Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC

Investigating body composition in wheelchair athletes

Subjects with spinal cord injury (SCI) are at risk for adverse changes in body composition (BC), which are harmful for their health and relevant to sport performance. This study investigated whole-body and regional BC in wheelchair athletes (WA) by comparing tetraplegic and paraplegic WA with a larger sample of healthy males athletes. Dual-energy X-ray absorptiometry (DXA) was used by one operator to measure subtotal (total-body less head) and regional (arms, legs and trunk) body composition (lean mass [LM], bone mineral content [BMC], fat mass [FM] and fat mass percentage [%FM]) in twenty-seven male WA aged 30.0±9.4y with chronic SCI. WA were classified as tetraplegic (lesion above T1; Tetra, n=10) and paraplegic (lesion at T1 and below; Para, n=17) and matched each to three healthy males athletes (n=81) on the basis of DXA area and BMI. BC outcomes were compared in Tetra and Para as well as Tetra and Para, and their respective control with the t-test for independent samples. Alpha value was set at 0.05 and p-values corrected for multiple comparisons (pc; Benjamini and Hochberg procedure). Percent FM was significant higher in Tetra vs. Para at the subtotal and regional level (0.02

Produção de Significações do Espaço e Sociabilidade em um Café Artesanal de Salvador

O presente artigo busca compreender a produção dos significados do espaço organizacional a partir dos modos de sociabilidade contemporâneos que se desenvolvem em um café artesanal na cidade de Salvador. No referencial sobre sociabilidade urbana, fizemos uso de Simmel (2006) e Frúgoli (2007), entre outros. Para as referências sobre espaço, recorremos, além de outros autores, a Santos (1982) e Serpa (2008). Dentro de Estudos Organizacionais, referenciamos, entre outros, Cavedon et al (2007) e Chanlat (2004); sobre organizações artesanais, utilizamos referências de Sennet (2009) e Fischer (2011). Em termos metodológicos, foi desenvolvido um estudo etnográfico, no qual se adotou como técnica de coleta o uso de diários de campo, a observação sistemática e participante e entrevistas. O texto mostra significações a partir de sociabilidades que se constroem em um movimento que concebe, simultaneamente, proximidade e distanciamento, evidenciando o café como elo entre os indivíduos, por meio do consumo. Tais elementos levam a novas formas de pensar a gestão desse tipo de organização, por meio da compreensão das práticas do cotidiano organizacional.

Significados permanentes e mutantes: sociabilidades e significações no cotidiano de um café

This article aims to unravel the meanings attributed to the organizational space by clients of a café, relating this phenomenon to cultural circularity and its reinterpretation and understanding it in the light of the meanings that cafés received historically. To achieve this, an ethnographic study was developed, in which we adopted techniques of systematic and participant observation, plus in-depth interviews. For the analysis of field data we used content analysis. The categorization and analysis of the data allowed us to identify repertoires of meanings that emerged from the field, which highlight the complexity inherent in the management of organizations whose core business is sociability. We perceived the historical continuity of meanings related to conviviality and shared space, but also unveiled meanings that reinforce contemporary aspects of the organization, such as those that refer to individuality and urban violence. The discussion of such aspects implies new challenges to contemporary management, considered from the perspective of organizational sociability and the survival of cafés as organizations that can contribute to innovations in building shared urban spaces.Keywords: cafés, organizational sociability, meanings.Este artigo tem por objetivo desvendar os significados atribuídos ao espaço organizacional pelos frequentadores de um café, compreendendo tal fenômeno em face da circularidade cultural e suas ressignificações, e à luz dos significados que os cafés receberam historicamente. Para tal, foi empreendido um estudo de cunho etnográfico, e adotadas as técnicas de observação sistemática e participante, além de entrevistas individuais em profundidade. Para a análise dos dados de campo, foi utilizada a análise de conteúdo. A categorização e a análise dos dados nos permitiram identificar repertórios de significados emersos do campo, que evidenciam a complexidade inerente à gestão de organizações cujo negócio central é a sociabilidade. Percebemos a perenidade histórica de significados relacionados ao convívio e ao espaço partilhado, mas também desvendamos significados que reforçam a contemporaneidade desse tipo de organização, como aqueles que remetem a fenômenos como individualidade e violência urbana. A discussão de tais aspectos implica novos desafios à gestão contemporânea, pensados sob o prisma da sociabilidade organizacional e da sobrevivência dos cafés como organizações que podem contribuir com inovações na construção de espaços urbanos compartilhados.Palavras-chave: cafés, sociabilidade organizacional, significados

A Vitalidade Artesanal da Gestão Contemporânea

Metáfora do fazer humano bem feito e com forte engajamento corporal-moral-afetivo, o fazer artesanal presta-se a muitas interpretações e usos. É, ao mesmo tempo, um conceito e uma prática; um conceito multiforme que compreende práticas fundamentalmente humanas. O fazer artesanal revela-se em toda a sua força pela marca profundamente humana que imprime em objetos, atividades e processos. Acreditamos que, por meio de um retorno aos princípios do trabalho artesanal, a gestão poderá repensar seus fundamentos, sobretudo os que foram herdados de uma lógica industrial e que destoam das expectativas contemporâneas para melhorar o futuro de nossas organizações e sociedades. Nesta introdução, selecionamos, caracterizamos e discutimos três desses princípios: o princípio da cultura, o princípio da materialidade e o princípio da territorialidade.

