Inflamma-miRs Profile in Myelodysplastic Syndrome Patients.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients.

Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression.

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.

4-[(E)-2-(Pyridin-2-yl)ethen-yl]pyridine-terephthalic acid (2/1).

The title 2:1 co-crystal, 2C12H10N2·C8H6O4, crystallizes with one mol-ecule of 4-[(E)-2-(pyridin-2-yl)ethen-yl]pyridine (A) and one half-mol-ecule of terephthalic acid (B) in the asymmetric unit. In the crystal, the components are linked through heterodimeric COOH⋯Npyridine synthons, forming linear aggregates of composition -A-B-A-B-. Further linkage through weak C-H⋯O and C-H⋯π inter-actions gives two-dimensional hydrogen-bonded undulating sheets propagating in the [100] and [010] directions. These layers are connected through additional weak C-H⋯O contacts, forming a three-dimensional structure.

Effect of 5-Azacitidine Treatment on Redox Status and Inflammatory Condition in MDS Patients.

This study focused on the impact of the treatment with the hypomethylating agent 5-azacitidine on the redox status and inflammation in 24 MDS patients. Clinical and genetic features of MDS patients were recorded, and peripheral blood samples were used to determine the activity of the endogenous antioxidant defense system (superoxide dismutase, SOD; catalase, CAT; glutathion peroxidase, GPx; and reductase, GRd, activities), markers of oxidative damage (lipid peroxidation, LPO, and advanced oxidation protein products, AOPP). Moreover, pro-inflammatory cytokines and plasma nitrite plus nitrate levels as markers of inflammation, as well as CoQ10 plasma levels, were also measured. Globally, MDS patients showed less redox status in terms of a reduction in the GSSG/GSH ratio and in the LPO levels, as well as increased CAT activity compared with healthy subjects, with no changes in SOD, GPx, and GRd activities, or AOPP levels. When analyzing the evolution from early to advanced stages of the disease, we found that the GPx activity, GSSG/GSH ratio, LPO, and AOPP increased, with a reduction in CAT. GPx changes were related to the presence of risk factors such as high-risk IPSS-R or mutational score. Moreover, there was an increase in IL-2, IL-6, IL-8, and TNF-α plasma levels, with a further increase of IL-2 and IL-10 from early to advanced stages of the disease. However, we did not observe any association between inflammation and oxidative stress. Finally, 5-azacitidine treatment generated oxidative stress in MDS patients, without affecting inflammation levels, suggesting that oxidative status and inflammation are two independent processes.

Genomic loss of HLA alleles may affect the clinical outcome in low-risk myelodysplastic syndrome patients.

The Revised International Prognostic Score and some somatic mutations in myelodysplastic syndrome (MDS) are independently associated with transformation to acute myeloid leukemia (AML). Immunity has also been implicated in the pathogenesis of MDS, although the underlying mechanism remains unclear. We performed a SNP array on chromosome 6 in CD34+ purified blasts from 19 patients diagnosed with advanced MDS and 8 patients with other myeloid malignancies to evaluate the presence of loss of heterozygosity (LOH) in HLA and its impact on disease progression. Three patients had acquired copy-neutral LOH (CN-LOH) on 6p arms, which may disrupt antigen presentation and act as a mechanism for immune system evasion. Interestingly, these patients had previously been classified at low risk of AML progression, and the poor outcome cannot be explained by the acquisition of adverse mutations. LOH HLA was not detected in the remaining 24 patients, who all had adverse risk factors. In summary, the clinical outcome of patients with advanced MDS might be influenced by HLA allelic loss, wich allows subclonal expansions to evade cytotoxic-T and NK cell attack. CN-LOH HLA may therefore be a factor favoring MDS progression to AML independently of the somatic tumor mutation load.

Terminologia embryologica, parto y anomalías de la reproducción: propuesta de términos embriológicos en español / Terminologia embryologica, childbirth and reproduction anomalies: proposal for embryological terms in Spanish

RESUMEN: En el área de las Ciencias Morfológicas, y en especial Embriología, se mantienen diversas denominaciones para diferentes estructuras en idioma español, que no se corresponden necesariamente con los definidos por Terminologia Embryologica (TE), escrita en latín y traducidas al inglés, sin embargo no existe una traducción oficial del latín al español en la TE. Por lo cual el objetivo de este trabajo consistió en realizar una propuesta de términos en español correspondientes a los términos incluidos en Partus [148], Numerus conceptuum [127], Cyclus genitalis masculinus [85], Anomaliae reproductionis [181] y Anomaliae implantationis[195]. Se analizó la última edición de Terminologia Embryologica (editada en el año 2017 y aprobada por la Asamblea General de IFAA en 2019), editada por la Federative International Programme on Anatomical Terminologies (FIPAT). Para ello se tradujeron literalmente todos los términos desde el idioma latín al español, y posteriormente se buscó la utilización de éstos términos en libros de Embriología, Obstetricia y artículos originales. A partir del análisis de éstas traducciones, encontramos términos cuya traducción se utiliza ampliamente y deben ser mantenidos; términos que requirieron ser modificados, pues su traducción no se utiliza o es incorrecta; términos que no se encontraron en la literatura y debiesen ser indicados como no utilizados; e incluso ausencia de términos que debieran existir en latín debido a su gran utilización en textos y artículos científicos. Además, se identificaron las modificaciones que sufrió la Terminologia Embryologica del año 2013, en las secciones de análisis indicadas anteriormente, y que se reflejaron en la última edición del 2017. Creemos que el presente trabajo puede colaborar y mejorar el desarrollo de la Terminologia Embryologica traducida al español, unificando el uso de los términos en la enseñanza e investigación de la Embriología.

SUMMARY: In Morphological Sciences, and especially Embryology, various terms are maintained for different structures in Spanish, which do not necessarily correspond to those defined by Terminologia Embryologica (TE), written in Latín and translated into English, however there is not an official translation from Latín to Spanish on the TE. Therefore, the aim of this work was to make a proposal of terms in Spanish corresponding to the terms included in Partus [148], Numerus conceptuum [127], Cyclusgenitalis masculinus [85], Anomaliae reproductionis [181] and Anomaliae implantationis [195]. The latest edition of Terminologia Embryologica (edited in 2017 and approved by the IFAA General Assembly in 2019), edited by the Federative International Program on Anatomical Terminologies (FIPAT), was analyzed. For this, all the terms were literally translated from Latín into Spanish, and later the use of these terms was sought in books on Embryology, Obstetrics and original articles. From the analysis of these translations, we find terms whose translation is widely used and should be maintained; terms that required to be modified, as their translation is not used or is incorrect; terms that were not found in the literature and should be indicated as not used; and even the absence of terms that should exist in Latín due to its great use in scientific texts and articles. In addition, the modifications that the Terminologia Embryologica underwent in 2013 were identified, in the analysis sections indicated above, and which were reflected in the last edition of 2017. We believe that this work may collaborate and improve the development of the Terminologia Embryologica translated into Spanish, unifying the use of terms in the teaching and research of Embryology.

Further insight into the inhibitory action of a LIM/double zinc-finger motif of an agmatinase-like protein.

Agmatine is a precursor for polyamine biosynthesis also associated to neurotransmitter, anticonvulsant, antineurotoxic and antidepressant actions in the brain. It results from decarboxylation of l-arginine by arginine decarboxylase and it is hydrolyzed to urea and putrescine by agmatinase. Recently, we have described a new protein which also hydrolyzes agmatine although its sequence greatly differs from all known agmatinases. This agmatinase-like protein (ALP) contains a LIM-like double Zn-finger domain close to its carboxyl terminus, whose removal results in a truncated variant with a 10-fold increased kcat, and a 3-fold decreased Km value for agmatine. Our proposal was that the LIM-domain functions as an autoinhibitory, regulatory entity for ALP. Results in this report provide additional support for the postulated inhibitory effect. The purified isolated LIM domain was shown to be competitively inhibitory to a truncated variant ALP (lacking the LIM-domain), but not to the wild-type species. The C453A variant was shown to be a Zn(2+)-free enzyme with kinetic parameters similar to those of the truncated-ALP. A molecular dynamic simulation of a modeled LIM-domain 3D structure showed that, as a consequence of C453A mutation, the coordination of the zinc ion is broken and the structure of the zinc finger is melted. The inhibitory action of the LIM/double Zinc-finger motif was associated to a significant conformational change, as detected by tryptophan fluorescence studies, but was not related to changes in the association of the enzyme with the catalytically essential Mn(2+).