in patients treated with eltrombopag. Moreover, an important role regarding heme metabolism was also present in non-responder patients. [ABSTRACT FROM AUTHOR]

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next‐generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR‐CLLs) and we demonstrate that IGHR‐CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non‐Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR‐CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR‐CLLs patients showed a shorter TFT than CLL patients carrying 13q−, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR‐CLLs, but also refined the prognosis of low‐risk cytogenetic patients (13q−/normal FISH). Hence, our study demonstrates that IGHR‐CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk‐stratification CLL model. What's new? The prognostic significance of the immunoglobulin heavy chain (IGH) translocation in chronic lymphocytic leukemia (CLL) is controversial and its mutational profile remains unknown. Here, the authors assessed for the first time the genetic landscape of CLL patients with IGH rearrangements by targeted next‐generation sequencing, characterising recurrently‐mutated genes with prognostic implications and demonstrating that these entities exhibit an intermediate mutational profile between CLL and non‐Hodgkin lymphoma. Moreover, the findings showed that the incorporation of next‐generation sequencing and the IGH‐probe in the CLL‐fluorescence in situ hybridisation panel used in clinical routine could be useful, especially for elucidating prognosis in normal FISH cases. [ABSTRACT FROM AUTHOR]

Keywords: Myelodysplastic syndromes; del(5q); non-del(5q); mutations; lenalidomide EN Myelodysplastic syndromes del(5q) non-del(5q) mutations lenalidomide e133 e137 5 05/19/20 20200515 NES 200515 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterised by ineffective haematopoiesis leading to peripheral blood cytopenias and an increased risk of transformation to acute myeloid leukaemia (AML) (Haferlach I et al. i , [5]; Makishima I et al. i , [8]). Lenalidomide (LEN) has been approved for the treatment of patients with del(5q) low-risk MDS and transfusion dependence. We collected 74 samples from patients with MDS at diagnosis or treatment-naïve with LEN follow-up treatment of two or more cycles; 32 patients presented with del(5q), while 42 patients did not have del(5q) in their karyotype (Table S1). As expected, responders were mainly classified in MDS with isolated del(5q) (71%), while non-responders were enriched in MDS with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD; 33%), and MDS with multilineage dysplasia (MDS-MLD; 26%; Table 1). 1 TableClinical characteristics of the patients. [Extracted from the article]

Summary: The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large‐scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies. [ABSTRACT FROM AUTHOR]

Background: The t(12;21)(p13;q22), which fuses ETV6 and RUNX1 genes, is the most common genetic abnormality in children with B-cell precursor acute lymphoblastic leukaemia. The implication of the fusion protein in leukemogenesis seems to be clear. However, its role in the maintenance of the disease continues to be controversial. Methods: Generation of an in vitro ETV6/RUNX1 knock out model using the CRISPR/Cas9 gene editing system. Functional characterization by RNA sequencing, proliferation assays, apoptosis and pharmacologic studies, and generation of edited-cell xenograft model. Results: The expression of ETV6/RUNX1 fusion gene was completely eliminated, thus generating a powerful model on which to study the role of the fusion gene in leukemic cells. The loss of fusion gene expression led to the deregulation of biological processes affecting survival such as apoptosis resistance and cell proliferation capacity. Tumour cells showed higher levels of apoptosis, lower proliferation rate and a greater sensitivity to PI3K inhibitors in vitro along as a decrease in tumour growth in xenografts models after ETV6/RUNX1 fusion gene abrogation. Conclusions: ETV6/RUNX1 fusion protein seems to play an important role in the maintenance of the leukemic phenotype and could thus become a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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Diagnosis of inherited bleeding disorders (IBDs) remains challenging, especially in the case of inherited platelet disorders, due to the heterogeneity of the clinical and laboratory phenotype, the limited specificity of platelet function tests, and the large number of potential culprit genes. Unraveling the underlying molecular defect provides the definitive diagnosis of IBDs, facilitating prognosis and clinical care, which are especially important for severe clinical syndromes and those that may be associated with an increased risk of malignancy. Until recently, Sanger sequencing of candidate genes has been the only method of molecular diagnosis, but this approach is time-consuming and costly and requires phenotype-based identification of any obvious candidate gene(s). Nowadays, high-throughput sequencing (HTS) allows the simultaneous and rapid investigation of multiple genes at a manageable cost. This HTS technology that includes targeted sequencing of prespecified genes, whole-exome sequencing, or whole-genome sequencing, is revolutionizing the genetic diagnosis of human diseases. Through its extensive implementation in research and clinical practice, HTS is rapidly improving the molecular characterization of IBDs. However, despite the availability of this powerful approach, many patients still do not receive a diagnosis. As IBDs are complex and rare diseases, development of more advanced laboratory assays, improvements in bioinformatic pipelines, and the formation of multidisciplinary teams are encouraged to advance our understanding of IBDs. [ABSTRACT FROM AUTHOR]