Metatranscriptomics captures dynamic shifts in mycorrhizal coordination in boreal forests.

Carbon storage and cycling in boreal forests-the largest terrestrial carbon store-is moderated by complex interactions between trees and soil microorganisms. However, existing methods limit our ability to predict how changes in environmental conditions will alter these associations and the essential ecosystem services they provide. To address this, we developed a metatranscriptomic approach to analyze the impact of nutrient enrichment on Norway spruce fine roots and the community structure, function, and tree-microbe coordination of over 350 root-associated fungal species. In response to altered nutrient status, host trees redefined their relationship with the fungal community by reducing sugar efflux carriers and enhancing defense processes. This resulted in a profound restructuring of the fungal community and a collapse in functional coordination between the tree and the dominant Basidiomycete species, and an increase in functional coordination with versatile Ascomycete species. As such, there was a functional shift in community dominance from Basidiomycetes species, with important roles in enzymatically cycling recalcitrant carbon, to Ascomycete species that have melanized cell walls that are highly resistant to degradation. These changes were accompanied by prominent shifts in transcriptional coordination between over 60 predicted fungal effectors, with more than 5,000 Norway spruce transcripts, providing mechanistic insight into the complex molecular dialogue coordinating host trees and their fungal partners. The host-microbe dynamics captured by this study functionally inform how these complex and sensitive biological relationships may mediate the carbon storage potential of boreal soils under changing nutrient conditions.

Cooperative Effects Drive Water Oxidation Catalysis in Cobalt Electrocatalysts through the Destabilization of Intermediates.

A barrier to understanding the factors driving catalysis in the oxygen evolution reaction (OER) is understanding multiple overlapping redox transitions in the OER catalysts. The complexity of these transitions obscure the relationship between the coverage of adsorbates and OER kinetics, leading to an experimental challenge in measuring activity descriptors, such as binding energies, as well as adsorbate interactions, which may destabilize intermediates and modulate their binding energies. Herein, we utilize a newly designed optical spectroelectrochemistry system to measure these phenomena in order to contrast the behavior of two electrocatalysts, cobalt oxyhydroxide (CoOOH) and cobalt-iron hexacyanoferrate (cobalt-iron Prussian blue, CoFe-PB). Three distinct optical spectra are observed in each catalyst, corresponding to three separate redox transitions, the last of which we show to be active for the OER using time-resolved spectroscopy and electrochemical mass spectroscopy. By combining predictions from density functional theory with parameters obtained from electroadsorption isotherms, we demonstrate that a destabilization of catalytic intermediates occurs with increasing coverage. In CoOOH, a strong (∼0.34 eV/monolayer) destabilization of a strongly bound catalytic intermediate is observed, leading to a potential offset between the accumulation of the intermediate and measurable O2 evolution. We contrast these data to CoFe-PB, where catalytic intermediate generation and O2 evolution onset coincide due to weaker binding and destabilization (∼0.19 eV/monolayer). By considering a correlation between activation energy and binding strength, we suggest that such adsorbate driven destabilization may account for a significant fraction of the observed OER catalytic activity in both materials. Finally, we disentangle the effects of adsorbate interactions on state coverages and kinetics to show how adsorbate interactions determine the observed Tafel slopes. Crucially, the case of CoFe-PB shows that, even where interactions are weaker, adsorption remains non-Nernstian, which strongly influences the observed Tafel slope.

Singular boundary behaviour and large solutions for fractional elliptic equations.

We perform a unified analysis for the boundary behaviour of solutions to nonlocal fractional equations posed in bounded domains. Based on previous findings for some models of the fractional Laplacian operator, we show how it strongly differs from the boundary behaviour of solutions to elliptic problems modelled upon the Laplace-Poisson equation with zero boundary data. In the classical case it is known that, at least in a suitable weak sense, solutions of the homogeneous Dirichlet problem with a forcing term tend to zero at the boundary. Limits of these solutions then produce solutions of some non-homogeneous Dirichlet problem as the interior data concentrate suitably to the boundary. Here, we show that, for equations driven by a wide class of nonlocal fractional operators, different blow-up phenomena may occur at the boundary of the domain. We describe such explosive behaviours and obtain precise quantitative estimates depending on simple parameters of the nonlocal operators. Our unifying technique is based on a careful study of the inverse operator in terms of the corresponding Green function.

