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

Disseminated Well-Differentiated Gastro-Entero-Pancreatic Tumors Are Associated with Metabolic Syndrome

The association of well-differentiated gastro-entero-pancreatic neuroendocrine tumors (WD GEP-NETs) with metabolic syndrome (MetS), abdominal obesity, and fasting glucose abnormalities was recently described. The aim of this study was to evaluate whether the presence of MetS or any MetS individual component was also influenced by GEP-NET characteristics at diagnosis. A cohort of patients with WD GEP-NETs (n = 134), classified according to primary tumor location (gastrointestinal or pancreatic), pathological grading (G1 (Ki67 ≤ 2%) and G2 (>3 ≤ 20%) (WHO 2010), disease extension (localized, loco-regional, and metastatic), and presence of hormonal secretion syndrome (functioning/non-functioning), was evaluated for the presence of MetS criteria. After adjustment for age and gender, the odds of having MetS was significantly higher for patients with WD GEP-NET grade G1 (OR 4.35 95%CI 1.30–14.53) and disseminated disease (OR 4.52 95%CI 1.44–14.15). GEP-NET primary tumor location or secretory syndrome did not influence the risk for MetS. None of the tumor characteristics evaluated were associated with body mass index, fasting plasma glucose category, or any of the individual MetS components. Patients with GEP-NET and MetS depicted a higher risk of presenting a lower tumor grade and disseminated disease. The positive association between MetS and GEP-NET characteristics further highlights the potential link between the two conditions.This work did not receive any funding either from public, commercial, or nonprofit agencies

Case Report: Pheochromocytoma and Synchronous Neuroblastoma in a Family With Hereditary Pheochromocytoma Associated With a MAX Deleterious Variant

Introduction: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic paraganglia. Recent studies have indicated that up to 40% of pheochromocytomas could be attributable to an inherited germline variant in an increasing list of susceptibility genes. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial pheochromocytomas and paragangliomas with an autosomal dominant pattern of inheritance, a median age at onset of 33 years and an overall frequency estimated at 1.9%. We describe a deleterious MAX variant associated with hereditary pheochromocytoma in a family with four affected individuals. Case presentation: The first patient presented with bilateral pheochromocytoma in 1995; genetic testing was proposed to his oldest son, when he was diagnosed with a bilateral pheochromocytoma with a synchronous neuroblastoma. Upon the identification of the MAX variant c.97C>T, p.(Arg33Ter), in the latter individual, his two siblings and their father were tested and the same variant was identified in all of them. Both siblings were subsequently diagnosed with pheochromocytoma (one of them bilateral) and choose to remain on active surveillance before they were submitted to adrenalectomy. All the tumours secreted predominantly norepinephrine, accordingly to the typical biochemical phenotype ascribed to variants in the MAX gene. Conclusion: This case series is, to our knowledge, the one with the largest number of individuals with hereditary pheochromocytoma with a deleterious MAX variant in the same family. It is also the first case with a synchronous pheochromocytoma and neuroblastoma in carriers of a MAX deleterious variant. This report draws attention to some ill-defined features of pheochromocytoma and other malignancies associated with a MAX variant and highlights the importance of understanding the genotype-phenotype correlation in hereditary pheochromocytoma and the impact of oriented genetic testing to detect, survey and treat patients and kindreds at risk

Coherent Control of Quantum Dynamics with Sequences of Unitary Phase-Kick Pulses

Coherent optical control schemes exploit the coherence of laser pulses to change the phases of interfering dynamical pathways in order to manipulate dynamical processes. These active control methods are closely related to dynamical decoupling techniques, popularized in the field of Quantum Information. Inspired by Nuclear Magnetic Resonance (NMR) spectroscopy, dynamical decoupling methods apply sequences of unitary operations to modify the interference phenomena responsible for the system dynamics thus also belonging to the general class of coherent control techniques. Here we review related developments in the fields of coherent optical control and dynamical decoupling, with emphasis on control of tunneling and decoherence in general model systems. Considering recent experimental breakthroughs in the demonstration of active control of a variety of systems, we anticipate that the reviewed coherent control scenarios and dynamical decoupling methods should raise significant experimental interest.Comment: 52 pages, 7 figure

Admission for Imported Malaria in Children, in Two Hospitals of Lisbon Urban Area

Introdução: Apesar de em Portugal não haver malária endógena,a crescente mobilidade das populações e os laços históricos com África possibilitam a importação de casos para o nosso país. O presente estudo pretende contribuir para melhorar o conhecimento epidemiológico e clínico da malária importada na região de Lisboa. Métodos: Realizou-se um estudo descritivo das crianças com malária, internadas em dois hospitais da Grande Lisboa, durante um período de seis anos (1999-2004). Resultados: Foram identificados 134 casos, sendo a mediana das idades de sete anos. A maioria (93,3%) era de origem africana e referia estadia em região endémica (90%). O Plasmodium falciparum foi o agente etiológico mais frequente (73%). A febre foi a manifestação clínica mais frequente, seguida de manifestações gastrointestinais e cefaleias. Ocorreram complicações em 42% dos doentes, sendo a trombocitopenia (19,4%) e a anemia grave (9%) as mais frequentes. A halofantrina e o quinino foram os anti-maláricos mais usados. Conclusões: A malária importada é uma patologia relativamente comum na Grande Lisboa e, dada a inespecificidade do quadro clínico, todas as crianças febris ou doentes com estadia recente num país endémico devem ser rastreadas para esta entidade

If players are sparse social dilemmas are too: Importance of percolation for evolution of cooperation

Spatial reciprocity is a well known tour de force of cooperation promotion. A thorough understanding of the effects of different population densities is therefore crucial. Here we study the evolution of cooperation in social dilemmas on different interaction graphs with a certain fraction of vacant nodes. We find that sparsity may favor the resolution of social dilemmas, especially if the population density is close to the percolation threshold of the underlying graph. Regardless of the type of the governing social dilemma as well as particularities of the interaction graph, we show that under pairwise imitation the percolation threshold is a universal indicator of how dense the occupancy ought to be for cooperation to be optimally promoted. We also demonstrate that myopic updating, due to the lack of efficient spread of information via imitation, renders the reported mechanism dysfunctional, which in turn further strengthens its foundations.Comment: 6 two-column pages, 5 figures; accepted for publication in Scientific Reports [related work available at http://arxiv.org/abs/1205.0541

A GIS–Integrated Wireless Sensors Network Tool for Water Risk Monitoring – Case of Khanh Hoa Water Supply and Sewerage Company, Vietnam

This paper investigates the feasibility of deploying a wireless sensor network (WSN) to monitor raw water quality at 2 major water treatment plants (WTPs) sites, operated by the The Khanh Hoa Water Supply and Sewerage Company (KHAWASSCO) in Vietnam: Canh Vo and Xuan Canh on the Cai River. The main aim is to propose a WSN for both WTPs which includes 2 clusters of sensors with 4 nodes each in order to monitor various parameters of water quality. Data management is integrated with a geographical information system (GIS) tool in order to provide a comprehensive spatio-temporal database in real time. This will assist decision makers in improving the management of the raw water quality at Cai River

Maternal sensitivity in early childhood and body mass index in adolescence: A population-based study on the role of self-regulation as a mediator

Maternal sensitivity has been implicated in various aspects of child health and development, including overweight. However, long-term effects, the role of paternal sensitivity and the explanatory pathways are unclear. This study examined whether maternal sensitivity in early childhood is prospectively associated with adolescent body mass index and whether children's self-regulation mediates this relation. Data from 540 children and their mothers were available from a large cohort study in the Netherlands. Maternal sensitivity was assessed at child ages 1, 3, and at 4 years paternal sensitivity was also included. Children's self-regulation skills were observed at age 3, eating behaviour was assessed at 10 years, and child BMI was measured at 13 years. Longitudinal structural equation modelling was applied. The cross-sectional association between maternal sensitivity and child self-regulation was significant, while lower levels of self-regulation and higher levels of food responsiveness and restrained eating predicted a higher child BMI at 13 years. Furthermore, a direct association of paternal sensitivity at 4 years with BMI at 13 years was found, but only in girls. Maternal sensitivity was not directly associated with child BMI after adjusting for covariates. Our findings showed the importance of self-regulation in the early years for subsequent weight development. Nevertheless, as self-regulation could not explain the relationship between parenting and child weight, research should focus on the contribution of other contextual factors, such as feeding styles and the social environment, to this relationship.The general design of Generation R Study is made possible by financial support from the Erasmus Medical Center and the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMW), the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport and the Ministry of Youth and Families. The current study was made possible by a grant awarded to Patricia Bravo by the National Agency for Research and Development (ANID)/Scholarship Program/DOCTORADO BECAS CHILE/2019–72200575 and by a grant from the Netherlands Organization for Health Research and Development (Mental Health Care Research Program, Fellowship 636320005 to Pauline W. Jansen). The funders had no role in the design and conduct of the study or the writing of the report. All authors declare that they have no conflicts of interest