The Phosphoinositide 3-Kinase Pathway in Human Cancer: Genetic Alterations and Therapeutic Implications

The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancer and represents an attractive target for therapies based on small molecule inhibitors. PI3K isoforms play an essential role in the signal transduction events activated by cell surface receptors including receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). There are eight known PI3K isoforms in humans, which have been subdivided into three classes (I-III). Therefore PI3Ks show considerable diversity and it remains unclear which kinases in this family should be targeted in cancer. The class IA of PI3K comprises the p110α, p110β and p110δ isoforms, which associate with activated RTKs. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110α, and inactivating mutations in the phosphatase and tensin homologue (PTEN) gene, a tumour suppressor and antagonist of the PI3K pathway. The PIK3CA mutations described in cancer constitutively activate p110α and, when expressed in cells drive oncogenic transformation. Moreover, these mutations cause the constitutive activation of downstream signaling molecules such as Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K) that is commonly observed in cancer cells. In addition to p110α, the other isoforms of the PI3K family may also play a role in human cancer, although their individual functions remain to be precisely identified. In this review we will discuss the evidence implicating individual PI3K isoforms in human cancer and their potential as drug targets in this context

Dual antibiotherapy of tuberculosis mediated by inhalable locust bean gum microparticles

Despite the existence of effective oral therapy, tuberculosis remains a deadly pathology, namely because of bacterial resistance and incompliance with treatments. Establishing alternative therapeutic approaches is urgently needed and inhalable therapy has a great potential in this regard. As pathogenic bacteria are hosted by alveolar macrophages, the co-localisation of antitubercular drugs and pathogens is thus potentiated by this strategy. This work proposes inhalable therapy of pulmonary tuberculosis mediated by a single locust bean gum (LBG) formulation of microparticles associating both isoniazid and rifabutin, complying with requisites of the World Health Organisation of combined therapy. Microparticles were produced by spray-drying, at LBG/INH/RFB mass ratio of 10/1/0.5. The aerodynamic characterisation of microparticles revealed emitted doses of more than 90% and fine particle fraction of 38%, thus indicating the adequacy of the system to reach the respiratory lung area, thus partially the alveolar region. Cytotoxicity results indicate moderate toxicity (cell viability around 60%), with a concentration-dependent effect. Additionally, rat alveolar macrophages evidenced preferential capture of LBG microparticles, possibly due to chemical composition comprising mannose and galactose units that are specifically recognised by macrophage surface receptors. (C) 2017 Elsevier B.V. All rights reserved.National Portuguese funding through FCT - Fundacao para a Ciencia e a Tecnologia [PTDC/DTP-FTO/0094/2012, UID/BIM/04773/2013, UID/Multi/04326/2013, UID/QUI/00100/2013, PEst-OE/QUI/UI4023/2011

Resistant starch production in wheat bread: effect of ingredients, baking conditions and storage

Resistant starch (RS) is defined as the sum of starch and products of starch degradation not absorbed in the small intestine of healthy individuals. RS appears to confer considerable health benefits. Processing conditions and ingredients may influence the formation of RS in foodstuffs. The aim of the present study was to investigate some of the factors that might influence RS formation in wheat bread, namely: 1) formulation; 2) loaf size; 3) baking conditions and 4) storage conditions. Seven bread formulations were prepared: reference recipe (control) and six experimental formulations. The effect of the loaf size and the baking conditions were also tested. Finally, the effect of storage was tested by keeping control breads under different storage conditions (temperature/time). Moisture and resistant starch contents were evaluated in all breads. A higher level of moisture in the dough and a larger loaf size enhanced the RS content. An extended baking process also favoured significantly the formation of RS. Storing the bread at room temperature for 3 days was shown to further increase the RS content. It is possible to increase the RS content of bread by modifying the ingredients ratio and processing conditions

Variações morfológicas induzidas por uma tempestade na Praia de Carcavelos, Portugal: contribuição para a gestão costeira