Children With Asparaginase-associated Pancreatitis Present Elevated Levels of Insulin, Total Cholesterol, and HOMA-IR Before Starting Acute Lymphoblastic Leukemia Treatment.

Asparaginase-associated pancreatitis frequently occurs in children with cancer. It is unknown if other factors can influence the development of pancreatitis. A total of 33 pediatric patients with a confirmed diagnosis of acute lymphoblastic leukemia were included in this study. Before acute lymphoblastic leukemia drug treatment, the metabolic parameters (glucose, insulin, homeostasis model assessment insulin resistance, total cholesterol, triglycerides) and body mass index percentile were compared. Children who had acute pancreatitis had higher levels of insulin, homeostasis model assessment insulin resistance, and total cholesterol, compared with children who did not develop acute pancreatitis. These metabolic alterations could play a role in the development of pancreatitis.

The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.

The sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) has been demonstrated to predict the response to high-dose cytarabine consolidation treatment in acute myeloid leukemia patients. Here, we evaluated SAMHD1 as potential biomarker for the response to high-dose cytarabine in mantle cell lymphoma (MCL) patients. We quantified SAMHD1 protein expression and determined the mutation status in patients of the MCL Younger and Elderly trials (n = 189), who had received high-dose cytarabine- or fludarabine-based polychemotherapy. Additionally, we quantified SAMHD1 expression in B cell lymphoma cell lines and exposed them to cytarabine, fludarabine, and clinically relevant combinations. Across both trials investigated, SAMHD1 mutations had a frequency of 7.1% (n = 13) and did not significantly affect the failure-free survival (FFS, P = .47). In patients treated with high-dose cytarabine- or fludarabine-containing regimes, SAMHD1 expression was not significantly associated with FFS or complete remission rate. SAMHD1 expression in B cell lymphoma cell lines, however, inversely correlated with their in vitro response to cytarabine as single agent (R = .65, P = .0065). This correlation could be reversed by combining cytarabine with other chemotherapeutics, such as oxaliplatin and vincristine, similar to the treatment regime of the MCL Younger trial. We conclude that this might explain why we did not observe a significant association between SAMHD1 protein expression and the outcome of MCL patients upon cytarabine-based treatment.

Toxicity Screening of a Gambierdiscus australes Strain from the Western Mediterranean Sea and Identification of a Novel Maitotoxin Analogue.

Dinoflagellate species of the genera Gambierdiscus and Fukuyoa are known to produce ciguatera poisoning-associated toxic compounds, such as ciguatoxins, or other toxins, such as maitotoxins. However, many species and strains remain poorly characterized in areas where they were recently identified, such as the western Mediterranean Sea. In previous studies carried out by our research group, a G. australes strain from the Balearic Islands (Mediterranean Sea) presenting MTX-like activity was characterized by LC-MS/MS and LC-HRMS detecting 44-methyl gambierone and gambieric acids C and D. However, MTX1, which is typically found in some G. australes strains from the Pacific Ocean, was not detected. Therefore, this study focuses on the identification of the compound responsible for the MTX-like toxicity in this strain. The G. australes strain was characterized not only using LC-MS instruments but also N2a-guided HPLC fractionation. Following this approach, several toxic compounds were identified in three fractions by LC-MS/MS and HRMS. A novel MTX analogue, named MTX5, was identified in the most toxic fraction, and 44-methyl gambierone and gambieric acids C and D contributed to the toxicity observed in other fractions of this strain. Thus, G. australes from the Mediterranean Sea produces MTX5 instead of MTX1 in contrast to some strains of the same species from the Pacific Ocean. No CTX precursors were detected, reinforcing the complexity of the identification of CTXs precursors in these regions.

