Drug repurposing opportunities in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is timeefficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.Cristina P. R. Xavier was supported by the Fundação para a Ciência e Tecnologia (FCT) and Fundo Social Europeu (FSE), Portugal, through the post-doc grant SFRH/BPD/122871/2016. This research group is supported by FEDER-Fundo Europeu de Desenvolvimento Regional through COMPETE 2020 and by FCT-Foundation for Science and Technology in the framework of project POCI-01-0145-FEDER-030457 and project POCI-01-0145-FEDER- 016390:CANCEL STEM

Synthesis of novel methyl 3-(Hetero)arylthieno[3,2-b]pyridine-2-carboxylates and antitumor activity evaluation: Studies in vitro and in ovo grafts of chick chorioallantoic membrane (cam) with a triple negative breast cancer cell line

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothie-no[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 µM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.This research was funded by Fundação para a Ciência e Tecnologia (FCT)—Portugal that financially supports CQUM (UID/QUI/686/2019), also financed by European Regional Development Fund (ERDF), COMPETE2020 and Portugal2020, the PTNMR network also supported by Portugal2020. C.P.R.X. is supported through the post-doc grant SFRH/BPD/122871/2016 and J.M.R. through the doctoral grant SFRH/BD/115844/2016, by FCT, ESF (European Social Fund) and HCOP (Human Capital Operational Programme)

Different ability of multidrug-resistant and-sensitive counterpart cells to release and capture extracellular vesicles

Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype. EVs’ cargo may include different players of MDR, such as microRNAS and drug-efflux pumps, which may be transferred from donor MDR cells to recipient drug-sensitive counterparts. The present work aimed to: (i) compare the ability of drug-sensitive and their MDR counterpart cells to release and capture EVs and (ii) study and relate those differences with possible distinct fate of the endocytic pathway in these counterpart cells. Our results showed that MDR cells released more EVs than their drug-sensitive counterparts and also that the drug-sensitive cells captured more EVs than their MDR counterparts. This difference in the release and capture of EVs may be associated with differences in the endocytic pathway between drug-sensitive and MDR cells. Importantly, manipulation of the recycling pathway influenced the response of drug-sensitive cells to doxorubicin treatment.This article is a result of the project NORTE-01-0145-FEDER-000029, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We thank Spanish MINECO (SAF2015-66312 to JMF) and for the REDIEX (Spanish Excellence Network in Exosomes) and the Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors thank the Portuguese Foundation for Science and Technology (FCT) for the PhD grant of DS (SFRH/BD/98054/2013). Cristina P.R. Xavier is supported by FCT and Fundo Social Europeu (FSE), through the post-doc grant SFRH/BPD/122871/2016. The authors also acknowledge the European COST Action-European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD, BM1202) for short-term mission fellowship (ECOST-STSM-BM1202-150317-083396) and Grupo Español de investigacion en Vesiculas Extracelulares for GEIVEX mobility fellowship which allowed the work of DS in CICbioGUNE

Synthesis of new proteomimetic quinazolinone alkaloids and evaluation of their neuroprotective and antitumor effects

New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs by the Mazurkiewicz-Ganesan approach. The neuroprotection capacity of these compounds on the rotenone-damage human neuroblastoma cell SH-SY5y was evaluated using the MTT assay. Compounds 1, 3, 5, and 7 showed more than 25% protection. The antitumor activity was investigated using the sulforhodamine B assay and some compounds were tested on the non-malignant MCF-12A cells. Fumiquinazoline G (1) was the most potent compound, with GI50 values lower than 20 µM. Compounds 5, 7, and 11 were more active in all tumor cell lines when compared to their enantiomers. Compounds 5, 7, 10, and 11 had very little effect in the viability of the non-malignant cells. Differences between enantiomeric pairs were also noted as being essential for these activities the S-configuration at C-4. These results reinforce the previously described activities of the fiscalin B (3) as substance P inhibitor and fumiquinazoline G (1) as antitumor agent showing potential as lead compounds for the development of drugs for treatment of neurodegenerative disorders and cancer, respectively.This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. The authors thank to national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE under the Strategic Funding UID/Multi/04423/2013, the projects POCI-01-0145-FEDER-028736 and PTDC/MAR-BIO/4694/2014 (POCI-01-0145-FEDER-016790; 3599-PPCDT)

Online security assessment with load and renewable generation uncertainty: The iTesla project approach

The secure integration of renewable generation into modern power systems requires an appropriate assessment of the security of the system in real-time. The uncertainty associated with renewable power makes it impossible to tackle this problem via a brute-force approach, i.e. it is not possible to run detailed online static or dynamic simulations for all possible security problems and realizations of load and renewable power. Intelligent approaches for online security assessment with forecast uncertainty modeling are being sought to better handle contingency events. This paper reports the platform developed within the iTesla project for online static and dynamic security assessment. This innovative and open-source computational platform is composed of several modules such as detailed static and dynamic simulation, machine learning, forecast uncertainty representation and optimization tools to not only filter contingencies but also to provide the best control actions to avoid possible unsecure situations. Based on High Performance Computing (HPC), the iTesla platform was tested in the French network for a specific security problem: overload of transmission circuits. The results obtained show that forecast uncertainty representation is of the utmost importance, since from apparently secure forecast network states, it is possible to obtain unsecure situations that need to be tackled in advance by the system operator

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

Terrestrial impact structures as geoheritage: an assessment method of their scientific value and its application to Brazil

Terrestrial impact structures are geological and geomorphological features with particular importance to understand the history and evolution of the planet. Impact structures are scattered around the world but in many countries these features are under threat, essentially due to anthropic factors. Impact structures with higher scienti c value should be considered as geological heritage and, consequently, be subjected to geoconservation strategies. In order to select the most important impact structures to be properly conserved and managed, this paper proposes a quantitative assessment method of the scienti c value of these structures. The eight Brazilian impact structures were used to test this method that has the potential to be applied to any geological context in any country. The structures known as Araguainha Dome-MT and Serra da Cangalha-TO reached a higher scienti c value, which justi es the need to develop geoconservation strategies and a proper management.The Conselho Nacional de Pesquisa e Desenvolvimento (CNPq / National Council for Research and Development) and the Programa Ciências sem Fronteiras / Science Without Borders Programme are acknowledged for the support of the postdoctoral grant No 233209/2013-1 of the 1st author. The work was co-funded by the European Union through the European Regional Development Fund, based on COMPETE 2020 (Programa Operacional da Competitividade e Internacionalização), project ICT (UID/ GEO/04683/2013) with reference POCI-01-0145- FEDER-007690 and Portuguese funds provided by Fundação para a Ciência e Tecnologia.info:eu-repo/semantics/publishedVersio

MORE CARE Overview

International audienceThis paper provides an overview of MORE CARE, a European R&D project financed within the 5th Framework Energy Programme. This project has as main objective the development of an advanced control software system, aiming to optimize the overall performance of isolated and weakly interconnected systems in liberalized market environments by increasing the share of wind energy and other renewable forms, including advanced on-line security functions. The main features of the control system comprise advanced software modules for load and wind power forecasting, unit commitment and economic dispatch of the conventional and renewable units and on-line security assessment capabilities integrated in a friendly Man-Machine environment. Pilot installations of advanced control functions are foreseen on the islands of Crete, Ireland and Madeira

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets