Prognostic role of TPL2 in early‑stage non‑small cell lung cancer

Non‑small cell lung cancer (NSCLC) accounts for ~70% of all lung cancer‑associated mortalities worldwide. The serine/threonine protein kinase tumor progression locus 2 [TPL2/MAP3 kinase 8 (MAP3K8)] may impact oncogenic events; however the role of TPL2 in lung carcinogenesis remains unclear. The present study was focused on the potential prognostic role of TPL2 in 101 patients with early‑stage NSCLC. Since TPL2 is a potential target of miR‑21, the association between TPL2 and miR‑21 expression was also examined. TPL2 and miR‑21 mRNA expression was quantified using reverse transcription quantitative polymerase chain reaction (RT‑qPCR). TPL2 protein levels were evaluated by immunohistochemistry (IHC). The present study identified that the mRNA expression of TPL2 was low in 52/101 (51%) cases and high in 49/101 (49%) cases. IHC analysis of TPL2 protein expression often demonstrated identical mRNA results. No statistically significant associations were observed between the mRNA expression of TPL2 and the predominant clinicopathological characteristics of the patients with NSCLC, as well as identifying no association between TPL2 and miR‑21. TPL2 mRNA expression was significantly higher in patients with NSCLC with good prognosis (disease‑free interval P=0.009; overall survival P=0.024), when compared with those of poor prognosis. Focusing on the difference in mRNA expression of TPL2 among the adenocarcinomas in affected patients, TPL2 was more highly expressed in lepidic adenocarcinomas compared with in the other subtypes (P=0.012). The present study is the first examination, to the best of our knowledge, of TPL2 in early‑stage NSCLC in relation to miR‑21, and in different adenocarcinoma subtypes. Future studies must clarify the mechanism by which TPL2 is involved in lung carcinogenesis due to its important translational implications

O papel de um instrumento de apoio à comunicação matemática numa turma do 4.º ano

Relatório de Estágio apresentado à Escola Superior de Educação de Lisboa para obtenção de grau de mestre em Ensino do 1.º e 2.º Ciclos do Ensino BásicoA criação de ambientes de sala de aula onde os alunos são agentes efetivos da sua aprendizagem e têm espaço para participar e expor os seus conhecimentos, sabendo que vão ser ouvidos pelo professor e colegas, é, cada vez mais, uma recomendação curricular da atualidade e objeto de estudo. Este relatório dá conta da intervenção realizada numa turma do 4.º ano de escolaridade, com o propósito de promover a aprendizagem, valorizando, sistematicamente, a comunicação. Em simultâneo, explana-se a investigação realizada nesta turma, que envolveu a avaliação do impacto da construção de um instrumento de apoio aos momentos de Comunicação Matemática, no contexto de uma rotina semanal da turma, a Apresentação do Problema da Semana. Com a pretensão de dar resposta às questões (i) quais os contributos de um instrumento de apoio à organização e estruturação dos momentos de comunicação matemática? e (ii) de que forma esse mesmo instrumento contribui para o desenvolvimento de estratégias de resolução de problemas?, investigou-se a evolução da turma quanto à comunicação das resoluções dos problemas e à variedade das estratégias utilizadas, antes e após a construção coletiva do instrumento de apoio. A análise de resultados, feita através da análise das produções dos alunos e das respostas a um questionário que instigou a reflexão sobre o papel do instrumento de apoio ao longo das várias apresentações do problema da semana, permitiu perceber uma crescente variedade de estratégias utilizadas e uma maior preocupação, por parte dos alunos, em organizar e estruturar os momentos de comunicação matemática, bem como em mobilizar um discurso com correção matemática. Este é um estudo que se limita a uma turma, não sendo as suas conclusões generalizáveis, mas que pode contribuir com uma estratégia para melhorar a comunicação matemática dos alunos, de uma forma que os envolve de forma direta e que prevê a sua participação e papel ativo na aprendizagem.ABSTRACT Creating classroom environments where students are effective agents of their learning process and have space to participate and exhibit their skills, knowing that they will be heard by the teacher and classmates, is an increasingly curricular recomendation and object of stdy nowadays. This report gives an account of the intervention carried out on a 4th grade level class, with the purpose of promoting learning, valuing, systematically, the communication. At the same time, explains research performed in this class, which involved the evaluation of the impact of the construction of an instrument in support of Mathematical Communication moments, in the context of a weekly routine of the class, The Presentation of rhe Problem of the Week. With the pretense of responding to questions (i) what are the contributions of an instrument of support to the organization and structuring of moments of mathematical communication? and (ii) how this same instrument contributes to the development of problem solving strategies?, it was investigated the evolution of the class regarding the communication of the resolutions of the problems and the variety of strategies used in problem solving, before and after the collective construction of the instrument. The analysis of results, through the analysis of students’ productions and the replies to a questionnaire that instigated the reflection about the role of the instrument of support along the various presentations of the problem of the week, allowed to realize a growing variety of strategies used and greater concern, on the part of students, to organise and structure the moments of mathematical communication as well as in mobilizing a discourse with mathematical correction. This is a study that is limited to a class, which makes its conclusions not generalizable, but that can contribute with a strategy to improve students’ math communication, in a way that involves them directly and provides their participation and active role in their own learning process.N/

The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins

Snakebite envenoming is a serious and neglected tropical disease that kills ~100,000 people annually. High-quality, genome-enabled comprehensive characterization of toxin genes will facilitate development of effective humanized recombinant antivenom. We report a de novo near-chromosomal genome assembly of Naja naja, the Indian cobra, a highly venomous, medically important snake. Our assembly has a scaffold N50 of 223.35 Mb, with 19 scaffolds containing 95% of the genome. Of the 23,248 predicted protein-coding genes, 12,346 venom-gland-expressed genes constitute the \u27venom-ome\u27 and this included 139 genes from 33 toxin families. Among the 139 toxin genes were 19 \u27venom-ome-specific toxins\u27 (VSTs) that showed venom-gland-specific expression, and these probably encode the minimal core venom effector proteins. Synthetic venom reconstituted through recombinant VST expression will aid in the rapid development of safe and effective synthetic antivenom. Additionally, our genome could serve as a reference for snake genomes, support evolutionary studies and enable venom-driven drug discovery

Antivenoms for the treatment of snakebite envenomings: The road ahead

The parenteral administration of antivenoms is the cornerstone of snakebite envenoming therapy. Efforts are made to ensure that antivenoms of adequate efficacy and safety are available world-wide. We address the main issues to be considered for the development and manufacture of improved antivenoms. Those include: (a) A knowledge-based composition design of venom mixtures used for immunization, based on biochemical, immunological, toxicological, taxonomic, clinical and epidemiological data; (b) a careful selection and adequate management of animals used for immunization; (c) well-designed immunization protocols; (d) sound innovations in plasma fractionation protocols to improve recovery, tolerability and stability of antivenoms; (e) the use of recombinant toxins as immunogens to generate antivenoms and the synthesis of engineered antibodies to substitute for animal-derived antivenoms; (f) scientific studies of the contribution of existing manufacturing steps to the inactivation or removal of viruses and other zoonotic pathogens; (g) the introduction of novel quality control tests; (h) the development of in vitro assays in substitution of in vivo tests to assess antivenom potency; and (i) scientifically-sound pre-clinical and clinical assessments of antivenoms. These tasks demand cooperative efforts at all main stages of antivenom development and production, and need concerted international partnerships between key stakeholders.Universidad de Costa Rica//UCR/Costa RicaInternational Foundation for Science//IFS/SueciaCiencia y Tecnología para el Desarrollo//CYTED/EspañaConsejo Superior de Investigaciones Científicas//CRUSA-CSIC/EspañaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Context- and Social-aware Middleware for Opportunistic Networks

Opportunistic networks are multi-hop ad hoc networks in which nodes opportunistically exploit any pair-wise contact to share and forward content, without requiring any pre-existing Internet infrastructure. Opportunistic networks tolerate partitions, long disconnections, and topology instability in general. In this challenging environment, leveraging users\u27 mobility represents the most effective way to deliver content to interested users. In this paper we propose a context- and social-aware middleware that autonomically learns context and social information on the users of the network, and that uses this information in order to predict users\u27 future movements. In order to evaluate the proposed middleware on a realistic scenario, we have designed and implemented a context- and social-aware content sharing service, exploiting the functionality of the middleware. Both the middleware and the content sharing service have been integrated with an existing data-centric architecture (the Haggle architecture) for opportunistic networks. Finally, we have validated the proposed content sharing application on a small-scale testbed and, on a larger scale, we have investigated the advantages provided by context- and social-aware sharing strategies by means of extensive simulations. The main result of this paper is the definition and implementation of a context- and social-aware middleware able to share context information with all the interested components improving the efficiency and performances of services and protocols in opportunistic networks. With respect to content sharing strategies that do not exploit context and social information, we have obtained up to 200% improvements in terms of hit rate (probability that users receive the content they request) and 99% reduction in resource consumption in terms of traffic generated on the network