Application of the metabolomics approach to the discovery of active compounds from Brazilian trees against resistant human melanoma cells.

INTRODUCTION: The chemical diversity of plants plays an essential role in the development of new drugs. However, new bioactive compound identification and isolation are challenging due to the complexity and time-consuming nature of the traditional process. Recently, alternative strategies have become popular, such as the statistical approach to correlate compounds with biological activities, overcoming bottlenecks in bioactive natural product research. OBJECTIVE: We aimed to determine bioactive compounds against resistant human melanoma cells from leaves of Aspidosperma subincanum, Copaifera langsdorffii, Coussarea hydrangeifolia, Guarea guidonea and Tapirira guianensis, using a metabolomics approach. MATERIAL AND METHODS: The extracts and fractions were obtained by accelerated solvent extraction (ASE) and tested against resistant melanoma cells SK-MEL-28 and SK-MEL-103. Chemical analysis was performed by high-performance diode array detector tandem mass spectrometry (HPLC-DAD-MS/MS). Chemical and biological data were analysed through univariate and multivariate analysis. RESULTS: The species present high chemical diversity, including indole alkaloids, glycosylated flavonoids, galloylquinic acid derivatives, cinnamic acid derivatives, and terpenes. The ASE fractionation separated the compounds according to the physicochemical properties; only C. langsdorffii and T. guianensis extracts were active. Both results from the chemical profile and the biological assay were treated using a metabolomics approach to identify the contribution of different classes of secondary metabolites in the viability of human melanoma cells. The analyses showed the metabolites from C. langsdorffii and T. guianensis, such as polyphenols and terpenes, were the main compounds correlated with the biological response. CONCLUSION: These findings afford alternative pathways that are trustworthy and less time-consuming to identify new bioactive compounds against multidrug-resistant human melanoma cells.

Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis.

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.

Crystal Structure and Magnetic Properties of Trinuclear Transition Metal Complexes (MnII, CoII, NiII and CuII) with Bridging Sulfonate-Functionalized 1,2,4-Triazole Derivatives.

Here we present the synthesis, structure and magnetic properties of complexes of general formula (Mn)(Me2NH2)4][Mn3(µ-L)6(H2O)6] and (Me2NH2)6[M3(µ-L)6(H2O)6] (M = CoII, NiII and CuII); L-2 = 4-(1,2,4-triazol-4-yl) ethanedisulfonate). The trinuclear polyanions were isolated as dimethylammonium salts, and their crystal structures determined by single crystal and powder X-ray diffraction data. The polyanionic part of these salts have the same molecular structure, which consists of a linear array of metal(II) ions linked by triple N1-N2-triazole bridges. In turn, the composition and crystal packing of the MnII salt differs from the rest of the complexes (with six dimethyl ammonia as countercations) in containing one Mn+2 and four dimethyl ammonia as countercations. Magnetic data indicate dominant intramolecular antiferromagnetic interactions stabilizing a paramagnetic ground state. Susceptibility data have been successfully modeled with a simple isotropic Hamiltonian for a centrosymmetric linear trimer, H = -2J (S1S2 + S2S3) with super-exchange parameters J = -0.4 K for MnII, -7.5 K for NiII and -45 K for CuII complex. The magnetic properties of these complexes and their easy processing opens unique possibilities for their incorporation as magnetic molecular probes into such hybrid materials as magnetic/conducting multifunctional materials or as dopant for organic conducting polymers.

Consensus on hemophilia in Mexico.

Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor VIII (hemophilia A or classic) or factor IX (hemophilia B). Sequencing of the genes involved in hemophilia has provided a description and record of the main mutations, as well as a correlation with the various degrees of severity. Hemorrhagic manifestations are related to levels of circulating factor, mainly affecting the musculoskeletal system and specifically the large joints (knees, ankles, and elbows). This document is a review and consensus of the main genetic aspects of hemophilia, from the inheritance pattern to the concept of women carriers, physiopathology and classification of the disorder, the basic and confirmation studies when hemophilia is suspected, the various treatment regimens based on infusion of the deficient coagulation factor as well as innovative factor-free therapies and recommendations for the management of complications associated with treatment (development of inhibitors and/or transfusion-transmitted infections), or secondary to articular hemorrhagic events (hemophilic arthropathy). Finally, relevant reviews of clinical and treatment aspects of hemorrhagic pathology characterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.

