Comunicação matemática em contexto de sala de aula : o papel da professora de uma turma do 5º ano de escolaridade

A presente comunicação tem como objetivo mostrar a importância do papel do professor no desenvolvimento da comunicação numa aula de Matemática. Tendo a convicção de que o desenvolvimento desta capacidade é uma condição necessária ao bom desempenho dos alunos na disciplina, veremos de que forma esta se desenvolve, a partir da interação de uma professora com um grupo de alunos. A consciencialização da importância do desenvolvimento nos alunos da comunicação matemática enquanto capacidade transversal materializa-se no decorrer de cada aula e dos registos escritos que constam do caderno diário dos alunos envolvidos. Neste contexto serão aqui analisadas algumas interações entre alunos e alunos e professor, relevantes para a promoção da comunicação matemática em sala de aula. São também abordados alguns aspetos essenciais diretamente relacionados com esta capacidade, de realçar, a seleção refletida das tarefas, a valorização das produções dos alunos, o incentivo à explicação de estratégias de resolução e gestão do trabalho a desenvolver nos diversos momentos da aula. Este estudo seguiu uma metodologia de estudo de caso, centrado numa professora do 5.º ano de escolaridade e baseando-se na observação direta da interação com uma turma. Com este estudo foi possível concluir que a professora dava uma particular atenção aos momentos de interação em pequeno e grande grupo e que valorizava a colocação de questões procurando não dar respostas aos alunos

AXL as a modulator of sunitinib response in glioblastoma cell lines

Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.This work was funded by Fundacao para a Ciencia e Tecnologia (FCT), Portugal (project: PTDC/SAU-TOX/114549/2009). Olga Martinho is a recipient of a Post-Doc fellowship (UMINHO/BPD/32/2013) from QREN. We would like to acknowledge Dr. Shuang-En Chuang from the National Health Research Institute, Taiwan, for providing AXL vectors, and Dr. Raquel Andrade for critical review of the manuscript

Protein Kinase WNK2 has a Tumour Suppressor Role in Gliomas

Malignant glioblastoma is the most common and lethal adult brain tumour type. Recently, the promoter region of the protein kinaseWNK2 gene was found to be hypermethylated in 29 of 31 infiltrative gliomas and about 5 of 7 meningiomas. We have previously described that theexperimental depletion of WNK2 expression decreases RhoA activity whilst leading to increased Rac1 activity. RhoA/Rac1 activities are important forcell migration and glioblastomas are very invasive tumours so that we tested the effects of WNK2 on wound-healing assays in glioma cell lines SW1088and A172. SW1088 cells express endogenous WNK2 and we observed that wound closure was increased upon experimental depletion of endogenousWNK2. In contrast, A172 cells display complete promoter region methylation and WNK2 re-expression was found to decrease migration. Consistently,we observed an increase in Rac1 activity in SW1088 cells upon WNK2 down-regulation, but lower levels of active Rac1 in A172 cells stably expressingWNK2 cDNA when compared with an equivalent cell line stably transfected with the same empty vector. Our studies indicate that loss of WNK2expression promotes Rac1 activation and may contribute to the highly invasive phenotype that glioblastomas present.Fundação para a Ciência e Tecnologi

ASPM is an oncoprotein and activates EGFR

Este resumo faz parte de: Book of abstracts of the Meeting of the Institute for Biotechnology and Bioengineering, 2, Braga, Portugal, 2010. A versão completa do livro de atas está disponível em: http://hdl.handle.net/1822/1096

Glucose addiction in cancer therapy : advances and drawbacks

Glucose addiction in cancer therapy: advances and drawbacks.In contrast to differentiated normal cells, which primarily use mitochondrial respiration to generate the energy needed for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions, a phenomenon known as the “Warburg effect” or aerobic glycolysis. In the last years, much attention to the metabolic reprogramming of cancer cells has been paid by many research groups and, as a result, this altered energy metabolism was recognized in 2011 as one of the “hallmarks of cancer”. Aerobic glycolysis allows a rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis. Metabolic reprogramming renders cancer cells dependent on specific metabolic enzymes or pathways that could be exploited in cancer therapy. The development of treatments that target tumor glucose metabolism is receiving renewed attention, with several drugs targeting metabolic pathways currently in clinical trials. However, the search for suitable targets may be limited by the high plasticity of the metabolic network that can induce compensatory routes. Moreover, deregulated glucose metabolism has been also shown as a prominent feature associated with resistance to either classical chemotherapy or oncogene-targeted therapies, strengthening the clinical potential of combining these therapies with glycolysis inhibitors. The aim of this review is to compare the advances of the different therapeutic strategies targeting the glucose “addiction” of tumor cells, highlighting the potential of these findings to be translated into effective weapons against cancer. Further, we will also present and discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, in which combination with glycolysis inhibitors are potentially useful

A 30-year long-term experience in appendix neuroendocrine neoplasms—granting a positive outcome

Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to cell cycle proliferation and/or senescence-type, apoptotic, and metastatic potential. Appendix NENs were detected in 74 patients, with 0.47% of incidence per appendectomy. The median age of the patients was 21.5 years, with two age peaks of incidence at 17.0 and 55.2 years. The median tumors size was 5.8 mm, and most were smaller than 10 mm. Lymphovascular and perineural invasion, as well as necrosis, was associated with larger tumor size. G1 tumors composed 96.0% of the cohort. The presence of moderate/strong p16 and the absent/low Bcl-2 expression was frequently observed and associated with a smaller size. This study represents one of the largest cohorts and with a long follow-up. For tumors smaller than 10 mm appendicectomy was sufficient as a curative procedure, as revealed by the good outcome. This series presented a 100% disease-free survival. The indolent phenotype of appendix NENs is supported by the expression of markers that point towards a strong inhibition of cell replication and growth inhibition.This study was supported by FCT—Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior by a research contract to João Vinagre (CEECIND/00201/2017). Further funding was obtained from the project “Advancing cancer research: from basic knowledge to application” NORTE-01-0145-FEDER-000029: “Projetos Estruturados de I & D & I”, funded by Norte 2020—Programa Operacional Regional do Norte. Additional funding was obtained from the project PTDC/MED-ONC/31438/2017 (The other faces of Telomerase: Looking beyond tumor immortalization), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI) and by Portuguese funds through FCT under project POCI-01-0145-FEDER-016390: CANCEL STEM”

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.FINEP (MCTI/FINEP/MS/SCTIE/DECIT-01/2013 - FPXII-BIOPLAT) and the Assistance Program and Incentive Research (PAIP), Barretos Cancer Hospital São Paulo, Brazil. The authors would like to acknowledge the technical support of Gabriela Lamberti in the clonogenic assays. A.L.C and R.M.R are recipients of a National Counsel of Technological and Scientific Development (CNPq) scholarship and O.C.M is recipient of a Portuguese Foundation for Science and Technology (FCT) scholarship (SFRH/BPD/108351/2015)info:eu-repo/semantics/publishedVersio

Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas

Acral lentiginous melanoma (ALM) is the less common subtype with singular characterization. TERT (human telomerase reverse transcriptase) promoter mutations have being described as recurrent in melanomas and infrequent in ALM, but their real incidence and clinical relevance is unclear. The objectives of this study were to describe the prevalence of TERT promoter mutations in ALM, and correlate with the molecular profile of other drive genes and clinical features. Sixty-one samples from 48 patients with ALM were analyzed. After DNA isolation, the mutation profiles of the hotspot region of BRAF, NRAS, KIT, PDGFRA, and TERT genes were determined by PCR amplification followed by direct Sanger sequencing. KIT, PDGFRA, and VEGFR2 gene amplification was performed by quantitative PCR. Clinical information such as survival, clinical stage, and Breslow tumor classification were obtained from medical records. TERT promoter mutations were found in 9.3% of the cases, BRAF in 10.3%, NRAS in 7.5%, KIT in 20.7%, and PDGFRA in 14.8% of ALM. None of the cases showed KIT, PDGFRA, or VEGFR2 gene amplification. We found an association between KIT mutations and advanced Clark level (IV and V, P=0.043) and TERT promoter mutations with low mitotic index. No other significant associations were observed between mutation profile and patients' clinical features nor survival rates. Oncogenic TERT promoter mutations are present in a fraction of ALMs. No relevant associations were found between TERT mutation status and clinical/molecular features nor survival. Mutations of KIT and PDGFRA are the most common genetic alterations, and they can be therapeutic targets for these patients.This project was supported by FAPESP - Brazil (2012/4194-1) to Vinicius de Lima Vazquez.info:eu-repo/semantics/publishedVersio

A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours

PURPOSE: To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA. METHODS: Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available. RESULTS: Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values. CONCLUSIONS: Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.info:eu-repo/semantics/publishedVersio

WNK2 inhibits autophagic flux in human glioblastoma cell line

The following are available online at http://www.mdpi.com/2073-4409/9/2/485/s1, Figure S1: Validation of WNK2 overexpression by RT-PCR.Autophagy is a cell-survival pathway with dual role in tumorigenesis, promoting either tumor survival or tumor death. WNK2 gene, a member of the WNK (with no lysine (K)) subfamily, acts as a tumor suppressor gene in gliomas, regulating cell migration and invasion; however, its role in autophagy process is poorly explored. The WNK2-methylated human glioblastoma cell line A172 WT (wild type) was compared to transfected clones A172 EV (empty vector), and A172 WNK2 (WNK2 overexpression) for the evaluation of autophagy using an inhibitor (bafilomycin A1—baf A1) and an inducer (everolimus) of autophagic flux. Western blot and immunofluorescence approaches were used to monitor autophagic markers, LC3A/B and SQSTM1/p62. A172 WNK2 cells presented a significant decrease in LC3B and p62 protein levels, and in LC3A/B ratio when compared with control cells, after treatment with baf A1 + everolimus, suggesting that WNK2 overexpression inhibits the autophagic flux in gliomas. The mTOR pathway was also evaluated under the same conditions, and the observed results suggest that the inhibition of autophagy mediated by WNK2 occurs through a mTOR-independent pathway. In conclusion, the evaluation of the autophagic process demonstrated that WNK2 inhibits the autophagic flux in glioblastoma cell line.This project was supported by the Barretos Cancer Hospital Internal Research Funds (PAIP) to Rui Manuel Reis and by the Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer Project), Campinas, Brazil. Ana Laura Vieira Alves is the recipient of a FAPESP master fellowship (2016/18907-0)