Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor that inhibits plasmin-dependent activation of several metalloproteinases. Downregulation of TFPI-2 could thus enhance the invasive potential of neoplastic cells in several cancers, including lung cancer. In this study, TFPI-2 mRNA was measured using a real-time PCR method in tumours of 59 patients with non-small-cell lung cancer (NSCLC). Tumour TFPI-2 mRNA levels appeared well correlated with protein expression evaluated by immunohistochemistry and were 4–120 times lower compared to those of nonaffected lung tissue in 22 cases (37%). Hypermethylation of the TFPI-2 gene promoter was demonstrated by restriction enzyme-polymerase chain reaction in 12 of 40 cases of NSCLC (30%), including nine of 17 for whom tumour TFPI-2 gene expression was lower than in noncancerous tissue. In contrast, this epigenetic modification was shown in only three of 23 tumours in which no decrease in TFPI-2 synthesis was found (P=0.016). Decreased TFPI-2 gene expression and hypermethylation were more frequently associated with stages III or IV NSCLC (eight out of 10, P=0.02) and the TFPI-2 gene promoter was more frequently hypermethylated in patients with lymph node metastases (eight out of 16, P=0.02). These results suggest that silencing of the TFPI-2 gene by hypermethylation might contribute to tumour progression in NSCLC

Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as “thymic hormones,” are produced by this gland. Although the majority of them have not been proven to be thymus-speciWc, thymic peptides comprise an eVective group of regulators, mediating important immune functions. Thymosin fraction Wve (TFV) was the Wrst thymic extract shown to stimulate lymphocyte proliferation and diVerentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin (proT) and thymosin 1 (T1) showed that they are of clinical signiWcance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeWciencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their eVect are yet not fully elucidated proT and T1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proT, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of T1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proT into the clinical setting

Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation

<p>Abstract</p> <p>Background</p> <p>Long-term acetate supplementation reduces neuroglial activation and cholinergic cell loss in a rat model of lipopolysaccharide-induced neuroinflammation. Additionally, a single dose of glyceryl triacetate, used to induce acetate supplementation, increases histone H3 and H4 acetylation and inhibits histone deacetylase activity and histone deacetylase-2 expression in normal rat brain. Here, we propose that the therapeutic effect of acetate in reducing neuroglial activation is due to a reversal of lipopolysaccharide-induced changes in histone acetylation and pro-inflammatory cytokine expression.</p> <p>Methods</p> <p>In this study, we examined the effect of a 28-day-dosing regimen of glyceryl triacetate, to induce acetate supplementation, on brain histone acetylation and interleukin-1β expression in a rat model of lipopolysaccharide-induced neuroinflammation. The effect was analyzed using Western blot analysis, quantitative real-time polymerase chain reaction and enzymic histone deacetylase and histone acetyltransferase assays. Statistical analysis was performed using one-way analysis of variance, parametric or nonparametric when appropriate, followed by Tukey's or Dunn's post-hoc test, respectively.</p> <p>Results</p> <p>We found that long-term acetate supplementation increased the proportion of brain histone H3 acetylated at lysine 9 (H3K9), histone H4 acetylated at lysine 8 and histone H4 acetylated at lysine 16. However, unlike a single dose of glyceryl triacetate, long-term treatment increased histone acetyltransferase activity and had no effect on histone deacetylase activity, with variable effects on brain histone deacetylase class I and II expression. In agreement with this hypothesis, neuroinflammation reduced the proportion of brain H3K9 acetylation by 50%, which was effectively reversed with acetate supplementation. Further, in rats subjected to lipopolysaccharide-induced neuroinflammation, the pro-inflammatory cytokine interleukin-1β protein and mRNA levels were increased by 1.3- and 10-fold, respectively, and acetate supplementation reduced this expression to control levels.</p> <p>Conclusion</p> <p>Based on these results, we conclude that dietary acetate supplementation attenuates neuroglial activation by effectively reducing pro-inflammatory cytokine expression by a mechanism that may involve a distinct site-specific pattern of histone acetylation and histone deacetylase expression in the brain.</p

The Gender Congruency Effect across languages in bilinguals: A meta-analysis

In the study of gender representation and processing in bilinguals, two contrasting perspectives exist: integrated vs. the autonomous (Costa, Kovacic, Fedorenko, & Caramazza, 2003). In the former, cross-linguistic interactions during the selection of grammatical gender values are expected; in the latter, they are not. To address this issue, authors have typically explored the cross-linguistic Gender Congruency Effect (GCE: a facilitation on the naming or translation of second language [L2] nouns when their first language [L1] translations are of the same gender, in comparison to those of a different gender). However, the literature suggests that this effect is sometimes difficult to observe and might vary as a function of variables such as the syntactic structure produced to translate or name the target (bare nouns vs. noun phrases), the phonological gender transparency of both languages (whether or not they have phonological gender cues associated with the ending letter [e.g., “–a” for feminine words and “–o” for masculine words in Romance languages]), the degree of L2 proficiency, and task requirements (naming vs. translation). The aim of the present quantitative meta-analysis is to examine the robustness of the cross-linguistic GCE obtained during language production. It involves 25 experiments from 11 studies. The results support a bilingual gender-integrated view, in that they show a small but significant GC effect regardless of the variables mentioned above.This paper was funded through the state budget with reference IF / 00784/2013 / CP1158 / CT0013. The study has also been partially supported by the FCT and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653). Government of Spain—Ministry of Education, Culture and Sports—through the Training program for Academic Staff (Ayudas para la Formación del Profesorado Universitario, FPU grant BOE-B-2017-2646), the research project (reference PSI2015-65116-P) granted by the Spanish Ministry of Economy and Competitiveness, and the grant for research groups (reference ED431B 2019/2020) from the Galician Government, as well as by the FCT (Foundation for Science and Technology, Portugal) through the state budget (reference IF / 00784/2013 / CP1158 / CT0013). Finally, the study has also been partially supported by the FCT and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653

Evolutionary diversity in tropical tree communities peaks at intermediate precipitation

This is the final version. Available from Nature Research via the DOI in this record. Time-calibrated molecular phylogenies are deposited at the Dryad Digital Repository (https://doi.org/10.5061/dryad.gf1vhhmk0). A full description with details of data accessibility for Neo-TropTree can be found at http://www.neotroptree.info/.Global patterns of species and evolutionary diversity in plants are primarily determined by a temperature gradient, but precipitation gradients may be more important within the tropics, where plant species richness is positively associated with the amount of rainfall. The impact of precipitation on the distribution of evolutionary diversity, however, is largely unexplored. Here we detail how evolutionary diversity varies along precipitation gradients by bringing together a comprehensive database on the composition of angiosperm tree communities across lowland tropical South America (2,025 inventories from wet to arid biomes), and a new, large-scale phylogenetic hypothesis for the genera that occur in these ecosystems. We find a marked reduction in the evolutionary diversity of communities at low precipitation. However, unlike species richness, evolutionary diversity does not continually increase with rainfall. Rather, our results show that the greatest evolutionary diversity is found in intermediate precipitation regimes, and that there is a decline in evolutionary diversity above 1,490 mm of mean annual rainfall. If conservation is to prioritise evolutionary diversity, areas of intermediate precipitation that are found in the South American ‘arc of deforestation’, but which have been neglected in the design of protected area networks in the tropics, merit increased conservation attention.Natural Environment Research Council (NERC)Conselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e TecnológicoNational Science Foundation (NSF)Mohamed bin Zayed Species Conservation FundLeverhulme TrustCoordenação de Aperfeiçoamento de Pessoal de Nível Superio

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference