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- Adenocarcinoma endocervical em mulheres jovensPublication . Soares, Sílvia; Sousa, Rita; Figueiredo, Anabela; Agapito, Paula; Fernandes, Graça; Castro, LígiaA incidência de adenocarcinoma do endocolo está a aumentar, principalmente em mulheres com idades entre os 20 e os 30 anos. O aumento desta incidência, segundo estudos recentes, pode dever-se a infeções persistentes pelo HPV associadas a fatores de risco endógenos e exógenos. O tratamento desta neoplasia requer, por vezes, histerectomia total e consequente infertilidade, sendo motivo de trauma psicológico. O presente trabalho pretende alertar para o desenvolvimento de adenocarcinoma em mulheres cada vez mais jovens, e adicionalmente, fazer uma reflexão acerca dos fatores que poderão estar associados ao aparecimento desta patologia e das causas relacionadas com um diagnóstico tardio, de forma a evitar atuações terapêuticas radicais. Para o efeito, é relatado um caso clínico, realizado no seguimento de uma citologia de rastreio de uma mulher de 30 anos, com diagnóstico citológico de células glandulares atípicas sem outras especificações (AGC, SOE), a qual foi encaminhada para a Unidade de Patologia Cervical do hospital de referência. Foi efetuada uma segunda citologia, em meio líquido, cujo diagnóstico foi adenocarcinoma endocervical (SOE), posteriormente confirmado histologicamente.
- Adenocarcinoma numa mulher histerectomizada – Estudo de casoPublication . Nunes, Catarina; Maia, C.; Leite, P.; Dominguez, R.A presença de células de tipo glandular na vagina em mulheres histerectomizadas pode ter várias origens. Estas células podem sofrer alterações malignas e originar adenocarcinoma primário da vagina. Esta neoplasia é rara, sendo o fator de risco mais frequente para o seu desenvolvimento a exposição intrauterina ao dietilestilbestrol. Relatamos o caso de uma paciente de 70 anos, com história clínica de histerectomia realizada aos 36 anos de idade para controlar hemorragia pós-aborto. No exame ecográfico foi detetada uma massa na parede anterior da vagina. Na citologia vaginal foram observadas células de tipo glandular atípicas, com características de adenocarcinoma, sem outras especificações. A biópsia realizada posteriormente mostrou um adenocarcinoma da vagina. Não há informação clínica acerca de uma possível exposição intrauterina ao composto dietilestilbestrol.
- An evolutionary perspective on the relationship between kinetochore size and CENP-E dependence for chromosome alignmentPublication . Almeida, Ana C.; Almeida, Ana C.; Rocha, Hélder; Rocha, Hélder; Raas, Maximilian W. D.; Raas, Maximilian W. D.; Witte, Hanh; Witte, Hanh; Sommer, Ralf J.; Sommer, Ralf J.; Snel, Berend; Snel, Berend; Kops, Geert J. P. L.; Kops, Geert J. P. L.; Gassmann, Reto; Gassmann, Reto; Maiato, Helder; Maiato, HelderChromosome alignment during mitosis can occur as a consequence of bi-orientation or is assisted by the CENP-E (kinesin-7) motor at kinetochores. We previously found that Indian muntjac chromosomes with larger kinetochores bi-orient more efficiently and are biased to align in a CENP-E-independent manner, suggesting that CENP-E dependence for chromosome alignment negatively correlates with kinetochore size. Here, we used targeted phylogenetic profiling of CENP-E in monocentric (localized centromeres) and holocentric (centromeres spanning the entire chromosome length) clades to test this hypothesis at an evolutionary scale. We found that, despite being present in common ancestors, CENP-E was lost more frequently in taxa with holocentric chromosomes, such as Hemiptera and Nematoda. Functional experiments in two nematodes with holocentric chromosomes in which a CENP-E ortholog is absent (Caenorhabditis elegans) or present (Pristionchus pacificus) revealed that targeted expression of human CENP-E to C. elegans kinetochores partially rescued chromosome alignment defects associated with attenuated polar-ejection forces, whereas CENP-E inactivation in P. pacificus had no detrimental effects on mitosis and viability. These data showcase the dispensability of CENP-E for mitotic chromosome alignment in species with larger kinetochores.
- Anti-neoplastic properties of hydralazine in prostate cancerPublication . Pinho dos Santos Graça, Maria Inês; Sousa, Elsa Joana; Costa-Pinheiro, Pedro; Quintela Vieira, Ana Filipa; Torres-Ferreira, Jorge; Martins, Maria Gabriela; Henrique, Rui; Jeronimo, CarmenProstate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.
- Application of CytoPath®easy vials in Cervical Cancer screening: Self‑sampling approachPublication . Fernandes, Sílvia P. M.; Vilarinho, Ana Sofia; Frutuoso, Amaro; Teixeira, Cidália; Silva, Regina Augusta A. P."CytoPath®Easy kit (DiaPath S.p.A.) offers a major advantage compared to other commercially available kits available for the screening of cervical cancer, as it does not require additional equipment for sample processing. Using this methodology, collected epithelial cells are immersed in a preservative liquid before setting as a thin layer on a slide via gravity sedimentation. Aims: To evaluate the suitability of the CytoPath®Easy kit for the processing of cervicalsamples, detection of pre‑neoplastic lesions, and nucleic preservation and extraction for HR‑HPV diagnosis. A total of 242 self‑sampled cervicalspecimens were utilized, with 192 collected in CytoPath®Easy vials and 50 collected and processed using the ThinPrepTM for comparative analysis. The samples underwent processing, Papanicolaou staining, and microscopic evaluation for morphological parameters. The extracted nucleic acids were assessed for purity and integrity, and the detection of high‑risk human papillomavirus (HR‑HPV) was carried out using the Alinitym HR HPV system kit (Abbott Laboratórios Lda). Both methods demonstrated effective performance, enabling the morphological assessment of the cervical epithelium. Statistical analysis indicated that ThinPrepTM yielded significantly better results in terms of cellularity. Conversely, CytoPath®Easy exhibited superior performance in terms of the quantity of extracted DNA and its degree of purification. Concerning the time consumed during processing, both methods were comparable, with the CytoPath®Easy methodology standing out for its cost‑effectiveness, as it does not necessitate additional instruments and consumables. The novel CytoPath®Easy methodology proves effective in preserving both nucleic acids and cell morphology characteristics, two crucial features for cervical cancer screening."
- Atipia das células glandulares: qual o diagnóstico?Publication . Pisco, Filipa; Sousa, Nelson; Fonseca, PaulaNo âmbito das patologias ginecológicas, o cancro do ovário apresenta a taxa de mortalidade mais elevada, uma vez que só é diagnosticado numa fase tardia quando surgem os primeiros sintomas. O caso em estudo corresponde a uma citologia de follow-up, após histerectomia total por carcinoma do ovário indiferenciado. A avaliação citológica sugeriu um Adenocarcinoma enquanto o diagnóstico histológico da lesão nodular revelou uma recidiva de Carcinoma Papilar Seroso do Ovário. A realização do exame histológico, neste e noutros casos, constitui uma peça fundamental para a confirmação do diagnóstico citológico, assim como para o diagnóstico diferencial.
- Betulinic acid for glioblastoma treatment: Reality, challenges and perspectivesPublication . Fernandes, Sílvia; Vieira, Mariana; Prudêncio, Cristina; Ferraz, RicardoBetulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Betulinic acid has been investigated for its potential therapeutic properties, and exhibits anti-inflammatory, antiviral, antimalarial, and antioxidant activities. Notably, its ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies. This review aims to compile information about the impact of betulinic acid as an antitumor agent, particularly in the context of glioblastoma. Importantly, betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types. Compelling evidence published highlights the acid’s therapeutic action in suppressing the Akt/NFκB-p65 signaling cascade and enhancing the cytotoxic effects of the chemotherapeutic agent temozolomide. Interesting findings with betulinic acid also suggest a focus on researching the reduction of glioblastoma’s invasiveness and aggressiveness profile. This involves modulation of extracellular matrix components, remodeling of the cytoskeleton, and secretion of proteolytic proteins. Drawing from a comprehensive review, we conclude that betulinic acid formulations as nanoparticles and/or ionic liquids are promising drug delivery approaches with the potential for translation into clinical applications for the treatment and management of glioblastoma.
- Cardiac molecular remodeling by anticancer drugs: Doxorubicin affects more metabolism while mitoxantrone impacts more autophagy in adult CD-1 male micePublication . Brandão, Sofia Reis; Reis-Mendes, Ana; Duarte-Araújo, Margarida; Neuparth, Maria João; Rocha, Hugo; Carvalho, Félix; Ferreira, Rita; Costa, Vera MarisaDoxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments.
- Caso raro de massa nodular adiposa na região supraclavicularPublication . Pinto, Ana; Suárez, Marisa; Scigliano, HorácioAs massas adiposas na região cervical e supraclavicular são relativamente raras, sendo o lipoma a forma mais frequente e o hibernoma a mais rara. Neste trabalho relata-se o caso de uma paciente de 72 anos com história clínica de massa lipomatosa nodular, localizada na região supraclavicular direita, submetida a biopsia aspirativa por agulha fina. O diagnóstico citológico foi de provável hibernoma. O estudo histológico da peça cirúrgica confirmou a suspeita citológica.
- Células endometriais atípicas pós-menopausa –Estudo de casoPublication . Cardoso, Ana; Alves, Diana; Leite, Paula; Dominguez, RuteA presença de células endometriais é considerada um fator de alerta em esfregaços ginecológicos de mulheres na segunda metade do ciclo menstrual ou a partir dos 45 anos. Em mulheres pós-menopáusicas, a presença de células endometriais atípicas pode revelar uma patologia uterina grave e requer uma avaliação mais aprofundada. Apresentamos um caso de uma mulher de 77 anos, em pós-menopausa, que se apresentava com perda hemática vaginal e sem alterações uterinas à ecografia. O exame citológico revelou grupos de células endometriais com atipia nuclear, que dentro do contexto clínico da paciente é considerado anormal. O resultado citológico foi células glandulares atípicas, a favorecer neoplasia. Baseado neste resultado, a paciente fez uma curetagem uterina, cujo diagnóstico foi carcinossarcoma, e fez histerectomia radical. Apesar do resultado citológico não ser concordante com o diagnóstico histológico, indicou a necessidade de se estudar o endométrio e permitiu o subsequente diagnóstico de carcinossarcoma.