DART: the distributed agent based retrieval toolkit

The technology of search engines is evolving from indexing and classification of web resources based on keywords to more sophisticated techniques which take into account the meaning and the context of textual information and usage. Replying to query, commercial search engines face the user requests with a large amount of results, mostly useless or only partially related to the request; the subsequent refinement, operated downloading and examining as much pages as possible and simply ignoring whatever stays behind the first few pages, is left up to the user. Furthermore, architectures based on centralized indexes, allow commercial search engines to control the advertisement of online information, in contrast to P2P architectures that focus the attention on user requirements involving the end user in search engine maintenance and operation. To address such wishes, new search engines should focus on three key aspects: semantics, geo-referencing, collaboration/distribution. Semantic analysis lets to increase the results relevance. The geo-referencing of catalogued resources allows contextualisation based on user position. Collaboration distributes storage, processing, and trust on a world-wide network of nodes running on users’ computers, getting rid of bottlenecks and central points of failures. In this paper, we describe the studies, the concepts and the solutions developed in the DART project to introduce these three key features in a novel search engine architecture

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs

A collaborative, semantic and context-aware search engine

Search engines help people to find information in the largest public knowledge system of the world: the Web. Unfortunately its size makes very complex to discover the right information. The users are faced lots of useless results forcing them to select one by one the most suitable. The new generation of search engines evolve from keyword-based indexing and classification to more sophisticated techniques considering the meaning, the context and the usage of information. We argue about the three key aspects: collaboration, geo-referencing and semantics. Collaboration distributes storage, processing and trust on a world-wide network of nodes running on users’ computers, getting rid of bottlenecks and central points of failures. The geo-referencing of catalogued resources allows contextualisation based on user position. Semantic analysis lets to increase the results relevance. In this paper, we expose the studies, the concepts and the solutions of a research project to introduce these three key features in a novel search engine architecture.213-21

Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis

To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations

Validação de conteúdo e análise da adesão ao uso da cartilha “Orientações para a Manutenção da Qualidade de Vida – Espinha Bífida” em crianças e adolescentes deambuladores e não deambuladores com espinha bífida

Objective: From the production of a booklet of home exercises “Orientações para a Manutenção da Qualidade de Vida – Espinha Bífida”, the aim was to validate the content, carry out the evaluation of the material (booklet) by caregivers, and analyze the adherence to the use of the booklet. Methods: For content validation, 8 expert judges evaluated the booklet through an adapted questionnaire, and the content validity index (CVI) was established for each aspect addressed. In the evaluation of the material carried out by the caregivers and in the analysis of adherence to the use of the booklet, 10 children and adolescents with spina bifida participated in this study. The booklet was read with the patients and their caregivers, who were trained to perform the exercises that are in the booklet at home. After delivery, a face-to-face return was scheduled, in 15 days, so that caregivers could report on the evaluation of the material as well as describe the adherence of these participants to the use of the booklet. Finally, a second meeting was scheduled - follow-up - to analyze long-term adherence. Results: Of the 27 aspects addressed in the content validation, 24 of these received scores above the acceptable index (CVI = 1.00). Most caregivers answered “agree” or “strongly agree” to all items analyzed regarding the evaluation of the booklet. In the short term, there was an adherence rate of 25% of the participants, and in the long term, 12.5%. Conclusion: The booklet “Orientações para a Manutenção da Qualidade de Vida – Espinha Bífida” proved to be a great resource to increase the physical therapy treatment of children and adolescents with spina bifida, according to the evaluation of expert judges and caregivers, for presenting adequate content, language and appearance, but showed moderate/low adherence by the participants.Objetivo: A partir da produção de uma cartilha de exercícios domiciliares “Orientações para a Manutenção da Qualidade de Vida – Espinha Bífida”, objetivou-se validar o conteúdo, realizar a avaliação do material (cartilha) pelos cuidadores, e analisar a adesão ao uso da cartilha. Métodos: Para validação do conteúdo, 8 juízes especialistas avaliaram a cartilha por meio de um questionário adaptado e foi estabelecido o índice de validade de conteúdo (IVC) para cada aspecto abordado. Na avaliação do material realizada pelos cuidadores e na análise da adesão ao uso da cartilha, participaram 10 crianças e adolescentes com espinha bífida e seus cuidadores. O pesquisador leu a cartilha e treinou os exercícios na presença do paciente e de seu cuidador, indicando como deveriam ser realizados em domicílio. Após a entrega foi marcado um retorno presencial, em 15 dias, para que os cuidadores pudessem relatar sobre a avaliação do material assim como, descrever sobre a adesão desses participantes ao uso da cartilha. Por fim, foi agendado um segundo encontro - follow-up – para analisar a adesão em longo prazo. Resultados: Dos 27 aspectos abordados na validação do conteúdo, 24 destes receberam pontuação acima do índice aceitável (IVC = 1,00). A maior parte dos cuidadores responderam “concordo” ou “concordo totalmente” para todos os itens analisados referente à avaliação do material. Em curto prazo foi observada uma taxa de adesão de 25% dos participantes e em longo prazo de 12,5%. Conclusão: A cartilha “Orientações para a Manutenção da Qualidade de Vida – Espinha Bífida” por apresentar clareza dos itens apresentados, facilidade de leitura e adequada compreensão, segundo a avaliação dos juízes especialistas e dos cuidadores, mostrou ser um ótimo recurso para incrementar o tratamento fisioterapêutico de criança e adolescentes com espinha bífida, porém evidenciou uma moderada/baixa adesão por parte dos participantes

Clinical utility of Next Generation Sequencing of plasma cell-free DNA for the molecular profiling of patients with NSCLC at diagnosis and disease progression

Background: The present study evaluates the utility of NGS analysis of circulating free DNA (cfDNA), which incorporates small amounts of tumor DNA (ctDNA), at diagnosis or at disease progression (PD) in NSCLC patients. Methods: Comprehensive genomic profiling on cfDNA by NGS were performed in NSCLC patients at diagnosis (if tissue was unavailable/insufficient) or at PD to investigate potential druggable molecular aberrations. Blood samples were collected as routinary diagnostic procedures, DNA was extracted, and the NextSeq 550 Illumina platform was used to run the Roche Avenio ctDNA Expanded Kit for molecular analyses. Gene variants were classified accordingly to the ESCAT score. Results: A total of 106 patients were included in this study; 44 % of cases were requested because of tissue unavailability at the diagnosis and 56 % were requested at the PD. At least one driver alteration was observed in 62 % of cases at diagnosis. Driver druggable variants classified as ESCAT level I were detected in 34 % of patients, including ALK-EML4, ROS1-CD74, EGFR, BRAF, KRAS p.G12C, PI3KCA. In the PD group, most patients were EGFR-positive, progressing to a first line-therapy. Sixty-three percent of patients had at least one driver alteration detected in blood and 17 % of patients had a known biological mechanism of resistance allowing further therapeutic decisions. Conclusions: The present study confirms the potential of liquid biopsy to detect tumour molecular heterogeneity in NSCLC patients at the diagnosis and at PD, demonstrating that a significant number of druggable mutations and mechanisms of resistance can be detected by NGS analysis on ctDNA

The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study

Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era

Análise da violência contra a mulher nos municípios do estado do Ceará de 2009 a 2018: Analysis of violence against women in the municipalities of the state of Ceará from 2009 to 2018

Analisar a violência de gênero notificada nos municípios do Estado do Ceará de 2009 a 2018.Estudo documental e retrospectivo, realizado no Ceará. A amostra foi extraída de dados secundários dos casos notificados de violência contra a mulher, nos anos de 2009 a 2018 no DATASUS e de 2011 a 2018 no Observatório de Violência Contra a Mulher. Ressalta-se que no Brasil no ano de 2017 a média geral de homicídio foi de 4,6 por 100 mil mulheres. No Estado do Ceará (8,1) casos de assassinato de mulheres em 2017, perdendo para os Estados do Rio Grande do Norte (11) e Roraima (8,2) casos (gráfico 3). O Estado do Ceará apresentou uma das menores taxas de notificações (74,1), perdendo para Maranhão (46,9) e Sergipe (59,4). Em relação às taxas de novos processos, o Ceará (154,9) tem os números mais baixos, estando na frente da Bahia (57,5), Alagoas (75,5) e Pará (135,2). A violência contra a mulher é passível de prevenção e necessita ser enfrentada pela sociedade. Infere-se que a sua superação implica a eliminação das condições desiguais da mulher em seu cotidiano. Entretanto, para   que esta condição seja alcançada, a elaboração e efetivação das políticas públicas têm um papel fundamental, de forma a incluir todos os setores da sociedade

Upper limb robotic rehabilitation for patients with cervical spinal cord injury: a comprehensive review

The upper extremities limitation represents one of the essential functional impairments in patients with cervical spinal cord injury. Electromechanics assisted devices and robots are increasingly used in neurorehabilitation to help functional improvement in patients with neurological diseases. This review aimed to systematically report the evidence-based, state-of-art on clinical applications and robotic-assisted arm training (RAT) in motor and functional recovery in subjects affected by cervical spinal cord injury. The present study has been carried out within the framework of the Italian Consensus Conference on "Rehabilitation assisted by robotic and electromechanical devices for persons with disability of neurological origin" (CICERONE). PubMed/MEDLINE, Cochrane Library, and Physiotherapy Evidence Database (PEDro) databases were systematically searched from inception to September 2021. The 10-item PEDro scale assessed the study quality for the RCT and the AMSTAR-2 for the systematic review. Two different authors rated the studies included in this review. If consensus was not achieved after discussion, a third reviewer was interrogated. The five-item Oxford CEBM scale was used to rate the level of evidence. A total of 11 studies were included. The selected studies were: two systematic reviews, two RCTs, one parallel-group controlled trial, one longitudinal intervention study and five case series. One RCT was scored as a high-quality study, while the systematic review was of low quality. RAT was reported as feasible and safe. Initial positive effects of RAT were found for arm function and quality of movement in addition to conventional therapy. The high clinical heterogeneity of treatment programs and the variety of robot devices could severely affect the generalizability of the study results. Therefore, future studies are warranted to standardize the type of intervention and evaluate the role of robotic-assisted training in subjects affected by cervical spinal cord injury

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway(1,2). Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis