How to make centralized acquisitions without a centralized budget

Presentación realizada en el marco de la Staff Training Week realizada en Eötvös Loránd University, Budapest (Hungría) entre el 3 y el 7 de abril de 2017

Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity

In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CL(ME0)) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CL(M10)) and CL(ME0) were modeled by an inhibitory E(MAX) model, and the estimates (relative standard error) of the maximum degree of inhibition (E(MAX)) and IC(50), plasma concentration of Q eliciting half of E(MAX) for CL(M10) and CL(ME0), were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration

Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively

Global Gene Expression Characterization of Circulating Tumor Cells in Metastasic Castration-Resistant Prostate Cancer Patients

BACKGROUND: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. METHODS: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. RESULTS: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. CONCLUSIONS: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PC

The role of premorbid iq and age of onset as useful predictors of clinical, functional outcomes, and recovery of individuals with a first episode of psychosis

Background: premorbid IQ (pIQ) and age of onset are predictors of clinical severity and long-term functioning after a first episode of psychosis. However, the additive influence of these variables on clinical, functional, and recovery rates outcomes is largely unknown. Methods: we characterized 255 individuals who have experienced a first episode of psychosis in four a priori defined subgroups based on pIQ (low pIQ < 85; average pIQ = 85) and age of onset (early onset < 18 years; adult onset = 18 years). We conducted clinical and functional assessments at baseline and at two-year follow-up. We calculated symptom remission and recovery rates using the Positive and Negative Symptoms of Schizophrenia Schedule (PANSS) and the Global Assessment Functioning (GAF or Children-GAF). We examined clinical and functional changes with pair-wise comparisons and two-way mixed ANOVA. We built hierarchical lineal and logistic regression models to estimate the predictive value of the independent variables over functioning or recovery rates. Results: early-onset patients had more severe positive symptoms and poorer functioning than adult-onset pa-tients. At two-year follow-up, only early-onset with low pIQ and adult-onset with average pIQ subgroups differed consistently, with the former having more negative symptoms (d = 0.59), poorer functioning (d = 0.82), lower remission (61% vs. 81.1%), and clinical recovery (34.1% vs. 62.2%). Con-clusions: early-onset individuals with low pIQ may present persistent negative symptoms, lower functioning, and less recovery likelihood at two-year follow-up. Intensive cognitive and functional programs for these individuals merit testing to improve long-term recovery rates in this subgroup. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Obtención del mejor punto de conexión de parques fotovoltaicos en redes de distribución radiales

El uso de las fuentes renovables de energía se ha incrementado exponencialmente a nivel mundial. Cuba ha implementado un plan hasta el 2030 donde las fuentes renovables juegan un papel fundamental dentro de la matriz energética nacional. La política con respecto a la instalación de centrales fotovoltaicas ha sido conectar pequeñas centrales de hasta 5 MW, principalmente en redes de distribución. En este trabajo se diseñó un algoritmo de optimización para instalar centrales fotovoltaicas en redes de distribución radiales. El algoritmo resuelve el problema a través de un flujo de carga combinado conun modelo de asignación N-P completo. El objetivo del algoritmo es obtener los mejores puntos para la conexión de centrales fotovoltaicas en nodos de una red de distribución eléctrica radial de modo que se minimicen las pérdidas totales de potencia activa o la desviación de tensión de la red. Universidad Tecnológica de La Habana, José Antonio Echeverría

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]

Plexiform neurofibroma of the submandibular gland in patient with von Recklinghausen's disease

Plexiform neurofibroma of the submandibular gland is an extremely rare tumor. Herein, we report a case of plexiform neurofibroma in a patient with a von Recklinghausen's disease (NF-1) who presented with a submandibular mass mimicking a submandibular gland tumor. Complete surgical excision provides the best treatment and final diagnosis. A neurofibroma should be considered in the differential diagnosis for submandibular mass

Quantitative assay for the detection of the V617F variant in the Janus kinase 2 (JAK2) gene using the Luminex xMAP technology

<p>Abstract</p> <p>Background</p> <p>The availability of clinically valid biomarkers contribute to improve the diagnosis and clinical management of diseases. A valine-to-phenylalanine substitution at position 617 (V617F) in the Janus kinase 2 (JAK2) gene has been recently associated with key signaling abnormalities in the transduction of haemopoietic growth-factor receptors and is now considered as a useful clinical marker of myeloproliferative neoplasms. Several methods have recently been reported to detect the JAK2 V617F point mutation and show variable sensitivity.</p> <p>Methods</p> <p>Using the Luminex xMAP technology, we developed a quantitative assay to detect the JAK2V617F variant. The method was based on polymerase chain reaction (PCR) followed by hybridization to specific probes coupled with internally dyed microspheres. The assay comprises 3 steps: genomic DNA extraction, end point PCR reaction, direct hybridization of PCR fragments and quantification. It has been tested with different sources of nucleic acid.</p> <p>Results</p> <p>Applied to whole blood samples, this quantitative assay showed a limit of detection of 2%. A highly sensitive allele-specific primer extension reaction performed in parallel allowed to validate the results and to identify the specimens with values below 2%.</p> <p>Conclusion</p> <p>Direct hybridization assay using the Luminex xMAP technology allows sensitive quantification of JAK2V617F from blood spots. It is simple and can be easily performed in a clinical setting.</p

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array

GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group.Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P =.1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.This work has been partially supported by grants of the Instituto de Salud Carlos III (ISCIII) (CP13/00080), ISCIII (PI12/02311), Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0069) (RD12/0036/0061), Ministerio de Economía y Competitividad/ Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (Innocampus; CEI‐2010‐1‐0010), Asociación Española Contra el Cancer (GCB120981SAN), and Joan Rodes (JR 14/00016). M.E.S. is supported by the Miguel Servet program (CP13/00080) of the ISCIII (Ministerio de Economía y Competitividad).Peer Reviewe