Avaliação do papel de DLL4 na neo-angiogénese tumoral em modelos murinos de cancro da próstata

O cancro da próstata é hoje em dia um importante problema de saúde pública. Em Portugal, é o tipo de cancro mais frequente no homem, causando cerca de 10% da mortalidade por cancro. A maioria dos homens são diagnosticados em estádios iniciais da doença e nalguns casos é desenvolvida recorrência e, eventualmente, doença metastática. Hoje em dia, a terapia utilizada no tratamento do cancro da próstata, na maioria dos casos, provoca efeitos secundários e não fornece uma cura, surgindo a necessidade do desenvolvimento de novas estratégias de quimioterapia para o controlo eficaz desta patologia. A terapia anti-angiogénica tem vindo a ser incorporada em vários protocolos terapêuticos contra o cancro, constituindo uma abordagem promissora como adjuvante da quimioterapia convencional. Contudo, sabe-se que os tumores tratados com fármacos bloqueadores do fator de crescimento vascular endotelial A (VEGFA), desenvolvem resistência ao tratamento e nem todos os tipos de tumores são sensíveis a esta terapia. Deste modo, surge a necessidade do desenvolvimento de terapias anti-angiogénicas alternativas para complementar os tratamentos existentes, melhorando-as e impedindo o desenvolvimento de resistências. Recentemente, a sinalização Delta-like 4 (Dll4)/Notch tem sido identificada como um novo e promissor alvo na angiogénese tumoral. O bloqueio da função de Dll4 tem demonstrado ter um efeito pró-angiogénico nos tumores, promovendo um aumento da neo-vasculatura tumoral. Paradoxalmente, este bloqueio inibe o desenvolvimento tumoral devido à formação de vasos imaturos e não-funcionais, com subsequente aumento do nível de hipoxia no tumor. Contudo, apesar da notoriedade destas informações, é fundamental a realização de mais estudos, nomeadamente, utilizando-se modelos de tumores autóctones, de forma a ser feita uma avaliação mais fiável da eficácia de terapias anti-angiogénicas baseadas no bloqueio de Dll4. Neste sentido, o trabalho de investigação desenvolvido tem como objetivo a caracterização da expressão alterada de Dll4 no desenvolvimento de tumores prostáticos. Para isso recorreu-se à análise de uma linha de murganhos TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate), que desenvolve adenocarcinoma da próstata, com sobre-expressão ou deleção de Dll4, no endotélio. A caracterização fenotípica dos mutantes com ganho-de-função endotelial de Dll4 revelou uma diminuição do crescimento tumoral, devido ao efeito anti-angiogénico de Dll4, impedindo a resposta das células endoteliais aos estímulos pró-angiogénicos. Simultaneamente verificou-se que o aumento dos níveis de expressão de Dll4 promove a estabilização dos vasos já existentes, através do recrutamento de células de suporte. iii Por outro lado, confirmou-se os resultados anteriormente referidos em outros modelos animais, em relação aos mutantes com perda-de-função endotelial de Dll4. No seu conjunto os resultados mostram que o gene Dll4 desempenha um papel fulcral como regulador negativo do crescimento vascular angiogénico e, ao mesmo tempo, como regulador positivo dos fatores de normalização da vasculatura tumoral. Estes fatos sustentam a hipótese do controlo do funcionamento de Dll4 apresentar potencial terapêutico na luta contra o cancro da próstata, como agonista ou antagonista, dependendo do tipo tumoral e do resultado da avaliação de segurança e eficácia destas terapias que deverão ser feitos, especialmente quando combinada com outros fármacos.Prostate cancer is an important public health problem. In Portugal, this is the most common type in humans, causing about 10% of cancer mortality. Most patients are diagnosed at early stages of the disease and in some cases develope recurrence and metastatic disease. Current treatments for prostate cancer are mainly associated with side effects and fail to provide a cure. The anti-angiogenic therapy has been incorporated in various cancer therapeutic protocols and it is a promising approach as an adjuvant to conventional chemotherapy. However, it is known that tumors treated with the currently approved anti-angiogenic VEGF-targeting drug can develop resistance and not all tumor types are sensitive to such therapy. Therefore, alternative angiogenesis-based therapies are required to complement the existing treatments, improve them and prevent the development of resistance. Recently, the Delta 4 (Dll4) / Notch signaling has been identified as a promising new target in tumor angiogenesis. The inhibition of Dll4 in tumors has revealed a pro-angiogenic effect, which leads to an increase in tumor neo-vasculature. Paradoxically, this blockage inhibits the tumor growth due to the formation of immature and non-functional vessels, with subsequent increased levels of tumor hypoxia. However, further studies using autochthones tumor models are needed for a more reliable evaluation the efficacy of Dll4-based anti-angiogenic therapies. In this work were carried out trials to characterize the altered expression of Dll4 in prostatic tumor development. For this we used the animal model TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate), which develops prostate adenocarcinoma with Dll4 overexpression or Dll4 deletion in the endothelium. Phenotypic characterization of mutants with gain-of-function endothelial Dll4 showed a decrease of tumor growth due to an anti-angiogenic effect of Dll4, preventing the endothelial cell’s response to pro-angiogenic stimuli. Simultaneously, the increased expression of Dll4 promoted the stabilization of existing vessels through the recruitment of support cells. Moreover, the results previously described in other animal models with Dll4 endothelial loss-of-function were confirmed. Taken together, these results show that the Dll4 gene plays an important role in prostatic tumor angiogenesis, both as a negative regulator of vascular growth and as a positive regulator of pro-maturation and vascular normalization factors. These observations support the hypothesis that controlling the function of Dll4 may represent an effective therapeutic approach for the treatment of solid tumors. The use of Dll4 agonists or antagonists will probably depend on the tumor type as well as on further toxicity and efficacy analyses, especially when combined with other drugs

MAMMALS IN PORTUGAL : A data set of terrestrial, volant, and marine mammal occurrences in P ortugal

Mammals are threatened worldwide, with 26% of all species being includedin the IUCN threatened categories. This overall pattern is primarily associatedwith habitat loss or degradation, and human persecution for terrestrial mam-mals, and pollution, open net fishing, climate change, and prey depletion formarine mammals. Mammals play a key role in maintaining ecosystems func-tionality and resilience, and therefore information on their distribution is cru-cial to delineate and support conservation actions. MAMMALS INPORTUGAL is a publicly available data set compiling unpublishedgeoreferenced occurrence records of 92 terrestrial, volant, and marine mam-mals in mainland Portugal and archipelagos of the Azores and Madeira thatincludes 105,026 data entries between 1873 and 2021 (72% of the data occur-ring in 2000 and 2021). The methods used to collect the data were: live obser-vations/captures (43%), sign surveys (35%), camera trapping (16%),bioacoustics surveys (4%) and radiotracking, and inquiries that represent lessthan 1% of the records. The data set includes 13 types of records: (1) burrowsjsoil moundsjtunnel, (2) capture, (3) colony, (4) dead animaljhairjskullsjjaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8),observation in shelters, (9) photo trappingjvideo, (10) predators dietjpelletsjpine cones/nuts, (11) scatjtrackjditch, (12) telemetry and (13) vocalizationjecholocation. The spatial uncertainty of most records ranges between 0 and100 m (76%). Rodentia (n=31,573) has the highest number of records followedby Chiroptera (n=18,857), Carnivora (n=18,594), Lagomorpha (n=17,496),Cetartiodactyla (n=11,568) and Eulipotyphla (n=7008). The data setincludes records of species classified by the IUCN as threatened(e.g.,Oryctolagus cuniculus[n=12,159],Monachus monachus[n=1,512],andLynx pardinus[n=197]). We believe that this data set may stimulate thepublication of other European countries data sets that would certainly contrib-ute to ecology and conservation-related research, and therefore assisting onthe development of more accurate and tailored conservation managementstrategies for each species. There are no copyright restrictions; please cite thisdata paper when the data are used in publications.info:eu-repo/semantics/publishedVersio

Mammals in Portugal: a data set of terrestrial, volant, and marine mammal occurrences in Portugal

Mammals are threatened worldwide, with ~26% of all species being included in the IUCN threatened categories. This overall pattern is primarily associated with habitat loss or degradation, and human persecution for terrestrial mammals, and pollution, open net fishing, climate change, and prey depletion for marine mammals. Mammals play a key role in maintaining ecosystems functionality and resilience, and therefore information on their distribution is crucial to delineate and support conservation actions. MAMMALS IN PORTUGAL is a publicly available data set compiling unpublished georeferenced occurrence records of 92 terrestrial, volant, and marine mammals in mainland Portugal and archipelagos of the Azores and Madeira that includes 105,026 data entries between 1873 and 2021 (72% of the data occurring in 2000 and 2021). The methods used to collect the data were: live observations/captures (43%), sign surveys (35%), camera trapping (16%), bioacoustics surveys (4%) and radiotracking, and inquiries that represent less than 1% of the records. The data set includes 13 types of records: (1) burrows | soil mounds | tunnel, (2) capture, (3) colony, (4) dead animal | hair | skulls | jaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8), observation in shelters, (9) photo trapping | video, (10) predators diet | pellets | pine cones/nuts, (11) scat | track | ditch, (12) telemetry and (13) vocalization | echolocation. The spatial uncertainty of most records ranges between 0 and 100 m (76%). Rodentia (n =31,573) has the highest number of records followed by Chiroptera (n = 18,857), Carnivora (n = 18,594), Lagomorpha (n = 17,496), Cetartiodactyla (n = 11,568) and Eulipotyphla (n = 7008). The data set includes records of species classified by the IUCN as threatened (e.g., Oryctolagus cuniculus [n = 12,159], Monachus monachus [n = 1,512], and Lynx pardinus [n = 197]). We believe that this data set may stimulate the publication of other European countries data sets that would certainly contribute to ecology and conservation-related research, and therefore assisting on the development of more accurate and tailored conservation management strategies for each species. There are no copyright restrictions; please cite this data paper when the data are used in publications

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Unilateral intrastriatal 6-hydroxydopamine lesion in mice: a closer look into non-motor phenotype and glial response

Parkinson’s disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson’s disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry’s degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.This work was supported by the Foundation for Science and Technology (FCT) through PhD Fellowships attributed to B.M.P. (SFRH/BD/120124/2016), E.L.C. (SFRH/BD/131278/2017), J.C. (SFRH/BD/5813/2020), S.B.A. (PD/BDE/135568/2018), D.M.F. (SFRH/BD/147947/2019), and CEEC attributed to C.S.C. (CEECIND/03887/2017), S.D.S. (CEECIND/00685/2020), and L.P. (CEECIND/ 02855/2020). ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI— Portuguese Platform of Bioimaging PPBI-POCI-01-0145-FEDER-022122; National funds, through the FCT—project UIDB/50026/2020 and UIDP/50026/2020; the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); Competitiveness Internationalization Operational Programme (POCI), and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-032619

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

Professores e Alunos: o engendramento da violência da escola

The school violence engendering is partially analyzed, considering the violence production in the school environment. This is a bibliographic research with quantitative and qualitative approach. Sources: 77 theses and 15 dissertations carried out in Brazil (2007 to 2012). Data collection and organization: Content Analysis. Main reference: Bernard Charlot and Pierre Bourdieu. Results: the sources showed that Brazilian teachers participate effectively in the school violence engendering, contributing to violence production in the school environment. The students are the main victims. The teacher is less affected by physical and verbal violence. The symbolic power is the most perpetrated by the teacher against the student. The school also plays a major role in it.Analisa-se o engendramento de uma face da violência da escola, tendo em vista a produção da violência em espaço escolar. Pesquisa bibliográfica quanti-qualitativa. Fontes: 77 dissertações e 15 teses produzidas no Brasil (2007 a 2012). Coleta e organização dos dados: Análise de Conteúdo. Fundamentação base: Bernard Charlot e Pierre Bourdieu. Resultados: as fontes apontaram que professores brasileiros são protagonistas na constituição da violência da escola, contribuindo para a produção da violência em espaço escolar. Os alunos são as principais vítimas dessa violência. O professor sofre menos violência física e verbal do que o aluno. A violência simbólica é a mais usada pelo professor contra o aluno. A escola também usa desse expediente

Extraprensa. Cultura e comunicação na América Latina (Edição Especial sep 2019)

A revista Extraprensa é um periódico destinado à publicação da produção científica nas áreas da cultura e da comunicação no Brasil e América Latina, abrangendo temas como a diversidade cultural, cidadania, expressões das culturas populares, artes, mídias alternativas, epistemologia e metodologia em cultura e comunicação