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Several clinical risk models have been proposed to predict outcome in follicular lymphoma (FL). The development of Next Generation Sequencing (NGS) technologies has allowed the integration of somatic gene mutations in clinical scores to build genotyped-based risk models, such as m7-FLIPI. We explored four clinical or clinicogenetic risk models in patients with symptomatic FL who received frontline immunochemotherapy. Out of 191 patients with FL grade 1-3a, 109 were successfully genotyped. Treatment consisted on rituximab (R) plus CVP/CHOP (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high-risk in FLIPI, FLIPI-2, PRIMA-PI or m7-FLIPI were 39.3%, 14%, 30.3%, 22%, respectively. No case with low-intermediate FLIPI was upgraded in m7-FLIPI, but 18 out of 42 higher-risk patients in FLIPI were downgraded to low-risk m7-FLIPI. Sensitivity and specificity for the prediction of POD24 was highest for FLIPI. The discrimination for progression free survival (PFS) and overall survival (OS) was best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only R-B patients, m7-FLIPI had higher discrimination for PFS and OS. Thus, FLIPI remains as the clinical risk score with higher discrimination in advanced FL patients treated with immunochemotherapy, but the performance of m7-FLIPI should be further investigated in patients treated with R-B.

Background Congenital diaphragmatic hernia (CDH) is a severe birth defect associated with high perinatal mortality and long-term morbidity. The etiology of CDH is poorly understood although abnormal retinoid signaling has been proposed to contribute to abnormal diaphragm development. Existing epidemiological data suggest that inadequate dietary vitamin A intake is a risk factor for developing CDH. Methods Using a mouse model of teratogen-induced CDH, the objective of this study was to test the hypothesis that low maternal vitamin A intake contributes to abnormal diaphragm development. To test this hypothesis, we optimized a model of altered maternal dietary vitamin A intake and a teratogenic model of CDH in mice that recapitulates the hallmark features of posterolateral diaphragmatic hernia in humans. Results Our data uniquely show that low maternal dietary vitamin A intake and marginal vitamin A status increases the incidence of teratogen-induced CDH in mice. Conclusion Low dietary vitamin A intake and marginal vitamin A status lead to an increased incidence of teratogen-induced CDH in mice, highlighting the importance of adequate dietary vitamin A intake and CDH risk. Impact This study describes and validates a mouse model of altered maternal and fetal vitamin A status. This study links existing epidemiological data with a mouse model of teratogen-induced congenital diaphragmatic hernia, highlighting the importance of low maternal vitamin A intake as a risk factor for the development of congenital diaphragmatic hernia. This study supports the Retinoid Hypothesis, which posits that the etiology of congenital diaphragmatic hernia is linked to abnormal retinoid signaling in the developing diaphragm.

Simple Summary This research predicted the overall survival of patients and cell-of-origin molecular subtypes of diffuse large B-cell lymphoma from Tokai University using gene expression data. A pancancer immune profiling panel was analyzed using artificial neural networks, and high accuracy of prediction was found. Additionally, the results were explained with other machine learning techniques and conventional bioinformatics analyses. Abstract Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent subtypes of non-Hodgkin lymphomas. We used artificial neural networks (multilayer perceptron and radial basis function), machine learning, and conventional bioinformatics to predict the overall survival and molecular subtypes of DLBCL. The series included 106 cases and 730 genes of a pancancer immune-oncology panel (nCounter) as predictors. The multilayer perceptron predicted the outcome with high accuracy, with an area under the curve (AUC) of 0.98, and ranked all the genes according to their importance. In a multivariate analysis, ARG1, TNFSF12, REL, and NRP1 correlated with favorable survival (hazard risks: 0.3–0.5), and IFNA8, CASP1, and CTSG, with poor survival (hazard risks = 1.0–2.1). Gene set enrichment analysis (GSEA) showed enrichment toward poor prognosis. These high-risk genes were also associated with the gene expression of M2-like tumor-associated macrophages (CD163), and MYD88 expression. The prognostic relevance of this set of 7 genes was also confirmed within the IPI and MYC translocation strata, the EBER-negative cases, the DLBCL not-otherwise specified (NOS) (High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements excluded), and an independent series of 414 cases of DLBCL in Europe and North America (GSE10846). The perceptron analysis also predicted molecular subtypes (based on the Lymph2Cx assay) with high accuracy (AUC = 1). STAT6, TREM2, and REL were associated with the germinal center B-cell (GCB) subtype, and CD37, GNLY, CD46, and IL17B were associated with the activated B-cell (ABC)/unspecified subtype. The GSEA had a sinusoidal-like plot with association to both molecular subtypes, and immunohistochemistry analysis confirmed the correlation of MAPK3 with the GCB subtype in another series of 96 cases (notably, MAPK3 also correlated with LMO2, but not with M2-like tumor-associated macrophage markers CD163, CSF1R, TNFAIP8, CASP8, PD-L1, PTX3, and IL-10). Finally, survival and molecular subtypes were successfully modeled using other machine learning techniques including logistic regression, discriminant analysis, SVM, CHAID, C5, C&R trees, KNN algorithm, and Bayesian network. In conclusion, prognoses and molecular subtypes were predicted with high accuracy using neural networks, and relevant genes were highlighted.

