A pharmacogenetic intervention for the improvement of the safety profile of antipsychotic treatments

Antipsychotic drugs fail to achieve adequate response in 30–50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG−, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG−), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG− patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG− clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes.This research was funded by grants from the Institute Carlos III (FIS PI11/02006; FIS PI16/01029). A.G.-R. was partially funded by a private grant from the Jové family. Genotyping was partially conducted by the CEGEN-PRB2-ISCIII node, which is supported by grant PT13/001, ISCIIISGEFI/ FEDER

Mezclas poliméricas cristal líquido/olefinas: morfología y propiedades de transporte

Se han preparado mezclas con diferentes composiciones a partir de un copolímero de etileno-1-octeno, sintetizado con un catalizador de tipo metaloceno y un polímero cristal líquido. La caracterizción estructural y morfológica de las películas obtenidas se realizó mediante difracción de rayos X, calorimetría diferencial de barrido y microscopía electrónica de barrido, mientras que el estudio de las propiedades físicas se ha llevado a cabo mediante análisis mecanodinámico, microdureza y ensayos esfuerzo-deformación, poniendo especial énfasis a la evaluación de sus propiedades de transporte de oxígeno

Implementation of an extended ZINB model in the study of low levels of natural gastrointestinal nematode infections in adult sheep

[EN] Background: In this study, two traits related with resistance to gastrointestinal nematodes (GIN) were measured in 529 adult sheep: faecal egg count (FEC) and activity of immunoglobulin A in plasma (IgA). In dry years, FEC can be very low in semi-extensive systems, such as the one studied here, which makes identifying animals that are resistant or susceptible to infection a difficult task. A zero inflated negative binomial model (ZINB) model was used to calculate the extent of zero inflation for FEC; the model was extended to include information from the IgA responses. Results: In this dataset, 64 % of animals had zero FEC while the ZINB model suggested that 38 % of sheep had not been recently infected with GIN. Therefore 26 % of sheep were predicted to be infected animals with egg counts that were zero or below the detection limit and likely to be relatively resistant to nematode infection. IgA activities of all animals were then used to decide which of the sheep with zero egg counts had been exposed and which sheep had not been recently exposed. Animals with zero FEC and high IgA activity were considered resistant while animals with zero FEC and low IgA activity were considered as not recently infected. For the animals considered as exposed to the infection, the correlations among the studied traits were estimated, and the influence of these traits on the discrimination between unexposed and infected animals was assessed. Conclusions: The model presented here improved the detection of infected animals with zero FEC. The correlations calculated here will be useful in the development of a reliable index of GIN resistance that could be of assistance for the study of host resistance in studies based on natural infection, especially in adult sheep, and also the design of breeding programs aimed at increasing resistance to parasitesSIThis work was supported by a competitive grant from the Castilla and León regional government (Junta de Castilla y León) (Ref. LE245A12-2); the EC-funded Innovative Training Network (ITN) NematodeSystemHealth (M. A. and J. M. P., P7-KBBE-2009-3-245140); the BBSRC grant BB/L004004070/1; the Spanish “Ramón y Cajal” Programme from the Spanish Ministry of Economy and Competitiveness (B. G. G., RYC-2012-10230) and a postdoctoral Jae-Doc contract from the Consejo Superior de Investigaciones Científicas (CSIC) and co-funded by the European Social Fund (M. M. V.

Comorbidity and osteoporotic fracture: approach through predictive modeling techniques using the OSTEOMED registry

Purpose To examine the response to anti-osteoporotic treatment, considered as incident fragility fractures after a minimum follow-up of 1 year, according to sex, age, and number of comorbidities of the patients. Methods For this retrospective observational study, data from baseline and follow-up visits on the number of comorbidities, prescribed anti-osteoporotic treatment and vertebral, humerus or hip fractures in 993 patients from the OSTEOMED registry were analyzed using logistic regression and an artificial network model. Results Logistic regression showed that the probability of reducing fractures for each anti-osteoporotic treatment consid- ered was independent of sex, age, and the number of comorbidities, increasing significantly only in males taking vitamin D (OR = 7.918), patients without comorbidities taking vitamin D (OR = 4.197) and patients with ≥ 3 comorbidities taking calcium (OR = 9.412). Logistic regression correctly classified 96% of patients (Hosmer–Lemeshow = 0.492) compared with the artificial neural network model, which correctly classified 95% of patients (AUC = 0.6). Conclusion In general, sex, age and the number of comorbidities did not influence the likelihood that a given anti-osteoporotic treatment improved the risk of incident fragility fractures after 1 year, but this appeared to increase when patients had been treated with risedronate, strontium or teriparatide. The two models used classified patients similarly, but predicted differently in terms of the probability of improvement, with logistic regression being the better fit

Genesis and evolution of the San Manuel iron skarn deposit (Betic Cordillera, SW Spain)

The San Manuel magnesian skarn is an iron deposit hosted in dolomitic marbles from a tectonic slice imbricated within the Ronda peridotites, in the westernmost part of the Betic Cordillera, Spain. According to the dominant mineral assemblage, the skarn is subdivided into three different zones, (1) forsterite ± calcite skarn, (2) calcite ± chlorite ± serpentine skarn, and (3) Ca-amphibole skarn. The main ore in the skarn is a ∼ 2.5 m thick, massive ore body situated in the middle of the sequence. In this paper, we firstly report a comprehensive major to trace element composition, texture, microstructure, and mineralogy characterization for zoned magnesioferrite-magnetite grains of the San Manuel deposit using a combination of (1) laser ablation inductively coupled plasma mass spectrometer, (2) focused ion beam combined with transmission electron microscopy, and (3) electron back-scattered diffraction. We have defined four different magnesioferrite-magnetite generations. A complete sequence of zoning includes cores of magnesioferrite (Mag-1; MgO up to 10.6 wt%) overprinted by three successive generations of magnetite, namely Mag-2, Mag-3, Mag-4. Mag-2 (MgO < 4 wt%), hosts composite forsterite ± calcite ± chlorite inclusions, consistently with high Si, Ca, and Sr (average: 8204 ppm, 8980 ppm, and 49 ppm respectively) contents detected by in situ laser ablation inductively coupled plasma (LA-ICP-MS). Mag-3 replacing former Mag-1 and Mag-2 includes nanometric spinel and gahnite exsolutions detected by focused ion beam combined with a transmission electron microscope (FIB-TEM), which is consistent with its high Al, Ti, V, and Ga (average: 5073 ppm, 368 ppm, and 20 ppm, respectively) trace element concentration. Mag-4 is the Fe-richest magnetite (up to 94.16 wt% FeO) forming the outermost rims in magnetite grains, and exhibiting the lowest total trace element contents. Approaches in temperature estimations employing magnetite-spinel exsolutions in Mag-3 suggest that the minimum temperature of the prograde stage reached temperatures below 700 °C, whereas Mag-4 should be formed during the retrograde stage. Magnetite microstructure studied by electron backscatter diffraction (EBSD) suggests Mag-4 formation under fluid-assisted dynamic conditions, which is consistent with the tectonic evolution of the emplacement. We propose that the San Manuel deposit formed by pulsed hydrothermal fluids derived from anatexis of crustal rocks during peridotite emplacement, promoting re-equilibration processes that led to the magnesioferrite-magnetite zoning.This study was funded by the Spanish project RTI2018-099157-A-I00, granted by the “Ministerio de Ciencia, Innovación y Universidades”, the grant PRE2019-088262 “Ayudas para contratos predoctorales para la formación de doctors” (FPI), defrayed by the “Ministerio de Ciencia, Innovación y Universidades. The Mexican research program “CONACYT-Ciencia Básica” A1-S-14574 is also thanked for proving additional funding for standards employed in LA-ICP-MS analysis. J.M. González-Jímenez also acknowledge funding provided by the Ramón y Cajal Fellowship RYC-2015-17596. We would like to thank X. Llovet from “Serveis Cientifico-Técnics” (CCiTUB) of the Universidad de Barcelona for his invaluable assistance with the electron probe micro-analyzer, and to C. Ortega-Obregón from the “Laboratorio de Estudios Isotópicos of the Centro de Geociencias” (UNAM, Mexico) for his help with the LA-ICP-MS analyses on magnetite. Moreover, we would like to express our gratitude to I. Sánchez from the “Centro de Instrumentación Científica “(CIC-UGR) for her supporting of the scanning electron microscope. The authors would like to acknowledge the use of “Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza”, particularly the help of C. Gallego and L. Casado Zueras from the “Advanced Microscopy Laboratory” (LMA) for their careful preparation of the EBSD maps and FIB samples, respectively

Negatively charged amino acids at the foot-and-mouth disease virus capsid reduce the virion-destabilizing effect of viral RNA at acidic pH

Elucidation of the molecular basis of the stability of foot-and-mouth disease virus (FMDV) particles is relevant to understand key aspects of the virus cycle. Residue N17D in VP1, located at the capsid inner surface, modulates the resistance of FMDV virion to dissociation and inactivation at acidic pH. Here we have studied whether the virion-stabilizing effect of amino acid substitution VP1 N17D may be mediated by the alteration of electrostatic charge at this position and/or the presence of the viral RNA. Substitutions that either introduced a positive charge (R,K) or preserved neutrality (A) at position VP1 17 led to increased sensitivity of virions to inactivation at acidic pH, while replacement by negatively charged residues (D,E) increased the resistance of virions to acidic pH. The role in virion stability of viral RNA was addressed using FMDV empty capsids that have a virtually unchanged structure compared to the capsid in the RNA-filled virion, but that are considerably more resistant to acidic pH than WT virions, supporting a virion-destabilizing effect of the RNA. Remarkably, no differences were observed in the resistance to dissociation at acidic pH between the WT empty capsids and those harboring replacement N17D. Thus, the virion-destabilizing effect of viral RNA at acidic pH can be partially restored by introducing negatively charged residues at position VP1 N17Work in F.S´s laboratory was funded by grants from MINECO-FEDER EU (AGL2017–84097-C2–1-R), Comunidad de Madrid co-fnanced with ECFEDER funds (P2018/BAA-4370). Work in M.G.M.´s laboratory was funded by grants from MINECO-FEDER EU (BIO2015–69928-R and RTI2018–096635-B-I00). Work by both groups was also funded by an institutional grant from Fundación Ramón Areces M.G.M. is an associate member of the Institute for Biocomputation and Physics of Complex Systems, Zaragoza, Spai

