A Pyranoxanthone as a potent antimitotic and sensitizer of cancer cells to low doses of Paclitaxel

Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.Portugal 2020: PTDC/SAU-PUB/28736/2017 (POCI-01-0145-FEDER-028736; FCT: SFRH/BD/116167/2016/ SFRH/BD/140844/2018/ PD/00016/2012info:eu-repo/semantics/publishedVersio

Yicathins B and C and analogues: total synthesis, lipophilicity and biological activities

Natural products had always be an important source of new hits and leads in drug discovery. The marine environment has been regarded as a significant souce of novel and exquisite bioactive compounds. Yicathins B and C are two marine derived xanthones that have shown antibacterial and antifungal activities. Herein, the total synthesis of these yicathins is reported for the first time as well as six novel analogues. As marine natural products tend to bear very lipophilic scaffolds, the lipophilicity of yicathins and its analogues was evaluated using the classical octanol:water system and a biomimetic model based system. As the xanthonic nucleus is a â privileged structureâ , other biological activities were evaluated, namely antitumor and anti-inflammatory activities. An interesting anti-inflammatory activity was identified for yicathins analogues that paves the way for the design of dual activity (anti-infective and anti-inflammatory) marine inspired xanthones derivatives.This work was supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE - Programa Operacional Factores de Competitividade (POFC) programme, under the projects PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599 - Promover a ProducAo Cientifica e Desenvolvimento Tecnologico e a ConstituicAo de Redes Tematicas (3599-PPCDT)) and PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER- 028736) in the framework of the programme PT2020. D. R. P. L. is grateful for research grant PTDC/MAR-BIO/4694/2014-BI-2017-003. J. X. S. thanks the FCT PhD Programmes and Programa Operacional Capital Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences), reference PD/00016/2012; through the FCT and POCH for PhD grants (SFRH/BD/98105/2013 and SFRH/BD/116167/2016). The authors would like to thank Sara Cravo and Gisela Adriano for the technical support, the Centro de Apoio Cientifico e Tecnoloxico a Investigation (C.A.C.T.I., University of Vigo, Pontevedra, Spain) for HRMS analysis, the Centro de Materiais da Universidade do Porto (CEMUP, Porto, Portugal) for HRMS, and the Departamento de Quimica da Universidade de Aveiro (Portuguese NMR network) for the NMR analysis

The association between stress and mood across the adult lifespan on default mode network

Aging of brain structure and function is a complex process characterized by high inter- and intra-individual variability. Such variability may arise from the interaction of multiple factors, including exposure to stressful experience and mood variation, across the lifespan. Using a multimodal neuroimaging and neurocognitive approach, we investigated the association of stress, mood and their interaction, in the structure and function of the default mode network (DMN), both during rest and task-induced deactivation, throughout the adult lifespan. Data confirmed a decreased functional connectivity (FC) and task-induced deactivation of the DMN during the aging process and in subjects with lower mood; on the contrary, an increased FC was observed in subjects with higher perceived stress. Surprisingly, the association of aging with DMN was altered by stress and mood in specific regions. An increased difficulty to deactivate the DMN was noted in older participants with lower mood, contrasting with an increased deactivation in individuals presenting high stress, independently of their mood levels, with aging. Interestingly, this constant interaction across aging was globally most significant in the combination of high stress levels with a more depressed mood state, both during resting state and task-induced deactivations. The present results contribute to characterize the spectrum of FC and deactivation patterns of the DMN, highlighting the crucial association of stress and mood levels, during the adult aging process. These combinatorial approaches may help to understand the heterogeneity of the aging process in brain structure and function and several states that may lead to neuropsychiatric disorders.The work was supported by SwitchBox-FP7-HEALTH-2010-Grant 259772-2 and by ON.2, O NOVO NORTE, North Portugal Regional Operational Programme 2007/2013, of the National strategic Reference Framework (NSRF) 2007/2013, through the European Regional Development Fund (ERDF)info:eu-repo/semantics/publishedVersio

Development of competences while solving real industrial interdisciplinary problems: a successful cooperation with industry

The development of projects in industrial context constitutes an exceptional opportunity for engineering students to develop competences expected by the labour market. Therefore, the adoption of this type of interaction within engineering curricula is highly recommended, not only at the end of the degree, but also in the previous years. The main purpose of this paper is to present and analyse a Project-Based Learning (PBL) semester in which six teams of Industrial Engineering and Management (IEM) students integrate different areas of knowledge, while solving real problems of five companies, emphasizing the technical solutions developed by the students and the feedback provided by the companies. Students' feedback will be also addressed. The main outcomes of this study reveal that most of the technical solutions lie in areas of Lean applications and ergonomic improvement of workplaces. Companies were very pleased with the results of this type of University-Business Cooperation (UBC).This work was funded by COMPETE-POCI-01-0145-FEDER-007043 and FCT-UID-CEC-00319-2013info:eu-repo/semantics/publishedVersio

SOD2 immunoexpression predicts lymph node metastasis in penile cancer

BACKGROUND: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme in lung, gastric, colorectal, breast cancer and cervical cancer malignant tumors has been observed. Its relationship with inguinal lymph node metastasis in penile cancer is unknown. METHODS: SOD2 protein expression levels were determined by immunohistochemistry in 125 usual type squamous cell carcinomas of the penis from a Brazilian cancer center. The casuistic has been characterized by means of descriptive statistics. An exploratory logistic regression has been proposed to evaluate the independent predictive factors of lymph node metastasis. RESULTS: SOD2 expression in more than 50% of cells was observed in 44.8% of primary penile carcinomas of the usual type. This expression pattern was associated with lymph node metastasis both in the uni and multivariate analysis. CONCLUSIONS: Our results indicate that SOD2 expression predicts regional lymph node metastasis. The potential clinical implication of this observation warrants further studies.Dr. Lara Termini (FAPESP 2005/57274-9); Dr. Luisa Lina Villa (FAPESP 2008/57889-1 and CNPq 573799/2008-3)

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

João Vinagre, Vasco Pinto and Ricardo Celestino contributed equally to the manuscript.Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the “alternative mechanism of telomere lengthening” (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and non-neoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target