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Cancer Drug Resistance 2020年第2期3卷 209-224页

作者： filipa Mendes Lurdes Gano Jorge Grilo Susana Cunha Célia Fernandes António Paulo DECN-Department of Nuclear Engineering and Sciences and C2TN-Center for Nuclear Sciences and Technologies Instituto Superior TécnicoUniversidade de LisboaEstrada Nacional 10Bobadela LRS 2695-066Portugal (Present adress)iMed.Ulisboa-Research Institute for Medicines Faculdade de FarmáciaUniversidade de LisboaAv.Professor Gama PintoLisboa 1649-003Portugal

Aim:Several cationic radiotracers originally developed as myocardial perfusion agents have shown potential for both early detection of cancer and non-invasive monitoring of multiple drug resistance(MDR)by single photon emission computed *** have introduced two cationic complexes,^(99m)Tc-DMEOP[di-methoxy-tris-pyrazolyl-^(99m)Tc-(CO)_(3)]and ^(99m)Tc-TMEOP[tri-methoxy-tris-pyrazolyl-^(99m)Tc-(CO)_(3)],which showed excellent preclinical results as cardiac imaging probes,namely a persistent heart uptake with rapid blood and liver *** study aimed at the evaluation of their usefulness for tumoral detection and functional assessment of ***:The uptake and efflux kinetics of ^(99m)Tc-DMEOP and ^(99m)Tc-TMEOP were evaluated in human prostate,lung,and breast cancer cell lines,including drug-resistant cell lines that are known to overexpress the MDR P-glycoprotein(Pgp).The effects of MDR modulators were also *** vivo studies were performed in xenografted tumor models,and the MDR phenotype of the tumors was confirmed by Western ***:The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for ^(99m)Tc-Sestamibi,increasing over *** uptake of ^(99m)Tc-TMEOP is greatly reduced in cells overexpressing Pgp and increased in the presence of a Pgp *** nude mice,the tumor uptake of ^(99m)Tc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp ***:The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for ^(99m)Tc-Sestamibi,increasing over *** uptake of ^(99m)Tc-TMEOP is greatly reduced in cells overexpressing Pgp,and increased in the presence of a Pgp *** nude mice,the tumor uptake of ^(99m)Tc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors.

关键词： Noninvasive imaging imaging probes tumoral detection multiple drug resistance P-glycoprotein

Skin models of cutaneous toxicity,transdermal transport and wound repair

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Burns & Trauma 2023年第1期11卷 393-407页

作者： Inês Vilela de Sousa Miguel J.S.Ferreira Luís B.Bebiano Sandra Simões Ana filipa Matos Rúben F.Pereira Pedro L.Granja i3S-Instituto de Investigação e Inovação em Saúde Universidade do PortoRua Dr.Manuel Pereira da Silva4200-393 PortoPortugal INEB-Instituto de Engenharia Biomédica Universidade do PortoRua do Campo Alegre8234150-180 PortoPortugal ICBAS-Instituto de Ciências Biomédicas Abel Salazar Universidade do PortoRua de Jorge Viterbo Ferreira 2284050-313 PortoPortugal FEUP-Faculdade de Engenharia da Universidade do Porto Rua Dr.Roberto Frias4200-465 PortoPortugal Department of Mechanical Aerospace and Civil EngineeringSchool of EngineeringFaculty of Science and Engineering&Henry Royce InstituteEngineering Building AThe University of ManchesterOxford RoadManchester M139PLUK ISEP-Instituto Superior de Engenharia do Porto Universidade do PortoRua Dr.António Bernardino de Almeida 4314200-072 PortoPortugal iMed.ULisboa Faculty of PharmacyUniversidade de LisboaAv.Prof.Gama Pinto1649-003 LisboaPortugal Faculty of Pharmacy Universidade de LisboaAv.Prof.Gama Pinto1649-003 LisboaPortugal

Skin is widely used as a drug delivery route due to its easy access and the possibility of using relatively painless methods for the administration of bioactive ***,the barrier properties of the skin,along with its multilayer structure,impose severe restrictions on drug transport and ***,bioengineered models aimed at emulating the skin have been developed not only for optimizing the transdermal transport of different drugs and testing the safety and toxicity of substances but also for understanding the biological processes behind skin *** though in vivo research is often preferred to study biological processes involving the skin,in vitro and ex vivo strategies have been gaining increasing relevance in recent ***,there is a noticeably increasing adoption of in vitro and ex vivo methods by internationally accepted ***,microfluidic organ-on-a-chip devices are nowadays emerging as valuable tools for functional and behavioural skin *** in miniaturization,automation and reliability still need to be addressed in order to create skin models that can predict skin behaviour in a robust,high-throughput manner,while being compliant with regulatory issues,standards and *** this review,skin models for transdermal transport,wound repair and cutaneous toxicity will be discussed with a focus on high-throughput *** microfluidic strategies driven by advancements in microfabrication technologies will also be revised as a way to improve the efficiency of existing models,both in terms of complexity and throughput.