Organic matter sources for tidal marsh sediment over the past two millennia in the Minho River estuary (NW Iberian Peninsula)

Environmental changes during the last 2 millennia in the Minho River tidal marsh (NW Portugal-Spain border) were reconstructed. Changes in the sources of organic matter (OM) delivered to the marsh were evaluated from elemental, isotopic and molecular composition using a 1 m sediment core. Carbon isotopic composition (delta13C) and organic carbon to total nitrogen ratio (Corg/N) provided valuable information concerning the origin of the OM. These parameters indicated a major input from land plants, reaching a maximum at 1100–1200 and 1750–1850 AD. These periods match with major flood events in the NW of the Iberian Peninsula, as reported by several authors. A significant reduction in the terrestrial signature occurred at 6–4 cm (ca. 1960–1985 AD), which is contemporaneous with the construction of several major dams on the Minho River. The distribution of selected lipid biomarkers, including n-alkanes, n-fatty acids and n-alkan-2-ones and specific parameters derived from the molecular distributions, were useful for refining bulk geochemical results. Long chain n- alkanes with an odd number of carbons are indicators of soil-and vascular plant derived terrestrial OM and were dominant throughout the core. In addition, a greater contribution of plankton-derived lipids was observed in the sections corresponding to ca. 1960–1985 AD (6–4 cm) and ca. 100–200 AD (96–94 cm). Although different degradation rates for individual compounds might have partly affected biomarker assemblages, the variations could be attributed to a sharp decrease in the freshwater contribution to the Minho River Estuary (dam construction) and a possible marine highstand, respectively. In addition, several parameters suggested changes in land use (including deforestation and farming) and probably the effects of mining exploitation during the Roman occupation of the area.We acknowledge the funding by the Foundation for Science and Technology (FCT) of Portugal for J.M. M’s PhD. Grant (SFRH/BD/45528/2008) and for the WestLog Project (PTDC/CTE-GIX/105370/2008). E.L. was awarded a Ralph E. Powe Junior Faculty Enhancement Award. This is a contribution to the IGCP Project 588 and to the Geo-Q Research Unit (Aranzadi).Peer reviewe

Lung cancer after heart transplantation: results from a large multicenter registry

[Abstract] In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan–Meier 2−year survival to 70% versus 16% among inoperable patients

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions

Intestinal metaplasia confers an increased risk of progression to gastric cancer. However, some intestinal metaplasia patients do not develop cancer. The development of robust molecular biomarkers to stratify patients with advanced gastric precursor lesions at risk of cancer progression will contribute to guiding programs for prevention. Starting from a genome-wide methylation study, we have simplified the detection method regarding candidate-methylation tests to improve their applicability in the clinical environment. We identified CpG methylation at the ZNF793 and RPRM promoters as a common event in intestinal metaplasia and intestinal forms of gastric cancer. Furthermore, we also showed that Helicobacter pylori infection influences DNA methylation in early precursor lesions but not in intestinal metaplasia, suggesting that therapeutic strategies to prevent epigenome reprogramming toward a cancer signature need to be adopted early in the precursor cascade. To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature

Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience

Abstract OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co-operative group between 1992 and 2004. METHODS: The median age at transplantation was 46 yr. Fifteen patients underwent the procedure as front-line therapy and four patients as salvage therapy. Most patients received peripheral stem cells (90%) coupled with BEAM or BEAC as conditioning regimen (79%). RESULTS: A 79% of patients achieved complete response, 5% partial response and 16% failed the procedure. After a median follow-up of 25 months, eight patients died (seven of progressive disease and secondary neoplasia), while actuarial overall survival and progression-free survival at 3 yr was 60% and 55%. Prognostic factors associated with a poor outcome included bone marrow involvement, transplantation in refractory disease state, attributing more than one factor of the age-adjusted-International Prognostic Index, Pretransplant peripheral T-cell lymphoma (PTCL) Score or Prognostic Index for PTCL. CONCLUSIONS: More than half of the patients with AIL that display unfavourable prognostic factors at diagnosis or relapse would be expected to be alive and disease-free after 3 yr when treated with HDC/ASCT. Patients who are transplanted in a refractory disease state do not benefit from this procedure