La hemofilia es un trastorno hemorrágico con patrón de herencia ligado al sexo, caracterizado por una incapacidad en la amplificación de la coagulación ocasionada por la deficiencia del factor VIII (hemofilia A o clásica) o del factor IX (hemofilia B). La secuenciación de los genes involucrados en la hemofilia ha permitido la descripción y registro de las principales mutaciones, así como la correlación con los diversos grados de severidad. Las manifestaciones hemorrágicas se relacionan con los niveles de factor deficiente circulante, afectando principalmente al sistema musculoesquelético y en particular a las grandes articulaciones (rodillas, tobillos y codos). El presente documento hace una revisión y consenso de los principales aspectos genéticos de la hemofilia, desde el patrón de herencia y el concepto de mujeres portadoras, la fisiopatología y clasificación de la enfermedad, los estudios básicos y de confirmación ante la sospecha de hemofilia, y de los diversos esquemas de tratamiento basados en la infusión del factor de coagulación deficiente hasta las terapias innovadoras libres de factor, así como de las recomendaciones para el manejo de las complicaciones asociadas al tratamiento (desarrollo de inhibidores y/o infecciones transmitidas por transfusión) o secundarias a los eventos hemorrágicos a nivel articular (artropatía hemofílica). La parte final del documento revisa los aspectos clínicos y de tratamiento relevantes de una patología hemorragica caracterizada por la deficiencia adquirida del FVIII mediada por anticuerpos neutralizantes denominada hemofilia adquirida.

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients.

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

NUQA: Estimating Cancer Spatial and Temporal Heterogeneity and Evolution through Alignment-Free Methods.

Longitudinal next-generation sequencing of cancer patient samples has enhanced our understanding of the evolution and progression of various cancers. As a result, and due to our increasing knowledge of heterogeneity, such sampling is becoming increasingly common in research and clinical trial sample collections. Traditionally, the evolutionary analysis of these cohorts involves the use of an aligner followed by subsequent stringent downstream analyses. However, this can lead to large levels of information loss due to the vast mutational landscape that characterizes tumor samples. Here, we propose an alignment-free approach for sequence comparison-a well-established approach in a range of biological applications including typical phylogenetic classification. Such methods could be used to compare information collated in raw sequence files to allow an unsupervised assessment of the evolutionary trajectory of patient genomic profiles. In order to highlight this utility in cancer research we have applied our alignment-free approach using a previously established metric, Jensen-Shannon divergence, and a metric novel to this area, Hellinger distance, to two longitudinal cancer patient cohorts in glioma and clear cell renal cell carcinoma using our software, NUQA. We hypothesize that this approach has the potential to reveal novel information about the heterogeneity and evolutionary trajectory of spatiotemporal tumor samples, potentially revealing early events in tumorigenesis and the origins of metastases and recurrences. Key words: alignment-free, Hellinger distance, exome-seq, evolution, phylogenetics, longitudinal.

Medial femoral cutaneous nerve conduction study with distal recording: A novel technique.

BACKGROUND: A new technique to obtain the sensory nerve action potential (SNAP) of the medial femoral cutaneous nerve is described. METHODS: SNAPs were recorded from 104 subjects with a bar recording electrode 10 cm proximal to the patella along an imaginary line drawn between the medial edge of the patella and the femoral pulse below the inguinal ligament. Stimulation was applied 14 cm proximal to the recording point. RESULTS: There were 104 healthy subjects. Onset latency of the SNAPs was 2.20 ± 0.16 ms (mean ± SD), peak latency was 2.70 ± 0.16 ms, peak-to-peak amplitude was 7.5 ± 3.0 µV, and conduction velocity was 51.5 ± 3.0 m/s. The side-to-side difference in the mean amplitude was 22.27 ± 13.6%. CONCLUSIONS: This new technique is easy, reliable, and reproducible, and should prove useful for the evaluation of neuropathies of the medial femoral cutaneous nerve.

Roseovarius bejariae sp. nov., a moderately halophilic bacterium isolated from a hypersaline steep-sided river bed.

An aerobic, Gram-stain-negative ovoid, designated as strain A21T, was isolated using the dilution-to-extinction method from a soil sample taken from Rambla Salada, an athalassohaline habitat located in Murcia (south-eastern Spain). Strain A21T is non-motile, has a respiratory metabolism and grows at NaCl concentrations within the range 0.5-15 % (w/v) [optimum, 5 % (w/v)], at 5-35 °C (optimum, 28 °C) and at pH 6-8 (optimum, pH 7.0). This strain is positive for catalase activity, oxidase activity and nitrate reduction. The 16S rRNA gene sequence indicates that it belongs to the genus Roseovarius in the class Alphaproteobacteria. The most closely related species are Roseovarius pacificus and Roseovarius halotolerans to which the strain A21T shows 16S rRNA gene sequence similarity values of 98.06 and 97.7 %, respectively. The average nucleotide identity in blast and digital DNA-DNA hybridization values between strain A21T and R. pacificus LMG 24575T are 76.8 and 21 %, respectively. The DNA G+C content based on the genome is 61.28 mol%. The major fatty acids (>5 % of the total fatty acids) of strain A21T are C18 : 1 ω7c/C18 : 1 ω6c and C16 : 0. The only detected isoprenoid quinone in strain A21T is ubiquinone 10 (Q-10). The polar lipid profile contains phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and three unidentified polar lipids. Based on the phylogenetic, genotypic, phenotypic and chemotaxonomic data, the strain represents a novel species of the genus Roseovarius, for which the name Roseovarius bejariae sp. nov. is proposed. Strain A21T (=CECT 9817T=LMG 31311T) is the type strain.

Effect of Mechanochemical Recrystallization on the Thermal Hysteresis of 1D FeII-triazole Spin Crossover Polymers.

The thermal hysteresis in the cooperative spin crossover (SCO) polymer [Fe(trz)(Htrz)2]n[BF4]n (1) has been tuned by a simple ball milling grinding process. Mechanical treatment affects the size and morphology of the crystallite domains, as confirmed by multiple complementary techniques, including ESEM, DLS, and PXRD data. Upon milling, the regular cubic shape particles recrystallize with slightly different unit cell parameters and preferential orientation. This macroscopic change significantly modifies the thermally induced SCO behavior, studied by temperature-dependent magnetic susceptibility, X-ray diffraction, and DSC analysis. Transition temperatures downshift, closer to room temperature, while hysteresis widens, when particle sizes are actually decreasing. We relate this counterintuitive observation to subtle modifications in the unit cell, offering new alternatives to tune and enhance SCO properties in this class of 1D-cooperative polymers.

Association of the genetic variants (-794 CATT5-8 and -173 G > C) of macrophage migration inhibitory factor (MIF) with higher soluble levels of MIF and TNFα in women with breast cancer.

BACKGROUND: Functional variants -173 G > C (rs755622) and -794CATT5-8 (rs5844572) MIF gene have been associated with the risk in several types of cancer, as well as with the increase of soluble levels of MIF and TNFα. However, in previous studies contradictory and uncertain results have been presented on the implication of MIF polymorphisms with the association in cancer, specifically in breast cancer (BC). We investigated whether the variants are associated with the susceptibility to develop BC and the soluble levels of MIF and TNFα in women with BC from western Mexico. MATERIALS AND METHODS: A total of 152 women with BC and 182 control subjects (CS) were enrolled in this study. The determination of genotypes -173 G > C and -794 CATT5-8 MIF polymorphisms was performed by PCR-RFLP and PCR, respectively. In addition, the soluble levels of MIF and TNFα in both studied groups were quantified by ELISA and MILLIPLEX assay, respectively. RESULTS: The most frequent allele found in BC was the G (74.3%) and 6 (54%) in the variants -173G > C and -794 CATT5-8 , respectively, without significant differences in both groups. Nevertheless, the women with BC carriers -173*C and -794CATT7 have higher levels of MIF in comparison with CS. An increase of MIF (BC: 11.1 ng/mL vs CS: 5.2 ng/mL, P < .001) and TNFα (BC: 24.9 ng/mL vs CS: 9.9 pg/mL, P < .001) was found. CONCLUSION: The functional variants of MIF are not genetic susceptibility markers for BC. Nevertheless, the alleles -173*C and -794CATT7 are associated with the increase of MIF circulating in women with BC.