BackgroundStandard therapy for COVID-19 is continuously evolving. Autopsy studies showed high prevalence of platelet-fibrin-rich microthrombi in several organs. The aim of the study was therefore to evaluate the safety and efficacy of antiplatelet therapy (APT) in hospitalised patients with COVID-19 and its impact on survival.Methods7824 consecutive patients with COVID-19 were enrolled in a multicentre international prospective registry (Health Outcome Predictive Evaluation-COVID-19 Registry). Clinical data and in-hospital complications were recorded. Data on APT, including aspirin and other antiplatelet drugs, were obtained for each patient.ResultsDuring hospitalisation, 730 (9%) patients received single APT (93%, n=680) or dual APT (7%, n=50). Patients treated with APT were older (74±12 years vs 63±17 years, pConclusionsAPT during hospitalisation for COVID-19 could be associated with lower mortality risk and shorter duration of mechanical ventilation, without increased risk of bleeding.Trial registration numberNCT04334291.

This two-part paper addresses the design of retail electricity tariffs for distribution systems with distributed energy resources (DERs). Part I presents a framework to optimize ex-ante two-part tariffs for a regulated retailer who faces stochastic wholesale prices on the one hand and stochastic demand on the other. In part II, the integration of DERs is addressed by analyzing their effect on the optimal two-part tariff and the induced welfare gains. Two DER integration models are considered: a decentralized model involving behind-the-meter DERs and a centralized model with retailer-integrated DERs. It is shown that DERs integrated under either model can achieve the same social welfare and that net metering is optimal. The retail prices for both models are equal and reflect the expected wholesale prices. The connection charges differ and are affected by the retailer's fixed costs and the statistical dependencies between wholesale prices and behind-the-meter DERs. These charges are higher under the decentralized model. An empirical analysis is presented to estimate the impact of DER on welfare distribution and cross-subsidies. It shows that, with the prevailing net-metering tariffs, consumer welfare decreases with the level of DER integration. Issues of cross-subsidy and practical drawbacks of decentralized integration are also discussed.

This work reviews the origin of the current Instituto de Catalisis y Petroleoquimica (ICP, Institute of Catalysis and Petroleum Chemistry) that belongs to the Consejo Superior de Investigaciones Cientificas (CSIC, Spanish National Research Council). The first papers on catalysis were published in Spanish scientific journals in 1908. In 1912, the first catalytic experiments were done in the research laboratories belonging to a new Spanish institution established in 1907, the Junta para la Ampliacion de Estudios e Investigaciones Cientificas (JAE, Council for Development of Studies and Scientific Researches), which was not dependent on the university. These laboratories were later integrated in the new Instituto Nacional de Fisica y Quimica (National Institute of Physics and Chemistry), opened in 1932 and located in a new building financed by the Rockefeller Foundation. In 1939, at the end of the Spanish Civil War (1936–1939), the JAE was abolished and replaced by CSIC. As a consequence of the reorganization process of the research institutes undertaken by CSIC, the Instituto de Quimica Fisica “Antonio Gregorio Rocasolano” (IQFR, Institute of Chemical Physics) was founded in 1946, which basically inherited the former National Institute of Physics and Chemistry, and on the very same premises. A new Catalysis Laboratory was established in 1953 in the IQFR under the leadership of Prof. Juan Francisco Garcia de la Banda, which evolved through several steps to become finally an independent research center in 1975 under the name of Instituto de Catalisis y Petroleoquimica (ICP, Institute of Catalysis and Petroleum Chemistry). The ICP moved to its present premises in 1990.

Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

Biopsy samples of lymph nodes from 38 patients with CLL were analyzed. We found differential expression in 1092 genes in two different subgroups: 418 overexpressed in one subgroup and 674 in another. Molecular pathways identified in one subgroup appear to be characterized by greater dependence of signaling by cytokines and activation of the NFkB pathway, while in the other seem to depend on cell cycle. Despite having found a differential expression between both subgroups, none of these genes reached FDR < 0.25. We have not found significant association with survival or any prognostic factors. Analysis of the differences between normal lymph node and CLL in 253 genes with difference in the intensity of expression revealed upregulated genes different to BCR: CD40, TCL1, IL-7, and PAX5. Using large-scale molecular analysis, we may obtain information about molecular mechanisms of CLL pathogenesis and may contribute to the identification of new therapeutic targets.

Vegetation modulates the effects of climate variability through soil–vegetation–atmosphere (SVAT) interactions. A quantitative understanding of such interactions requires the proper integration of the water cycle and photosynthesis. While biochemical models have widely been used to estimate primary production, the effects of water stress on transpiration and carbon assimilation rates, and its feedbacks into the water cycle are not generally represented. The objective of this study is to investigate the limiting effects of soil moisture and evaporative demand on photosynthesis, and to understand its interactions with other hydrological processes. Our approach consists of integrating a physically based land surface hydrological model (LSHM) with a biochemical model for leaf photosynthesis and a substrate-structure separation model for respiration, including parameterizations of the diurnal cycle of Rubisco concentration and species-specific stomatal conductance (resistance). Exploratory simulations to evaluate the model against results from previous studies indicated that the model captures basic processes of canopy physiology well. Sensitivity analysis shows that water stress at sub-daily time-scales is an important limiting factor of photosynthesis, thus constraining carbon assimilation. On the other hand, the results further suggest that the biological control of transpiration via stomatal sensitivity is only significant under soil water stress conditions. Overall, the integrated model is capable of estimating not only carbon assimilation, but also the length of the growing season, as well as feedbacks between vegetation and soil hydrology processes.

Life cycle assessment (LCA) is an ISO standardized method designed to evaluate the impact of human activities on the environment using objective and measurable indicators. To be effective an LCA analysis should be cost-efficient in data gathering and the methods used for calculating the impact categories ought to be universally applicable. The land use impact category of an LCA deals with impacts of land occupation and land use change on water balance, soil and vegetation. This paper proposes to use a modelling approach to generate indicators for the land use impact of CO2 emission reduction projects on the ecosystem water balance. The rate variables of the water balance selected to describe the land use impacts are evapotranspiration, surface runoff, discharge, groundwater recharge and soil loss through water erosion. They are simulated making use of the SWAT model. The paper describes the application of the proposed methodology for two locations with different site characteristics and land use patterns. Special attention was paid to aspects of data availability and reliability. Comparison of the simulation results with literature data revealed that SWAT provides reasonable results, which can be used for assessing the land use impact in LCA. The sensitivity analysis indicated low dependency of the model output to minor and moderate changes in model input, with the exception of changes in precipitation and leaf area index (LAI). The study also indicated that the land use library in SWAT needs further development to become universally applicable for LCA purposes. A scenario analysis allowed us to predict the impact of land occupation on the hydrology and erosion of both study areas. Finally, the LCA indicators giving the impact on the water balance per functional unit were calculated by expressing the SWAT outputs per kilogram of CO2 emission reduction. Copyright © 2005 John Wiley & Sons, Ltd.

In the present study, we describe the modifications in the expression of type II 5′deiodinase activity (5′D) in Xenopus laevis oocytes by injection of polyadenylated (poly A) mRNA from hypothyroid rat Harderian gland. The time-course study showed that the expression of the enzyme was dependent on time. Thus, enzyme activity was observed in oocytes 6 and 12 hours after the injection with poly A mRNA, reaching a maximal value at 24 hours. The activity was partially inhibited by 6-n-propyl-thiouracil, completely inhibited by iopanoic acid and exhibited a higher affinity for the T4 (Km = 1.5 nM) than rT3 (Km = 20 nM). The expression of the enzyme was modified in different experimental conditions: (a) exhibited diurnal variations with maximal peak values at night, (b) was inhibited by light at night and, (c) was activated by isoproterenol. On the other hand, we have also identified, for the first time, the size of mRNA capable of inducing 5′D in rats.

Vasoactive intestinal peptide (VIP) receptors and beta-adrenergic receptors were investigated in rat Harderian gland membranes using 125I-VIP and 125I-cyanopindolol (125I-CYP), respectively, as ligands. The receptor bindings were rapid, reversible, saturable, specific, and dependent on time, temperature, and membrane concentration. The stoichiometric data suggested the presence of two classes of VIP receptors with Kd values of 0.36 and 65.37 nM and binding capacities of 323 and 39,537 fmol VIP/mg protein, respectively. The interaction showed a high degree of specificity, as suggested by competitive displacement experiments with several peptides structurally or not structurally related to VIP as follows: VIP > helodermin > rGRF > PHI > > secretin. Glucagon, somatostatin, insulin, and pancreastatin were ineffective at concentrations up to 1 microM. However, the stoichiometric data suggest the presence of one class of binding sites for 125I-CYP. The Kd for the single site was 290 pM with a binding capacity of 32 pmol/L. The pharmacological characterization of 125I-CYP binding to membranes showed that only isoproterenol, a beta-adrenergic agonist, and norepinephrine, an alpha beta-adrenergic agonist, was as effective as propranolol in inhibiting 125I-CYP binding to Harderian gland membranes. However, alpha 1- and alpha 2-adrenergic agonists and blockers such as methoxamine, prazosin, clonidine, and yohimbine were shown to be ineffective. These results demonstrate the presence of specific VIP and beta-adrenergic receptors in the Harderian gland and suggest a role for VIP and beta-adrenergic agonists in the physiology of this gland.

Ion/molecule reactions are commonly used to characterize structures due to their high specificity. Herein, we present ambient ion/molecule reactions performed in the course of low-temperature plasma (LTP) ionization of condensed-phase analytes in order to increase the specificity of LTP-based ambient analysis.The ion population of the cold plasma is modified by addition of a reagent to the plasma before it is directed at a surface bearing the analyte. Desorbed ions were analyzed using linear ion trap-Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS).Acylium ions generated from tetramethylurea react with 1,3-dioxane analyte to afford distinctive Eberlin product ions. Reactions of alkylamines, such as n-hexylamine and n-octylamine, with benzaldehyde produce the corresponding imines. Reaction of ruthenocene with trifluoroacetic anhydride forms the unusual trifluoroacetate ruthenocene.A LTP source can be used to generate reagent ions that can undergo ion/molecule reactions in the ambient environment with an analyte at condensed phase on a surface. The experiment is a 'reactive' version of the standard low-temperature plasma (LTP) ambient ionization experiment. This approach provides additional information by combining ion/molecule chemistry with conventional MS and MS/MS data to characterize particular analytes.

In this work, the use of liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC-TOFMS) has been evaluated for the profiling of relatively low-molecular weight protein species in both genetically modified (GM) and non-GM maize. The proposed approach consisted of a straightforward sample fractionation with different water and ethanol-based buffer solutions followed by separation and detection of the protein species using liquid chromatography with a small particle size (1.8 μm) C(18) column and electrospray-time-of-flight mass spectrometry detection in the positive ionization mode. The fractionation of maize reference material containing different content of transgenic material (from 0 to 5% GM) led to five different fractions (albumins, globulins, zeins, zein-like glutelins, and glutelins), all of them containing different protein species (from 2 to 52 different species in each fraction). Some relevant differences in the quantity and types of protein species were observed in the different fractions of the reference material (with different GM contents) tested, thus revealing the potential use of the proposed approach for fast protein profiling and to detect tentative GMO markers in maize.