关键词： Skin In vitro models Ex vivo models Transdermal transport assays Wound healing assays Toxicity assays Microfluidic chip Skin-on-a-chip

CTNS Molecular Genetics Profile in a Portuguese Cystinosis Population

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Open Journal of Genetics 2018年第4期8卷 91-100页

作者： filipa Ferreira Ines Leal David Sousa Teresa Costa Conceicao Mota Ana Marta Gomes Daniela Lopes Maria do Carmo Macario Isabel Tavares Helena pinto Joao Paulo Oliveira Rita Magrico Celia Carmona Sonia Ramos Raquel Neiva Ana Marcao Laura Vilarinho Newborn Screening Metabolism and Genetics UnitHuman Genetics DepartmentNational Institute of Health Dr Ricardo JorgePortoPortugal Centro Hospitalar Lisboa Norte Hospital de Santa MariaLisboaPortugal Centro Hospitalar Universitario do Porto PortoPortugal Centro Hospitalar Vila Nova de Gaia EspinhoPortugal Centro Hospitalar Universitario de Coimbra CHUCCoimbraPortugal Servico de Genetica Medica Centro Hospitalar de Sao JoaoPortoPortugal Unidade de Genetica Faculdade de Medicina da Universidade do PortoPortoPortugal I3S—Instituto de Investigacao e Inovacao em Saude PortoPortugal Servico de Nefrologia do Hospital Garcia de Orta AlmadaPortugal Research and Development Unit Department of Human GeneticsNational Institute of Health Dr Ricardo JorgePortoPortugal

Background: Cystinosis is a multisystemic autosomal recessive deficiency of the lysosomal membrane transporter protein (cystinosin) caused by mutations in CTNS gene. Objective: This study summarizes the Portuguese experience in the diagnosis and management of patients with this rare disease over the past few years and reports recurrent mutations in the CTNS gene. Methods: Unrelated patients from different pediatric and adult hospitals all over Portugal with non-nephrotic proteinuria, hypercalciuria, hypokalemia impaired proximal reabsorption of amino acids, glycosuria and hypophosphatemia, suggestive of a Fanconi syndrome and ocular problems, were studied. Intra-leukocyte cystine levels were determined and molecular analysis was performed, to determine the presence or absence of the 57-kb deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. Results: From 1998 to 2017, twenty-one cystinotic patients were biochemically diagnosed. From the remaining seventeen (four deceased), eleven were studied for CTNS gene. Five out of eleven patients were homozygous for the 57-kb deletion (10/22;45.5%), and other five were compound heterozygous for this variant (15/22;68.2%). The other mutations found were p.Q128X (c.721 C>T;2/22), p.S139F (c.755 C>T;4/22) and c.18-21delGACT (p.T7FfsX7;1/22). All of these seventeen cystinotic patients are in treatment. Approximately 84% are adults, 16% are young children, and 54.5% are kidney transplant recipient. Conclusions: The authors would like to emphasize the importance of first screening for the 57-kb deletion since it is very common in our population. This genetic study is the first in our country and it could be the basis for future genetic counseling in Portuguese population.

关键词： Cystinosis CTNS Gene Mutational Spectrum Kidney Failure 57-kb Deletion

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

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World Journal of Gastroenterology 2022年第31期28卷 4310-4327页

作者： Pedro Moutinho-Ribeiro Ines A Batista Sofia T Quintas Bárbara Adem Marco Silva Rui Morais Armando Peixoto Rosa Coelho Pedro Costa-Moreira Renato Medas Susana Lopes Filipe Vilas-Boas Manuela Baptista Diogo Dias-Silva Ana L Esteves filipa Martins Joanne Lopes Helena Barroca Fátima Carneiro Guilherme Macedo Sonia A Melo Serviço de Gastrenterologia Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal Faculty of Medicine University of PortoPorto 4200Portugal Instituto de Investigacao e Inovacao em Saúde(i3S) Universidade do PortoPorto 4200Portugal IPATIMUP-Institute of Molecular Pathology and Immunology University of PortoPorto 4200Portugal Instituto de Ciencias Biomédicas Abel Salazar(ICBAS) University of PortoPorto 4050Portugal Servico de Cirurgia Geral Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal Unidade de Saúde Familiar Serpa pinto ACeS Porto OcidentalPorto 4250Portugal Serviço de Anatomia Patológica Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PDAC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer *** ultrasound(EUS)is a premium image modality for PDAC screening and precursor lesion *** no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PDAC compared with healthy subjects or those harboring benign pancreatic *** To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by *** This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,*** patients provided written informed *** and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all ***-guided tissue acquisition was done whenever *** statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was *** graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(8

关键词： Glypican-1 Circulating exosomes Endoscopic ultrasound Pancreatic cancer risk groups Pancreatic cancer precursor lesions Genetic predisposition