Predictors of Local Control for Stereotactic Ablative Radiotherapy (SAbR) in Pulmonary Oligometastases from Gastrointestinal Malignancies

Background/aim: To assess predictors of local control (LC) for stereotactic ablative radiotherapy (SAbR) in pulmonary oligometastatic disease (OMD) from gastrointestinal (GI) malignancies. Patients and methods: Patients with pulmonary OMD treated with SAbR from January 2016 to December 2018 were included in this observational analysis. Primary endpoint was LC. Uni- and multivariate analyses to assess variable correlations were conducted. Results: Thirty-seven patients and 59 lung metastases were evaluated. The delivered dose was 30-60 Gy in 3-8 fractions. After a median follow-up of 23.0 months (range=6.3-50.4 months), LC rate at 1/2 years was 89.7%/85.0%, and increased to 96.0%/91.0% for lesions treated with a biologically effective dose (BED10) ≥100 Gy (p=0.03). RECIST response at 6 months was predictive for LC (p=0.002). Conclusion: SAbR is an effective option for pulmonary OMD from GI malignancies. A BED10 ≥100 Gy and radiological response at 6 months can affect LC

Depoimentos sobre o Colóquio

Depoimentos sobre o Colóquio Metamorfose do Poder Local, Itinerários do Desenvolvimento, realizado em setembro de 2012, em Salvador-Ba

Randomised controlled trial combining vitamin E-functionalised chocolate with physical exercise to reduce the risk of protein-energy malnutrition in predementia aged people: study protocol for Choko-Age

Objective: Protein-energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. Methods and analysis: In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the 'Joint Programming Initiative A healthy diet for a healthy life'. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9-1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. Ethics and dissemination: All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects' regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. Trial registration number: NCT05343611

Design and validation of a 63K genome-wide SNP-genotyping platform for caribou/reindeer (Rangifer tarandus)

Background Development of large single nucleotide polymorphism (SNP) arrays can make genomic data promptly available for conservation problematic. Medium and high-density panels can be designed with sufficient coverage to offer a genome-wide perspective and the generated genotypes can be used to assess different genetic metrics related to population structure, relatedness, or inbreeding. SNP genotyping could also permit sexing samples with unknown associated metadata as it is often the case when using non-invasive sampling methods favored for endangered species. Genome sequencing of wild species provides the necessary information to design such SNP arrays. We report here the development of a SNP-array for endangered Rangifer tarandus using a multi-platform sequencing approach from animals found in diverse populations representing the entire circumpolar distribution of the species. Results From a very large comprehensive catalog of SNPs detected over the entire sample set (N = 894), a total of 63,336 SNPs were selected. SNP selection accounted for SNPs evenly distributed across the entire genome (~ every 50Kb) with known minor alleles across populations world-wide. In addition, a subset of SNPs was selected to represent rare and local alleles found in Eastern Canada which could be used for ecotype and population assignments - information urgently needed for conservation planning. In addition, heterozygosity from SNPs located in the X-chromosome and genotyping call-rate of SNPs located into the SRY gene of the Y-chromosome yielded an accurate and robust sexing assessment. All SNPs were validated using a high-throughput SNP-genotyping chip. Conclusion This design is now integrated into the first genome-wide commercially available genotyping platform for Rangifer tarandus. This platform would pave the way to future genomic investigation of populations for this endangered species, including estimation of genetic diversity parameters, population assignments, as well as animal sexing from genetic SNP data for non-invasive samples

Magnetic resonance-guided focused ultrasound unilateral thalamotomy for medically refractory essential tremor: 3-year follow-up data

IntroductionMagnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy of the ventralis intermediate (Vim) nucleus is an “incisionless” treatment for medically refractory essential tremor (ET). We present data on 49 consecutive cases of MRgFUS Vim thalamotomy followed-up for 3 years and review the literature on studies with longer follow-up data.MethodsA retrospective chart review of patients who underwent MRgFUS thalamotomy (January 2018–December 2020) at our institution was performed. Clinical Rating Scale for Tremor (CRST) and Quality of Life in Essential Tremor (QUEST) scores were obtained pre-operatively and at each follow-up with an assessment of side effects. Patients had post-operative magnetic resonance imaging within 24 h and at 1 month to figure out lesion location, size, and extent. The results of studies with follow-up ≥3 years were summarized through a literature review.ResultsThe CRST total (baseline: 58.6 ± 17.1, 3-year: 40.8 ± 18.0) and subscale scores (A + B, baseline: 23.5 ± 6.3, 3-year: 12.8 ± 7.9; C, baseline: 12.7 ± 4.3, 3-year: 5.8 ± 3.9) and the QUEST score (baseline: 38.0 ± 14.8, 3-year: 18.7 ± 13.3) showed significant improvement that was stable during the 3-year follow-up. Three patients reported tremor recurrence and two were satisfactorily retreated. Side effects were reported by 44% of patients (severe: 4%, mild and transient: 40%). The improvement in tremor and quality of life in our cohort was consistent with the literature.ConclusionWe confirmed the effectiveness and safety of MRgFUS Vim thalamotomy in medically refractory ET up to 3 years