Quantitative diffusion and perfusion MRI in the evaluation of endometrial cancer. Validation with histopathological parameters

Objectives: To investigate the role of quantitative Magnetic Resonance Imaging (MRI) in preoperative assessment of tumour aggressiveness in patients with endometrial cancer, correlating multiple parameters obtained from diffusion and dynamic contrast-enhanced (DCE) MR sequences with conventional histopathological prognostic factors and inflammatory tumour infiltrate.Methods: Forty-four patients with biopsy-proven endometrial cancer underwent preoperative MR imaging at 3T scanner, including DCE imaging, diffusion-weighted imaging (DWI) and intravoxel incoherent motion imaging (IVIM). Images were analysed on dedicated post-processing workstations and quantitative parameters were extracted: K-trans, K-ep, V-e and AUC from the DCE; ADC from DWI; diffusion D, pseudo diffusion D*, perfusion fraction f from IVIM and tumour volume from DWI. The following histopathological data were obtained after surgery: histological type, grading (G), lympho-vascular invasion (LVI), lymph node status, FIGO stage and inflammatory infiltrate.Results: ADC was significantly higher in endometrioid histology, G1-G2 (low grade), and stage IA. Significantly higher D* were found in endometrioid subptype, negative lymph nodes and stage IA. The absence of LVI is associated with higher f values. K-trans and V-e values were significantly higher in low grade. Higher D*, f and AUC occur with the presence of chronic inflammatory cells, D * was also able to distinguish chronic from mixed type of inflammation. Larger volume was significantly correlated with the presence of mixed-type inflammation, LVI, positive lymph nodes and stage >= IB.Conclusions: Quantitative biomarkers obtained from pre-operative DWI, IVIM and DCE-MR examination are an in vivo representation of the physiological and micro-structural characteristics of endometrial carcinoma allowing to obtain the fundamental parameters for stratification into Risk Classes.Advances in knowledge: Quantitative imaging biomarkers obtained from DWI, DCE and IVIM may improve preoperative prognostic stratification in patients with endometrial cancer leading to a more informed therapeutic choice

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

Transcriptomic and genomic structural variation analyses on grape cultivars reveal new insights into the genotype-dependent responses to water stress

Grapevine (Vitis vinifera L.) is importantly cultivated worldwide for table grape and wine production. Its cultivation requires irrigation supply, especially in arid and semiarid areas. Water deficiency can affect berry and wine quality mostly depending on the extent of plant perceived stress, which is a cultivar-specific trait. We tested the physiological and molecular responses to water deficiency of two table grape cultivars, Italia and Autumn royal, and we highlighted their different adaptation. Microarray analyses revealed that Autumn royal reacts involving only 29 genes, related to plant stress response and ABA/hormone signal transduction, to modulate the response to water deficit. Instead, cultivar Italia orchestrates a very broad response (we found 1037 differentially expressed genes) that modifies the cell wall organization, carbohydrate metabolism, response to reactive oxygen species, hormones and osmotic stress. For the first time, we integrated transcriptomic data with cultivar-specific genomics and found that ABA-perception and –signalling are key factors mediating the varietal-specific behaviour of the early response to drought. We were thus able to isolate candidate genes for the genotype-dependent response to drought. These insights will allow the identification of reliable plant stress indicators and the definition of sustainable cultivar-specific protocols for water management

Calcineurin gamma catalytic subunit ppp3cc inhibition by mir-200c-3p affects apoptosis in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) outpaces all the other forms of the female reproductive system malignancies. MicroRNAs have emerged as promising predictive biomarkers to therapeutic treatments as their expression might characterize the tumor stage or grade. In EOC, miR-200c is considered a master regulator of oncogenes or tumor suppressors. To investigate novel miR-200c-3p target genes involved in EOC tumorigenesis, we evaluated the association between this miRNA and the mRNA expression of several potential target genes by RNA-seq data of both 46 EOC cell lines from Cancer Cell line Encyclopedia (CCLE) and 456 EOC patient bio-specimens from The Cancer Genome Atlas (TCGA). Both analyses showed a significant anticorrelation between miR-200c-3p and the protein phosphatase 3 catalytic subunit γ of calcineurin (PPP3CC) levels involved in the apoptosis pathway. Quantitative mRNA expression analysis in patient biopsies confirmed the inverse correlation between miR-200c-3p and PPP3CC levels. In vitro regulation of PPP3CC expression through miR-200c-3p and RNA interference technology led to a concomitant modulation of BCL2- and p-AKT-related pathways, suggesting the tumor suppressive role of PPP3CC in EOC. Our results suggest that inhibition of high expression of miR-200c-3p in EOC might lead to overexpression of the tumor suppressor PPP3CC and subsequent induction of apoptosis in EOC patients

Telemedicine will not keep us apart in COVID-19 pandemic

not applicabl

FRI0110 Methotrexate monotherapy in real life: a drug survival analysis. comparison between very early arthritis and early arthritis cohorts

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Teacher performance evaluation: conflict, uncertainties and the search for meaning(s)

O texto que propomos parte de uma pesquisa longitudinal, realizada em Portugal entre 2008 e 2010, com professores do 1º Ciclo do Ensino Básico. Procura evidenciar os conflitos e incertezas que a avaliação do desempenho docente tem produzido e a busca de sentido(s) para esta avaliação e para o ‘ser professor/a’. A implementação de sistemas de avaliação do desempenho dos professores insere-se na procura de soluções para esta inquietação. Foi o que aconteceu em Portugal, em Janeiro de 2007, com a publicação em Diário da República do novo Estatuto da Carreira Docente e o Decreto que regulamentava a Avaliação do Desempenho Docente. As tensões emergiram entre docentes e Ministério da Educação, agudizaram-se com a tomada de consciência da problemática da avaliação do desempenho dos docentes com impacto na carreira profissional e provocaram incertezas e desmotivação face ao sentido do trabalho docente com impacto na identidade profissional dos professores.This article stems from a longitudinal research carried out with primary school teachers in Portugal between 2008 and 2010. The research sought to identify the conflicts and uncertainties, which have been caused by the evaluation of teacher performance, as well as to search for meaning(s) related to that evaluation and to ‘being a teacher’. The implementation of systems for the evaluation of teacher performance fits into the search for solutions to that concern. This is what happened in Portugal, in January 2007, when the new Statute of the Teaching Profession and the law to regulate Teacher Performance Assessment were published in Diário da República – the official government publication. Tensions arose between teachers and the Ministry of Education and they were aggravated by an awareness of how the problem of teacher performance evaluation would impact on the professional career of teachers and how it would cause uncertainties and demotivation concerning the vocation of teaching and its subsequent impact on the professional identity of teachers

The role of C and N dopants incorporation in phase change materials

Phase change memory (PCM) technology is considered to be among the most promising alternatives to conventional technologies in embedded memories [1]. To allow operation at relatively high temperatures in embedded applications, it is crucial to improve the stability of the amorphous phase. Carbon and nitrogen doping have been shown to significantly increase the crystallization temperature [1-3]. Moreover, the high RESET current requirement [2], which is a limit to the scalability of GeTe and GST, can be reduced by the incorporation of a dopant element [4]. In this presentation we focus on correlating experimental results and ab initio simulations to understand the effect of C and N incorporation in GeTe and GST PCM devices. Understanding the effect of dopants on the change of electronic properties and the mechanisms of the phase transformation requires analysis of the local order and structure of the amorphous to crystalline phases. In this context, we demonstrate that carbon and nitrogen deeply affects the structure and the dynamical properties of the amorphous phase of GeTe. In particular, the inclusion of N and C dopant elements in GeTe has a drastic effect on the vibrational modes of GeTe therefore improving the stability of the glass. This effect goes with an increased mechanical rigidity explaining why these doped GeTe compounds have a higher crystallization temperature than the undoped ones. Finally we will explore, mainly by FTIR and XRD measurements, the effect of C and N dopants during the annealing of amorphous PCMaterials towards their crystalline phases. These results will be discussed in order to understand the origin of the differences of the doped PCMaterials amorphous phase stability (data retention) observed between full sheet materials and the materials integrated in PCM devices. [1] A. Fantini et al., 2010 IEEE International Electron Devices Meeting (IEDM), 2010, pp. 29.21.21-29.21.24. [2] G. Betti Beneventi et al., Solid-State Electronics, 65-66 (2011) 197-204. [3] V. Sousa et al., EPCOS 2011. [4] Q. Hubert et al., IMW 2012.A.R.C. Themoter

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis