Otx015 epi‐drug exerts antitumor effects in ovarian cancer cells by blocking gnl3‐mediated radioresistance mechanisms: Cellular, molecular and computational evidence

Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra‐Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015‐mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC

The Echinococcus canadensis (G7) genome: A key knowledge of parasitic platyhelminth human diseases

Background: The parasite Echinococcus canadensis (G7) (phylum Platyhelminthes, class Cestoda) is one of the causative agents of echinococcosis. Echinococcosis is a worldwide chronic zoonosis affecting humans as well as domestic and wild mammals, which has been reported as a prioritized neglected disease by the World Health Organisation. No genomic data, comparative genomic analyses or efficient therapeutic and diagnostic tools are available for this severe disease. The information presented in this study will help to understand the peculiar biological characters and to design species-specific control tools. Results: We sequenced, assembled and annotated the 115-Mb genome of E. canadensis (G7). Comparative genomic analyses using whole genome data of three Echinococcus species not only confirmed the status of E. canadensis (G7) as a separate species but also demonstrated a high nucleotide sequences divergence in relation to E. granulosus (G1). The E. canadensis (G7) genome contains 11,449 genes with a core set of 881 orthologs shared among five cestode species. Comparative genomics revealed that there are more single nucleotide polymorphisms (SNPs) between E. canadensis (G7) and E. granulosus (G1) than between E. canadensis (G7) and E. multilocularis. This result was unexpected since E. canadensis (G7) and E. granulosus (G1) were considered to belong to the species complex E. granulosus sensu lato. We described SNPs in known drug targets and metabolism genes in the E. canadensis (G7) genome. Regarding gene regulation, we analysed three particular features: CpG island distribution along the three Echinococcus genomes, DNA methylation system and small RNA pathway. The results suggest the occurrence of yet unknown gene regulation mechanisms in Echinococcus. Conclusions: This is the first work that addresses Echinococcus comparative genomics. The resources presented here will promote the study of mechanisms of parasite development as well as new tools for drug discovery. The availability of a high-quality genome assembly is critical for fully exploring the biology of a pathogenic organism. The E. canadensis (G7) genome presented in this study provides a unique opportunity to address the genetic diversity among the genus Echinococcus and its particular developmental features. At present, there is no unequivocal taxonomic classification of Echinococcus species; however, the genome-wide SNPs analysis performed here revealed the phylogenetic distance among these three Echinococcus species. Additional cestode genomes need to be sequenced to be able to resolve their phylogeny.Fil: Maldonado, Lucas Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Assis, Juliana. Fundación Oswaldo Cruz; BrasilFil: Gomes Araújo, Flávio M.. Fundación Oswaldo Cruz; BrasilFil: Salim, Anna C. M.. Fundación Oswaldo Cruz; BrasilFil: Macchiaroli, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Cucher, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Fox, Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Oliveira, Guilherme. Instituto Tecnológico Vale; Brasil. Fundación Oswaldo Cruz; BrasilFil: Kamenetzky, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

Transitional ‘hospital to home’ care of older patients: healthcare professionals’ perspectives

Author's accepted version (postprint).This is an Accepted Manuscript of an article published by Wiley in Scandinavian Journal of Caring Sciences on 27/08/2020.Available online: https://onlinelibrary.wiley.com/doi/epdf/10.1111/scs.12904acceptedVersio

Effect of Grain Refinement and Cooling Rate on the Microstructure and Mechanical Properties of Secondary Al-Si-Cu Alloys

The effect of AlTi5B1 grain refinement and different solidification rates on metallurgical and mechanical properties of a secondary AlSi7Cu3Mg alloy is reported. While the Ti content ranges from 0.04 up to 0.225 wt.%, the cooling rate varies between 0.1 and 5.5 C/s. Metallographic and thermal analysis techniques have been used to quantitatively examine the macro- and microstructural changes occurring with grain refiner addition at various cooling rates. The results indicate that a small AlTi5B1 addition produces the greatest refinement, while no significant reduction of grain size is obtained with a great amount of grain refiner. On increasing the cooling rate, a lower amount of AlTi5B1 master alloy is necessary to produce a uniform grain size throughout the casting. The combined addition of AlTi5B1 and Sr does not produce any reciprocal interaction or effect on primary a-Al and eutectic solidification. The grain refinement improves the plastic behavior of the alloy and increases the reliability of castings, as evidenced by the Weibull statistics

Chromium nitrides effects on low temperature impact toughness and durability of duplex stainless steels forgings.

The chromium nitrides effects on duplex stainless steels low temperature impact toughness and durability were investigated. A duplex rolled ring was cut as different blocks, and different Cr\u2082N amounts were obtained by trial heat treatments, with the solution annealing furnace temperature set at low and high levels, 1040 and 1140 \ub0C respectively, and the transfer time ranging between 5 and 120 s in order to prevent the \u3c3 phase formation. Micrographic examinations, low temperature Charpy impact tests and durability assessments were carried out on specimens sampled from the blocks cores. The material strength was evaluated by hardness tests. The results showed how an increase in transfer time allows the N diffusion in the austenite phase, reducing the nitrides quantity in the ferrite phase. A synergistic effect between the transfer time and the solution annealing temperature on the amount of intermetallic particles was observed. Clear effects of the Cr\u2082N presence on both material low temperature impact toughness and pitting corrosion resistance were found

The efficacy of anti-pd-l1 treatment in melanoma is associated with the expression of the ecm molecule emilin2

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy

High Temperature Fatigue Behaviour of Secondary AlSi7Cu3Mg Alloys

none3siThe high temperature fatigue behaviour of secondary AlSi7Cu3Mg alloys has been investigated. The alloy has been solubilized and aged for different times to obtain the age-hardening profile. The peak hardness is reached at 180 °C after 4 h ageing treatment. Further, the hardness stabilizes showing a plateau in the range between 5 and 10 hours of ageing treatment. The heat treatment leads to a complete dissolution of Cu-rich phases, spheroidization of eutectic Si particles and precipitation inside the α-Al matrix. Several fatigue tests have been carried out on selected heat-treated specimens both at room and elevated temperatures (200 and 300 °C). The obtained results show how the fatigue strength decreases with increasing the testing temperaturenoneDe Mori, Alessandro; Timelli, Giulio; Berto, FilippoDe Mori, Alessandro; Timelli, Giulio; Berto, Filipp