The presence of isoenzymes mediating the conversion of thyroxine to 3,5,3′-triiodothyronine has been studied according to characteristic kinetics and physiological regulation. In this paper, we report the expression of type II 5′-deiodinase (5′D) activity in oocytes of Xenopus laevis. Oocytes injected with total RNA extracted from rat Harderian gland, and then incubated up to five days demonstrated a progressive increase in 5′D activity, reaching a maximal value at 24 h; then, 5′D activity remained almost stable for an additional period of four days. Characteristics of the enzyme activity expressed by oocytes included its inhibition by iopanoic acid, but not by propylthiouracil, and its increase during β-adrenergic agonist treatment and hypothyroidism. The expressed activity manifests characteristics typical of the type II isoenzyme. Deiodinating activity in oocytes also exhibited diurnal variations. In this study, 5′D activity expressed in oocytes exhibited low values when animals were killed during the day, and high values when animals were killed at night. Maximal values were reached 3–4 h before the nocturnal peak of 5′D activity in Harderian gland crude homogenates. Results suggest that the in vivo activation of 5′D by isoproterenol, hypothyroidism, or dark exposure may be caused by an increase in the synthesis and/or maturation of the RNA expressing the enzyme.

Follicular lymphoma (FL) is the most common type of low-grade non-Hodgkin’s lymphoma. A subset of FL patients shows a favorable treatment response, and remains in complete remission with long-term follow-up, while another subset of patients has a clinical course characterized by frequent relapses and a shorter survival. Survival predictors for FL are mainly based on clinical data, and they seem to lack accuracy enough predicting survival among patients with advanced stage disease. The aim of this study is to build a survival predictor based on a set of biological markers using Tissue Micro Arrays (TMA). To this purpose, we have retrospectively analysed the expression of a group of 40 selected genes - related with apoptosis control, cell cycle, B-cell differentiation and signaling- in a series of 192 FLs using TMA. The association of these molecules with survival, and their usefulness to discriminate among FLIPI groups was evaluated. Results were quantified using different tools; singularly nuclear markers were scanned using the Bliss system and the quantitative expression was measured using the TMAscore v.1.0 image analysis software (Bacus Laboratories, Inc.). The mean overall survival (OS) was 74 months, and 38 months for progression-free survival (PFS). Statistically significant differences in OS were found with the Follicular Lymphoma International Prognostic Index (FLIPI) score (p < 0.01). No significant OS or PFS differences were observed between FL grades 1–3, between grades 3a and 3b, or using Ki67 expression. Univariate analysis revealed several TMA markers with capacity to predict OS and PFS. After multivariate analysis, a set of 4 apoptosis and cell-cycle markers was integrated into a FLIPI-independent clinical predictor, with the capacity to recognize two groups of FL patients with statistically significant differences in OS (83% versus 43% of OS at 120 months; p< 0.001). Then, patients were classified into low-risk (FLIPI: 0–2) and high-risk groups (FLIPI: 3–5), and the protein-based predictor model was used in both groups. High-risk FLIPI patients were stratified by the protein-based predictor into two groups with OS probability of 79,3% versus 14,2% at 120 months, p < 0.001, and low-risk FLIPI patients were also separated into two groups with OS probability of 100% versus 60,4% at 120 months, p < 0.01. The model is now being validated in a blind set. These results suggest that an integrated use of the FLIPI and the protein-based model could reach a higher accuracy predicting survival in FL.

Solid catalysts often have a non-uniform internal composition as a result of their method of preparation and working conditions. Such products sometimes command interest because of their better performance. Variables influencing internal distribution during their preparation are considered on the basis of experimental and theoretical studies. Activity and selectivity of these catalysts depend upon the internal distribution of the active species. Activation energies, reaction orders, and apparent diffusion coefficients are masked in relation to their real values, due to the mutual interdependence between mass transport phenomena and chemical reaction.

Kinetics of isopropyl alcohol dehydrogenation on Cr 2 O 3 prepared by decomposition of the corresponding hydroxide in air at 400 °C has been studied. Experimental results point to a change in the semiconductor type of the Cr 2 O 3 catalyst during the reaction. In order to confirm this hypothesis, the H 2 and O 2 adsorption on both types of Cr 2 O 3 , as well as the modification of the electrical resistance, at constant temperature, versus hydrogen pressure and versus feed during the reaction have been studied. Results are in agreement with the existence of two forms of Cr 2 O 3 which, in principle, behave as p (oxidized form) and n (reduced form) semiconductors. The study of isopropyl alcohol dehydrogenation kinetics on ZnCr 2 O 4 leads us to the conclusion that this possible p → n transition is not a quality which is exclusive for Cr 2 O 3 . These points are discussed and their importance and possible implications on future work duly considered.