Expression of miRNA-25 in young and old lung adenocarcinoma

Background: An appropriate personalized molecular testing ensures the most efficacious treatment in lung cancer. It is still controversial whether younger lung adenocarcinoma (LUAD) patients have different molecular features compared with their older counterparts. MicroRNAs have been involved in lung cancer and their altered expression has been suggested as a potential biomarker in the pathogenesis, diagnosis, prognosis, and therapy of LUAD. Materials and Methods: To analyze putative differences in miR-25 expression between young (with age ≤50 years) and old adenocarcinoma patients, we quantified miR-25 levels with NanoString technology in 88 LUAD specimens. We further investigated a cohort of 309 LUAD patients from the cancer genome atlas (TCGA) database to test our hypothesis. Results: miR-25 expression was upregulated in young LUAD patients in comparison to the older ones (P = 0.03) in our series. The analysis of public database TCGA confirmed our results, which miR-25 differentially expressed in the two aged groups (P = 0.0009). Moreover, a consequential pairing of miR-25 with a target region in phosphatase and tensin homolog (PTEN) 3' untranslated region (UTR) and actually low PTEN expression seemed to be associated with high miR-25 (P = 0.001) in young patients. Conclusions: The interaction of miR-25 and PTEN in young LUAD may define a subgroup of patients, highlighting the concept of molecular testing in different age subtypes

Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma.

Background: MiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle. Target transcripts for immune checkpoint molecules such as PD-1/PD-L1 and (programmed cell death-1/its ligand and cytotoxic T-lymphocyte antigen 4) have proven to be beneficial against several solid tumors, including lung adenocarcinoma. Methods: Simultaneous quantification of the expression level of miR-33a and PD-1, PD-L1 and CTLA4 mRNAs with NanoString technology was performed in 88 lung adenocarcinoma specimens. A cohort of 323 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database was further analyzed, in order to test our hypothesis. Potential interference of PD-1, PD-L1 and CTLA4 gene expression by miR-33a was predicted using the microRNA target prediction program RNA22. Results: High miR-33a expression was significantly associated with younger (p = 0.005), female (p = 0.04), patients with low grade (p < 0.0001), early stage (p = 0.03) tumors, and better survival. The hypothesis of the involvement of miR-33a in PD-1/PD-L1/CTLA4 mechanisms was corroborated by the finding of putative miR-33a binding sites in all three genes using the RNA22 method. We found an inverse correlation between miR-33a and PD-1 levels (p = 0.01), as well as for PD-L1 (p = 0.01) and CTLA4 (p = 0.03) expression, and a significant better prognosis for patients with high miR-33a/low PD-1. TCGA database analysis confirmed that miR-33a high levels were associated with low PD-1 expression and with longer survival on a larger population. Conclusions: Our study emphasizes the notion of a potential value of miR-33a as a favorable prognostic marker through PD-1 regulation

Differential microRNA Expression Profile between Young and Old Lung Adenocarcinoma Patients.

Background Lung cancer is the leading cause of cancer related mortality and approximately 80% is represented by non-small cell lung cancer (NSCLC). In the last decade, age of patients at diagnosis has decreased, with an incidence of approximately 13.4% in patients under 50 years. Previous studies have hypothesized that lung cancer in young patients could represent a separated clinicalpathological entity; however it is still controversial whether younger patients have a different outcome compared with their older counterparts. MicroRNAs (miRNAs) have recently been defined to play a key role in cancer pathogenesis and their aberrant expression has been suggested as a potential biomarker of prognosis in lung adenocarcinoma. To understand the molecular features of young and old adenocarcinoma patients, we investigated the expression levels of a panel of miRNAs selected from recent literature. Methods Thirty-five lung ADC from patients under 50 years old were enrolled as the younger group and thirty-five ADC older than 50 years were collected as the older group. After miRNA isolation from formalin-fixed and paraffin-embedded tumor tissues, the expression levels of 30 miRNAs were analyzed by NanoString technology and compared between the two groups. Survival data were used to assess the prognostic impact of miRNAs. The software miRgator v3.0 was used to predict the putative pathways targeted by miRNAs. Results The analysis revealed that 7 miRNAs (miR-25-3p, miR-29c-3p, miR-33a-5p, miR-144-3p, miR-153-3p, miR-342-5p and miR-485-3p) were differently expressed in the two groups (Mann-Whitney U test, p&lt;0.05). All these miRNAs showed higher expression levels in young compared to old patients, and their predicted targets included EGFR, MET, VEGF-A,TP53 and PDGFRa. miR-144-3p had an opposite influence on overall survival, since its upregulation was associated with a better outcome in young patients (p= 0.01) and a worse prognosis in the old group (p= 0.03). Conclusion Our study provides new insights about the role of miRNAs in lung adenocarcinoma occurring in young patients. We observed that lung cancer in young and old patients may be influenced by different regulatory mechanisms since we found 7 miRNAs as downregulated in the older group, probably due to distinct age-related genetic and epigenetic alterations. Moreover, one of the deregulated miRNAs showed a different prognostic impact in the two groups thus confirming that young and old patients deserve a specific clinical approach. Further validations are needed to better define if an age-based genomic signature could be used as prognostic marker in lung cancer