Effects of nonselective and selective cyclooxygenase inhibitors on the contractions of isolated bronchial smooth muscle in the horse

We evaluated the effects of nonselective cyclooxygenase (COX)-1/COX-2 inhibitors (acetylsalicylic acid, indomethacin, ibuprofen, flunixin meglumine, phenylbutazone), preferential COX-2 inhibitors (diclofenac, meloxicam, carprofen), selective COX-1 inhibitor (SC-560), and selective COX-2 inhibitors (celecoxib, firocoxib, parecoxib) on the contractions of isolated bronchi induced by electrical field stimulation (EFS). Bronchial rings, obtained from lungs of slaughtered horses, were put in isolated organ baths, and the mechanical activity was measured by means of isotonic transducers. Electrical Field Stimulation was applied to the preparations, and the effects of drugs on the amplitude of evoked contractions were measured. Nonselective COX inhibitors did not modify EFS-induced contractions to a relevant degree, except indomethacin which caused a concentration-dependent decrease of the contraction amplitude. Conversely, preferential COX-2 inhibitors enhanced the contractions in a concentration-related fashion, whilst the selective COX-1 inhibitor reduced them. Among selective COX-2 inhibitors, parecoxib increased EFS-evoked contractions whereas celecoxib and firocoxib were ineffective. These results suggest that the inhibition of prostanoid synthesis does not modify the electrical field-stimulated contractions of isolated horse bronchi. Since EFS-induced contractions of horse bronchi were previously shown to be of full cholinergic nature, the increase caused by diclofenac, meloxicam, carprofen, and parecoxib could be due to an inhibition of acetylcholinesterase; in accordance, these drugs potentiated exogenous acetylcholine-induced but not carbachol-induced bronchial contraction. Indomethacin and SC-560 might instead decrease bronchial contractions by inhibiting calcium currents. Clinical use of meloxicam and carprofen in horses with bronchial hyper-responsiveness requires caution for a potential risk of causing adverse effects due to bronchoconstriction

Target Therapy in Platinum-Refractory/Resistant Ovarian Cancer: From Preclinical Findings to Current Clinical Practice

Epithelial ovarian cancer (EOC) is the sixth most common malignancy in women. Ovarian tumors consist of several clinical and pathological entities that share an anatomic site. The gold standard treatment, both in front-line and in adjuvant setting, is represented by carboplatin/paclitaxel combination. Conversely, the second-line treatment is not well defined. The response to platinum is the major prognostic factor for survival. In this review we discuss the current views on platinum-refractory/resistant patient treatment only, which includes patients progressing or relapsing within 6 months from the last platinum-based course. Concerning this subgroup, the activity of several conventional drugs was confirmed in different trials without a significant impact in terms of overall survival. In the last years particular emphasis was given to targeted anti-angiogenetic therapy which produced a survival improvement with an acceptable toxicity profile. New “ad hoc” approaches, with a major attention to outcome-predictive factors, are eagerly awaited

Host shifts result in parallel genetic changes when viruses evolve in closely related species.

Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in novel hosts, we experimentally evolved replicate lineages of an RNA virus (Drosophila C Virus) in 19 different species of Drosophilidae and deep sequenced the viral genomes. We found a strong pattern of parallel evolution, where viral lineages from the same host were genetically more similar to each other than to lineages from other host species. When we compared viruses that had evolved in different host species, we found that parallel genetic changes were more likely to occur if the two host species were closely related. This suggests that when a virus adapts to one host it might also become better adapted to closely related host species. This may explain in part why host shifts tend to occur between related species, and may mean that when a new pathogen appears in a given species, closely related species may become vulnerable to the new disease

Host-pathogen coevolution increases genetic variation in susceptibility to infection

It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations

Ethnic analogies and differences in fetal heart rate variability signal: A retrospective study

