Cognitive decline in patients with prostate cancer: study protocol of a prospective cohort, NEON-PC

Introduction: Prostate cancer is the most prevalent oncological disease among men in industrialised countries. Despite the high survival rates, treatments are often associated with adverse effects, including metabolic and cardiovascular complications, sexual dysfunction and, to a lesser extent, cognitive decline. This study was primarily designed to evaluate the trajectories of cognitive performance in patients with prostate cancer, and to quantify the impact of the disease and its treatments on the occurrence of cognitive decline. Methods: Participants will be recruited from two main hospitals providing care to approximately half of the patients with prostate cancer in Northern Portugal (Portuguese Institute of Oncology of Porto and São João Hospital Centre), and will comprise a cohort of recently diagnosed patients with prostate cancer proposed for different treatment plans, including: (1) radical prostatectomy; (2) brachytherapy and/or radiotherapy; (3) radiotherapy in combination with androgen deprivation therapy and (4) androgen deprivation therapy (with or without chemotherapy). Recruitment began in February 2018 and is expected to continue until the first semester of 2021. Follow-up evaluations will be conducted at 1, 3, 5, 7 and 10 years. Sociodemographic, behavioural and clinical characteristics, anxiety and depression, health literacy, health status, quality of life, and sleep quality will be assessed. Blood pressure and anthropometrics will be measured, and a fasting blood sample will be collected. Participants' cognitive performance will be evaluated before treatments and throughout follow-up (Montreal Cognitive Assessment and Cube Test as well as Brain on Track for remote monitoring). All participants suspected of cognitive impairment will undergo neuropsychological tests and clinical observation by a neurologist. Ethics and dissemination: The study was approved by the Ethics Committee of the hospitals involved. All participants will provide written informed consent, and study procedures will be developed to ensure data protection and confidentiality. Results will be disseminated through publication in peer-reviewed journals and presentation in scientific meetings.This study was funded by FEDER through the Operational Programme Competitiveness and Internationalisation and national funding from the Foundation for Science and Technology-FCT (Portuguese Ministry of Science, Technology and Higher Education) under the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017), and the Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04750/2020/PT) financed by national funds from FCT. SM was funded under the scope of the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017). Individual PhD grants attributed to ARC (SFRH/BD/102181/2014) and NA (SFRH/BD/119390/2016) were funded by FCT and the ‘Programa Operacional Capital Humano’ (POCH/FSE)

Androgen-deprivation therapy and cognitive decline in the NEON-PC prospective study during the COVID-19 pandemic

Background: Androgen-deprivation therapy (ADT) has been associated with cognitive decline, but results are conflicting. This study describes changes in cognitive performance in patients with prostate cancer, according to ADT, during the first year after prostate cancer diagnosis. Patients and methods: Patients with prostate cancer treated at the Portuguese Institute of Oncology of Porto (n = 366) were evaluated with the Montreal Cognitive Assessment (MoCA), before treatment and after 1 year. All baseline evaluations were performed before the coronavirus disease 2019 (COVID-19) pandemic and 69.7% of the 1-year assessments were completed after the first lockdown. Cognitive decline was defined as the decrease in MoCA from baseline to the 1-year evaluation below 1.5 standard deviations of the distribution of changes in the whole cohort. Participants scoring below age- and education-specific normative reference values in the MoCA were considered to have cognitive impairment. Age- and education-adjusted odds ratios (aORs) were computed for the association between ADT and cognitive outcomes. Results: Mean MoCA scores increased from baseline to the 1-year evaluation (22.3 versus 22.8, P < 0.001). Cognitive decline was more frequent in the ADT group, and even more after the onset of the COVID-19 pandemic (aOR 6.81 versus 1.93, P for interaction = 0.233). The 1-year cumulative incidence of cognitive impairment was 6.9% (9.1% before and 3.7% after the pandemic onset), which was higher among patients receiving ADT, but only after the pandemic (aOR 5.53 versus 0.49, P for interaction = 0.044). Conclusions: ADT was associated with worse cognitive performance of patients with prostate cancer, mostly among those evaluated after the first COVID-19 lockdown. © 2022 The AuthorsFunding text 1: This study was funded by the European Regional Development Fund through the Operational Programme Competitiveness and Internationalisation, and national funding from the Fundação para a Ciência e a Tecnologia - FCT (Portuguese Ministry of Science, Technology and Higher Education) under the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017), and the Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020) and Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (LA/P/0064/2020), financed by national funds from FCT . AC and SM were funded under the scope of the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017). An individual PhD grant attributed to NA (SFRH/BD/119390/2016) was funded by FCT and the ‘ Programa Operacional Capital Humano ’ (POCH/FSE). ; Funding text 2: This study was funded by the European Regional Development Fund through the Operational Programme Competitiveness and Internationalisation, and national funding from the Fundação para a Ciência e a Tecnologia - FCT (Portuguese Ministry of Science, Technology and Higher Education) under the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017), and the Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020) and Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (LA/P/0064/2020), financed by national funds from FCT. AC and SM were funded under the scope of the project ‘NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline’ (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017). An individual PhD grant attributed to NA (SFRH/BD/119390/2016) was funded by FCT and the ‘Programa Operacional Capital Humano’ (POCH/FSE). The authors have no relevant financial or nonfinancial interests to disclose. The datasets generated and analysed in this study will not be publicly available given that the included patients do not specifically provide their consent for public sharing of their data and that anonymization is unlikely to be feasible, because the identification of patients treated in only one institution within a relatively short period may be possible when taking sociodemographic and clinical characteristics into account. Ethics approval was obtained from the Ethics Committee of the Portuguese Institute of Oncology of Porto (Ref. CES 89/017) and by the Portuguese Data Protection Authority (Authorisation 3478/2017). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants after the project's aims and procedures had been fully explained by a member of the research team. Not applicable

The desmosome and pemphigus

Desmosomes are patch-like intercellular adhering junctions (“maculae adherentes”), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required

Curcuminoid Binding to Embryonal Carcinoma Cells: Reductive Metabolism, Induction of Apoptosis, Senescence, and Inhibition of Cell Proliferation

Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4–6 days to either preparation in cell culture media reduced cell division (1–5 µM), induced senescence (6–7 µM) or comprehensive cell death (8–10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5–4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6–10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways

Detection of dengue virus serotype 3 by reverse transcription-polymerase chain reaction in Aedes aegypti (Diptera, Culicidae) captured in Manaus, Amazonas

The detection of dengue virus serotypes from Aedes aegypti in Manaus, state of Amazonas was carried out using the reverse transcription-polymerase chain reaction technique. Fourteen pools out 82 (17.1%) were positive for DENV3, providing a minimal infection rate of 2.1% of all analyzed infected female specimens of three different areas of the city

Dengue virus type 3 isolation from Aedes aegypti in the municipality of Nova Iguaçu, State of Rio de Janeiro

In a prospective field study conducted from July 2000 to June 2001, adult Aedes aegypti and Ae. albopictus mosquitoes were caught from the municipality of Nova Iguaçu, State of Rio de Janeiro, Brazil. Virus isolation in Ae. albopictus clone C6/36 cell line and a semi-nested reverse transcription-polymerase chain reaction detected only dengue virus type 3 in three pools of Ae. aegypti, despite the co-circulation of DEN-1, DEN-2 and DEN-3 serotypes in that area. No viruses were detected in Ae. albopictus mosquitoes. This virological surveillance consists in a sentinel system alerting for dengue outbreaks