Proposal for the management of COVID-19-associated coagulopathy in children.

SARS-CoV-2 infection (COVID-19) has become a pandemic with a high case fatality rate that mainly affects adults. Most severely ill adult patients develop a coagulopathy that was not described until recently, and which is currently considered a main cause of death. Everything indicates that a similar phenomenon also occurs in children with COVID-19. Anticoagulant treatment has become one of the therapeutic foundations for this infection; however, its implementation in children can be difficult since, until recently, it was not considered in the pediatric population. Evidence regarding the use of anticoagulants in COVID-19 is rapidly generated, changes constantly, it is often difficult to interpret, and can be contradictory. After an extensive review of the published literature, a proposal was generated that offers suggestions for anticoagulant treatment, considering available resources in Mexico.

La infección por SARS-CoV-2 (COVID-19) se ha constituido en una pandemia con alto índice de letalidad que afecta principalmente a los adultos. La mayor parte de los pacientes adultos graves desarrolla una coagulopatía que no estaba descrita, la cual actualmente se considera la principal causa de muerte. Todo indica que un fenómeno parecido ocurre también en el niño con COVID-19. El tratamiento anticoagulante se ha convertido en uno de los fundamentos terapéuticos de esta infección; sin embargo, su establecimiento en el niño puede ser difícil ya que, hasta hace poco, no estaba considerado en la población pediátrica. La evidencia respecto al uso de anticoagulantes en COVID-19 se genera con rapidez, cambia constantemente, con frecuencia es difícil de interpretar y puede ser contradictoria. Después de una extensa revisión de la literatura publicada, se generó una propuesta que ofrece sugerencias para el tratamiento anticoagulante en la que se consideran los recursos disponibles en México.

Investigating the potential clinical benefit of Selumetinib in resensitising advanced iodine refractory differentiated thyroid cancer to radioiodine therapy (SEL-I-METRY): protocol for a multicentre UK single arm phase II trial.

BACKGROUND: Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial. METHODS: SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data. DISCUSSION: The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field. TRIAL REGISTRATION: SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.

Draft genome sequence of Lactobacillus plantarum C4 (CECT 9567), a potential probiotic strain isolated from kefir.

Lactobacillus plantarum C4 (CECT 9567) was isolated from kefir and has been extensively studied because of its probiotic properties. Here we report the genome sequence of this strain. The genome consists of 3,221,350 bp, and contains 3058 CDSs with an average G + C content of 44.5%. The genome harbors genes encoding the AraC-family transcription regulator, the penicillin-binding protein Pbp2A, and the Na+/H+ antiporter NapA3, which have important roles in the survival of lactobacilli in the gastrointestinal tract. Also, the genome encodes the catalase KatE, NADH peroxidase and glutathione peroxidase, which enable anaerobic respiration, and a nitrate reductase complex, which enable anaerobic respiration. Additionally, genes encoding plantaricins and sactipeptides, and genes involved in the use of fructooligosaccharides and in the production of butyric acid were also identified. BLASTn analysis revealed that 91.4% of CDSs in C4 genome aligned with those of the reference strain L. plantarum WCFS1, with a mean identity of 98.96%. The genome information of L. plantarum C4 provides the basis for understanding the probiotic properties of C4 and to consider its use as a potential component of functional foods.