Field data based information on the coastal sediment dynamics becomes even more relevant for coastal managers in the present context of climate changes. Due to the sea level rise and the increase of frequency and intensity of coastal storms, coastal managers need to implement effective and efficient solutions for increasing coastal resilience, namely through reprofiling the beach for restoring the sediment balance and providing space for the beach natural dynamics. The study characterises and quantifies the morphological changes in an Atlantic urban sandy beach under extreme wave energy and sea level conditions. The erosion of the foreshore and backshore of this particular beach was characterised as function of the intensity and duration of the hydrodynamic forcing parameters (waves and sea level). This 24-hour duration storm event, which delivered to the beach a total energy of 1.7x109 J, caused the seaward displacement by the undertow current of approximately 3x103 m3 of median well sorted sand from the beach foreshore and backshore.Informação sobre a dinâmica sedimentar costeira baseada em dados de campo torna-se ainda mais relevante para gestores costeiros no presente contexto de alterações climáticas. Devido à subida do nível do mar e ao aumento da frequência e intensidade de tempestades marítimas, os gestores costeiros necessitam de implementar soluções eficazes e eficientes para melhorar a resiliência costeira, nomeadamente através do reperfilamento da praia para restabelecer o balanço sedimentar e conceder espaço para a dinâmica natural da praia. O estudo caracteriza e quantifica as variações morfológicas numa praia arenosa, urbana e Atlântica sob ação de condições extremas de energia das ondas e nível do mar. A erosão da face e do topo da praia foi caracterizada em função da intensidade e duração dos parâmetros forçadores hidrodinâmicos (ondas e nível do mar). Este evento de tempestade com duração de 24 horas, que transmitiu à praia uma energia total de 1.7x109 J, causou a extração de aproximadamente 3x103 m3 de areia média da face e do topo da praia e o seu transporte pela corrente de retorno para maiores profundidades.info:eu-repo/semantics/publishedVersio

Functional food components, intestinal permeability and inflammatory markers in patients with inflammatory bowel disease

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Inflammatory bowel diseases (IBD) are characterized by a chronic inflammatory process that affects the intestinal barrier structure. Recent evidence suggests that some food components can influence the integrity of the intestinal barrier and thus its permeability. We aimed at assessing the effect of food components on the intestinal permeability (IP) and on inflammatory markers in individuals with IBD by a single-blind randomized clinical study. Of the 53 individuals included, 47% (n = 25) had been diagnosed with IBD. The participants were divided into 4 groups. IBD patients were allocated to intervention group (n = 14) vs. no intervention group (n = 11), and the same happened with 28 control participants without disease (n = 14 in intervention group vs. n = 14 without intervention). Symptomatology, nutritional status, biochemical parameters (specifically serum zonulin (ZO) to measure IP) were evaluated on all individuals on an eight week period following a diet plan with/without potentially beneficial foods for the IP. At the beginning of the study, there were no significant differences in ZO values between individuals with and without IBD (p > 0.05). The effect of specific food components was inconclusive; however, a trend in the reduction of inflammatory parameters and on the prevalence of gastrointestinal symptomatology was observed. More controlled intervention studies with diet plans, including food components potentially beneficial for the integrity of the intestinal barrier, are of the utmost importance.info:eu-repo/semantics/publishedVersio

Probable Person-to-Person Transmission of Legionnaires’ Disease

Correspondence to the Editor.Legionnaires’ disease is an often severe form of pneumonia that is typically acquired by susceptible persons (e.g., elderly persons and smokers) through inhalation of aerosols that contain legionella species.1-4 A cluster of cases of this disease occurred in Vila Franca de Xira, Portugal, in 2014

An Overview

Funding Information: Funding: This work was supported by FCT–Fundação para a Ciência e a Tecnologia (grants UIDB/04567/2020 and UIDP/04567/2020 to CBIOS, PTDC/BIA-MOL/31104/2017, and PhD grants 2020.07813.BD to Í.G. and 2020.04630.BD to D.C.). C.F.-P. and R.M. are funded by FCT Scientific Employment Stimulus contract with the reference numbers CEEC/CBIOS/NUT/2018 and CEEC/04567/CBIOS/2020, respectively. Authors also acknowledge COFAC/ILIND–Cooperativa De Formação E Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). Authors also acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 804229. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is co-funded by FCT/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement.Kidney diseases constitute a worldwide public health problem, contributing to morbidity and mortality. The present study aimed to provide an overview of the published data regarding the potential beneficial effects of polyphenols on major kidney diseases, namely acute kidney injury, chronic kidney disease, diabetic nephropathy, renal cancer, and drug-induced nephrotoxicity. This study consists of a bibliographical review including in vitro and in vivo studies dealing with the effects of individual compounds. An analysis of the polyphenol metabolome in human urine was also conducted to estimate those compounds that are most likely to be responsible for the kidney protective effects of polyphenols. The biological effects of polyphenols can be highly attributed to the modulation of specific signaling cascades including those involved in oxidative stress responses, anti-inflammation processes, and apoptosis. There is increasing evidence that polyphenols afford great potential in renal disease protection. However, this evidence (especially when in vitro studies are involved) should be considered with caution before its clinical translation, particularly due to the unfavorable pharmacokinetics and extensive metabolization that polyphenols undergo in the human body. Future research should consider polyphenols and their metabolites that indeed reach kidney tissues.publishersversionpublishe

The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors