CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy

Síndrome Nefrótico secundario a Leptospirosis

Un caso clínico de Leptospirosis canina con sintomatología neurológica aguda de tipo convulsiv

Physical properties of soil in the early stage of an agroforestry system in the High Andean zone

In Nariño, Colombia, land use has generated some problems such as erosion, compaction, lack of fertility, among others, so it is necessary to search for alternatives to mitigate these impacts. The objective of this study was to evaluate some physical properties of the soil in an agroforest system with Morella pubescens (Humb. & Bonpl. ex Willd.) Wilbur with Smallanthussonchifolius (Poepp.) H.Rob, in the experimental farm of Botana, in the city of Pasto, Nariño, where the bulk density, real density, total porosity, structural stability properties and distribution of aggregates were analyzed. The datas were obtained in two phases: f1 and f2 before and after agroforestry system implementation, respectively. A randomized complete block design with three treatments and three replications were used. The treatments corresponded to plant densities, T1: S sonchifoliuos, sowed to 1x1m, T2:0.8x0.8m y T3:0.5x0.5m, with three replications. M pusescens was stablished to 4x4m between plants and 9 m between rows and the control (f1). The statistics have differences between f1 (control) and f2 (treatments), to the structural stability properties and distribution of aggregates. The ground suffered a structural stability change to stable lightly (0.97 D.P.M) in f1 to a stable moderate (2.53 D.P.M), in f2. The distribution of aggregates passed to 60% in f1 to 70.3% in f2, with a media aggregation status. The different agroforest systems management could help, in the long term, by improving the structure of the ground through the vegetal material of arboreal component, the application of a minimum farming and the addition of organic matter

Zirconium Metal−Organic Polyhedra with Dual Behavior for Organophosphate Poisoning Treatment

Organophosphate nerve agents and pesticides are extremely toxic compounds because they result in acetylcholinesterase (AChE) inhibition and concomitant nerve system damage. Herein, we report the synthesis, structural characterization, and proof-of-concept utility of zirconium metal−organic polyhedra (Zr-MOPs) for organophosphate poisoning treatment. The results show the formation of robust tetrahedral cages [((n-butylCpZr)3(OH)3O)4L6]Cl6 (Zr-MOP-1; L = benzene-1,4- dicarboxylate, n-butylCp = n-butylcyclopentadienyl, Zr-MOP-10, and L = 4,4′-biphenyldicarboxylate) decorated with lipophilic alkyl residues and possessing accessible cavities of ∼9.8 and ∼10.7 Å inner diameters, respectively. These systems are able to both capture the organophosphate model compound diisopropylfluorophosphate (DIFP) and host and release the AChE reactivator drug pralidoxime (2-PAM). The resulting 2-PAM@ Zr-MOP-1(0) host−guest assemblies feature a sustained delivery of 2-PAM under simulated biological conditions, with a concomitant reactivation of DIFP-inhibited AChE. Finally, 2-PAM@Zr-MOP systems have been incorporated into biocompatible phosphatidylcholine liposomes with the resulting assemblies being non-neurotoxic, as proven using neuroblastoma cell viability assays.Spanish MCIN/AEI PID2020-113608RB-I00FEDER/Junta de Andalucia-Conserjeria de Economia y Conocimiento B-FQM-364-UGR18 B-FQM-006-UGR18FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades P18-RT-612 P20_00672Fondazione CRUIprograma Juan de la Cierva FormacionSpanish Government PID2020-118117RB-I00Center for Forestry Research & Experimentation (CIEF)European Commission SEJIGENT/2021/059 PROMETEU/2021/054La Caixa Foundation 100010434 LCF/BQ/PR20/11770014"Maria de Maeztu" Program for Centers of Excellence in RD CEX2019-000919-MH2020-MSCA-IF2019-888972-PSust-MO

First-Trimester Sequential Screening for Preeclampsia Using Angiogenic Factors : Study Protocol for a Prospective, Multicenter, Real Clinical Setting Study

The incidence of preeclampsia (PE) is about 2-8%, making it one of the leading causes of perinatal morbidity and maternal mortality in the world. Early prophylactic low dose administration (150 mg) of acetylsalicylic acid is associated with a significant reduction in the incidence of early-onset PE, intrauterine growth restriction (IUGR), and neonatal mean stay in the intensive care unit (ICU). Universal implementation of a first-trimester screening system including angiogenic and antiangiogenic markers [the Placental Growth Factor (PlGF) and/or soluble fms-like Tyrosine Kinase-1 (sFlt-1)] has shown a prediction rate of 90% for early-onset PE but entails a high financial cost. The aim of this study is to determine the predictive and preventive capacity of a universal PE first-trimester two-step sequential screening model, determining the PlGF only in patients previously classified as intermediate risk by means of a multivariate model based on resources already used in the standard pregnancy control, in a real clinical setting. We hypothesize that this screening model will achieve similar diagnostic performance as the universal determination of PlGF but at a lower economic cost. This is a prospective, multicentric, cohort study in a real-world clinical setting. Every singleton pregnancy will be recruited at the routine first pregnancy visit. In a first step, the first-trimester risk of PE will be calculated using a multivariate Gaussian distribution model, based on medical history, mean blood pressure, Pregnancy-Associated Plasma Protein A (PAPP-A), and Uterine Artery Doppler Pulsatility Index (UTPI). Patients will be classified into three risk groups for PE: (1) risk ≥ 1/50, high-risk with no further testing (blinded PlGF); (2) risk between 1/51 and 1/500, medium-risk requiring further testing; and (3) risk ≤ 1/501, low-risk with no further testing. In a second step, the PlGF will only be determined in those patients classified as intermediate risk after this first step, and then reclassified into high- or low-risk groups. Prophylactic administration of aspirin (150 mg/day) will be prescribed only in high risk patients. As a secondary objective, sFlt-1 values will be blindly determined in patients with high and intermediate risk to assess its potential performance in the screening for PE. The study will be conducted in accordance with the principles of Good Clinical Practice. This study is approved by the Aragon Research Ethics Committee (CEICA) on 3 July 2020 (15/2020). , identifier: NCT04767438

New Light in Star-Forming Dwarf Galaxies: The PMAS Integral Field View of the Blue Compact Dwarf Galaxy Mrk 409

We present an integral field spectroscopic study of the central 2x2 kpc^2 of the blue compact dwarf galaxy Mrk 409, observed with the Potsdam MultiAperture Spectrophotometer. This study focuses on the morphology, two-dimensional chemical abundance pattern, excitation properties and kinematics of the ionized interstellar medium in the starburst component. We also investigate the nature of the extended ring of ionized gas emission surrounding the bright nuclear starburst region of Mrk 409. PMAS spectra of selected regions along the ring, interpreted with evolutionary and population synthesis models, indicate that their ionized emission is mainly due to a young stellar population with a total mass of ~1.5x10^6 M_sun, which started forming almost coevally ~10 Myr ago. This stellar component is likely confined to the collisional interface of a spherically expanding, starburst-driven super-bubble with denser, swept-up ambient gas, ~600 pc away from the central starburst nucleus. The spectroscopic properties of the latter imply a large extinction (C_H-beta>0.9), and the presence of an additional non-thermal ionization source, most likely a low-luminosity Active Galactic Nucleus. Mrk 409 shows a relatively large oxygen abundance (12+log(O/H)~8.4) and no chemical abundance gradients out to R~600 pc. The ionized gas kinematics displays an overall regular rotation on a northwest-southwest axis, with a maximum velocity of 60 km/s; the total mass inside the star-forming ring is about 1.4x10^9 M_sun.Comment: Accepted for publication in Ap

Minimizing acquisition-related radiomics variability by image resampling and batch effect correction to allow for large-scale data analysis

Objective: To identify CT-acquisition parameters accounting for radiomics variability and to develop a post-acquisition CTimage correction method to reduce variability and improve radiomics classification in both phantom and clinical applications. Methods: CT-acquisition protocols were prospectively tested in a phantom. The multi-centric retrospective clinical study included CT scans of patients with colorectal/renal cancer liver metastases. Ninety-three radiomics features of first order and texture were extracted. Intraclass correlation coefficients (ICCs) between CT-acquisition protocols were evaluated to define sources of variability. Voxel size, ComBat, and singular value decomposition (SVD) compensation methods were explored for reducing the radiomics variability. The number of robust features was compared before and after correction using two-proportion z test. The radiomics classification accuracy (K-means purity) was assessed before and after ComBat- and SVD-based correction. Results: Fifty-three acquisition protocols in 13 tissue densities were analyzed. Ninety-seven liver metastases from 43 patients with CT from two vendors were included. Pixel size, reconstruction slice spacing, convolution kernel, and acquisition slice thickness are relevant sources of radiomics variability with a percentage of robust features lower than 80%. Resampling to isometric voxels increased the number of robust features when images were acquiredwith different pixel sizes (p < 0.05). SVD-based for thickness correction and ComBat correction for thickness and combined thickness–kernel increased the number of reproducible features (p < 0.05). ComBat showed the highest improvement of radiomics-based classification in both the phantom and clinical applications (K-means purity 65.98 vs 73.20). Conclusion: CT-image post-acquisition processing and radiomics normalization by means of batch effect correction allow for standardization of large-scale data analysis and improve the classification accuracy

ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies

Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies, and there is a connection between atherosclerosis and autoimmunity. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.Ministerio de Economía y Competitividad (SVP-2014-068289); P.D. was supported by an AECC grant (AIO 2012, Ayudas a Investigadores en Oncología 2012); A.S.-B. is a Juan de la Cierva researcher (IJC2018-035279-I); I.M.-F. was a fellow of the research training program funded by Ministerio de Economía y Competitividad (SVP-2014-068216); and A.R.R. and J.V. are supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC). The project leading to these results has received funding from la Caixa Banking Foundation under the project code HR17-00247 and from SAF2016-75511-R and PID2019-106773RB-I00 grants to A.R.R. (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–201

National survey: how do we approach the patient at risk of clinical deterioration outside the ICU in the spanish context?

Background: Anticipating and avoiding preventable intrahospital cardiac arrest and clinical deterioration are important priorities for international healthcare systems and institutions. One of the internationally followed strategies to improve this matter is the introduction of the Rapid Response Systems (RRS). Although there is vast evidence from the international community, the evidence reported in a Spanish context is scarce. Methods: A nationwide cross-sectional research consisting of a voluntary 31-question online survey was performed. The Spanish Society of Intensive, Critical and Coronary Care Medicine (SEMICYUC) supported the research. Results: We received 62 fully completed surveys distributed within 13 of the 17 regions and two autonomous cities of Spain. Thirty-two of the participants had an established Rapid Response Team (RRT). Common frequency on measuring vital signs was at least once per shift but other frequencies were contemplated (48.4%), usually based on professional criteria (69.4%), as only 12 (19.4%) centers used Early Warning Scores (EWS) or automated alarms on abnormal parameters. In the sample, doctors, nurses (55%), and other healthcare professionals (39%) could activate the RRT via telephone, but only 11.3% of the sample enacted this at early signs of deterioration. The responders on the RRT are the Intensive Care Unit (ICU), doctors, and nurses, who are available 24/7 most of the time. Concerning the education and training of general ward staff and RRT members, this varies from basic to advanced and specific-specialized level, simulating a growing educational methodology among participants. A great number of participants have emergency resuscitation equipment (drugs, airway adjuncts, and defibrillators) in their general wards. In terms of quality improvement, only half of the sample registered RRT activity indicators. In terms of the use of communication and teamwork techniques, the most used is clinical debriefing in 29 centers. Conclusions: In terms of the concept of RRS, we found in our context that we are in the early stages of the establishment process, as it is not yet a generalized concept in most of our hospitals. The centers that have it are in still in the process of maturing the system and adapting themselves to our context

First-Trimester Sequential Screening for Preeclampsia Using Angiogenic Factors: Study Protocol for a Prospective, Multicenter, Real Clinical Setting Study

IntroductionThe incidence of preeclampsia (PE) is about 2–8%, making it one of the leading causes of perinatal morbidity and maternal mortality in the world. Early prophylactic low dose administration (150 mg) of acetylsalicylic acid is associated with a significant reduction in the incidence of early-onset PE, intrauterine growth restriction (IUGR), and neonatal mean stay in the intensive care unit (ICU). Universal implementation of a first-trimester screening system including angiogenic and antiangiogenic markers [the Placental Growth Factor (PlGF) and/or soluble fms-like Tyrosine Kinase-1 (sFlt-1)] has shown a prediction rate of 90% for early-onset PE but entails a high financial cost. The aim of this study is to determine the predictive and preventive capacity of a universal PE first-trimester two-step sequential screening model, determining the PlGF only in patients previously classified as intermediate risk by means of a multivariate model based on resources already used in the standard pregnancy control, in a real clinical setting. We hypothesize that this screening model will achieve similar diagnostic performance as the universal determination of PlGF but at a lower economic cost.Methods and AnalysisThis is a prospective, multicentric, cohort study in a real-world clinical setting. Every singleton pregnancy will be recruited at the routine first pregnancy visit. In a first step, the first-trimester risk of PE will be calculated using a multivariate Gaussian distribution model, based on medical history, mean blood pressure, Pregnancy-Associated Plasma Protein A (PAPP-A), and Uterine Artery Doppler Pulsatility Index (UTPI). Patients will be classified into three risk groups for PE: (1) risk ≥ 1/50, high-risk with no further testing (blinded PlGF); (2) risk between 1/51 and 1/500, medium-risk requiring further testing; and (3) risk ≤ 1/501, low-risk with no further testing. In a second step, the PlGF will only be determined in those patients classified as intermediate risk after this first step, and then reclassified into high- or low-risk groups. Prophylactic administration of aspirin (150 mg/day) will be prescribed only in high risk patients. As a secondary objective, sFlt-1 values will be blindly determined in patients with high and intermediate risk to assess its potential performance in the screening for PE.Ethics and DisseminationThe study will be conducted in accordance with the principles of Good Clinical Practice. This study is approved by the Aragon Research Ethics Committee (CEICA) on 3 July 2020 (15/2020).Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT04767438