Aim: We aimed to analyze computerized cardiotocographic (cCTG) parameters (including fetal heart rate baseline, short-term variability, Delta, long-term irregularity [LTI], interval index [II], low frequency [LF], movement frequency [MF], high frequency [HF], and approximate entropy [ApEn]) in physiological term pregnancies in order to correlate them with ethnic differences. The clinical meaning of numerical parameters may explain physiological or paraphysiological phenomena that occur in fetuses of different ethnic origins. Methods: A total of 696 pregnant women, including 384 from Europe, 246 from sub-Saharan Africa, 45 from South-East Asia, and 21 from South America, were monitored from the 37th to the 41st week of gestation. Statistical analysis was performed with the analysis of variance test, Pearson correlation test and receiver–operator curves (P < 0.05). Results: Our results showed statistically significant differences (P < 0.05) between white and black women for Delta, LTI, LF, MF, HF, and ApEn; between white and Asian women for Delta, LTI, MF, and the LF/(HF + MF) ratio; and between white and Latina women for Delta, LTI, and ApEn. In particular, Delta and LTI performed better in the white group than in the black, Asian, and Latina groups. Instead, LF, MF, HF, and ApEn performed better in the black than in the white group. Conclusion: Our results confirmed the integrity and normal functionality of both central and autonomic nervous system components for all fetuses investigated. Therefore, CTG monitoring should include both linear and nonlinear components of fetal heart rate variability in order to avoid misinterpretations of the CTG trace among ethnic groups

The chemical enrichment of long gamma-ray bursts nurseries up to z = 2

Aims. We investigate the existence of a metallicity threshold for the production of long gamma-ray bursts (LGRBs). Methods. We used the host galaxies of the Swift/BAT6 sample of LGRBs. We considered the stellar mass, star formation rate (SFR), and metallicity determined from the host galaxy photometry and spectroscopy up to z = 2 and used them to compare the distribution of host galaxies to that of field galaxies in the mass-metallicity and fundamental metallicity relation plane. Results. We find that although LGRBs also form in galaxies with relatively large stellar masses, the large majority of host galaxies have metallicities below log(O=H) ∼ 8:6. The extension to z = 2 results in a good sampling of stellar masses also above Log(M=M) ∼ 9:5 and provides evidence that LGRB host galaxies do not follow the fundamental metallicity relation. As shown by the comparison with dedicated numerical simulations of LGRB host galaxy population, these results are naturally explained by the existence of a mild (∼0:7 Z) threshold for the LGRB formation. The present statistics does not allow us to discriminate between different shapes of the metallicity cutoff, but the relatively high metallicity threshold found in this work is somewhat in disagreement to most of the standard single-star models for LGRB progenitors. © ESO, 201

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Host shifts result in parallel genetic changes when viruses evolve in closely related species.

Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in novel hosts, we experimentally evolved replicate lineages of an RNA virus (Drosophila C Virus) in 19 different species of Drosophilidae and deep sequenced the viral genomes. We found a strong pattern of parallel evolution, where viral lineages from the same host were genetically more similar to each other than to lineages from other host species. When we compared viruses that had evolved in different host species, we found that parallel genetic changes were more likely to occur if the two host species were closely related. This suggests that when a virus adapts to one host it might also become better adapted to closely related host species. This may explain in part why host shifts tend to occur between related species, and may mean that when a new pathogen appears in a given species, closely related species may become vulnerable to the new disease

Evaluar : cómo aprenden los estudiantes el proceso de valoración

Evaluar es una operación de la mente que se manifiesta independientemente de toda intencionalidad formativa. La evaluación aparece como un acontecimiento en cierto modo inevitable y necesario, dado que nuestra naturaleza limitada nos obliga a decidir sobre el valor de todo aquello que nos rodea. Por tanto, el hecho de evaluar, antes de ser una acción mental, es una experiencia. Se estudia la operación mental de evaluar, observándola a través de la lente de diferentes teorías y epistemologías, cada una de las cuales presenta sus puntos fuertes y sus debilidades, para después aplicar todo ello al contexto educativo y a sus implicaciones en los estudiantes y en el proceso de aprendizaje. Las experiencias educativas que se presentan constituyen un ejemplo de cómo estimular intencionadamente la producción y la formación de actos de evaluación en los estudiantes, dentro y a través de la didáctica de las distintas disciplinas, para educar en un uso consciente de la evaluación que tenga muy en cuenta sus procesos, su metodología y sus efectos.Biblioteca de Educación del Ministerio de Educación y Formación Profesional; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]