Translational Potential of Epigenetic-Based Markers on Fine-Needle Aspiration Thyroid Specimens

The awareness of epigenetic alterations leading to neoplasia attracted the attention of researchers toward its potential use in the management of cancer, from diagnosis to prognosis and prediction of response to therapies. Our group has focused its attention on the epigenomics of thyroid neoplasms. Although most of the epigenetic studies have been applied on histological samples, the fact is that cytology, through fine-needle aspiration, is a primary diagnostic method for many pathologies, of which thyroid nodules are one of the most paradigmatic examples. This has led to an increasing literature report of epigenetic studies using these biological samples over the past decade. In this review, our group aimed to document recent research of epigenetic alterations and its associated assessment techniques, based on cytology material. Our review covers the main epigenetic categories—DNA methylation, histone modification, and RNA-silencing—whose evidence in thyroid cytology samples may represent solid soil for future prospectively designed studies aiming at validating patterns of epigenetic alterations and their potential use in the clinical management of thyroid neoplasms

Epigenomics in Hurthle Cell Neoplasms: Filling in the Gaps Towards Clinical Application

It has been widely described that cancer genomes have frequent alterations to the epigenome, including epigenetic silencing of various tumor suppressor genes with functions in almost all cancer-relevant signalling pathways, such as apoptosis, cell proliferation, cell migration and DNA repair. Epigenetic alterations comprise DNA methylation, histone modification, and microRNAs dysregulated expression and they play a significant role in the differentiation and proliferation properties of TC. In this review, our group assessed the published evidence on the tumorigenic role of epigenomics in Hurthle cell neoplasms (HCN), highlighting the yet limited, heteregeneous and non-validated data preventing its current use in clinical practice, despite the well developed assessment techniques available. The identified evidence gaps call for a joint endeavour by the medical community towards a deeper and more systematic study of HCN, aiming at defining epigenetic markers in early diagnose, allowing for accurate stratification of maligancy and disease risk and for effective systemic treatment.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 —Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Additional funding by the European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalization—COMPETE2020, and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-016390: CANCEL STEM and from the FCT under the project POCI-01-0145-FEDER-031438: The other faces of telomerase: Looking beyond tumor immortalization (PDTC/MED_ONC/ 31438/2017). Additional funding through the Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo – Bolsa Edward Limbert MERCK/SPEDM 2019. SC is supported by FCT in the framework of a PhD grant (SFRH/BD/ 147650/2019)

Study protocol for a pilot randomised controlled trial evaluating the feasibility and effectiveness of non-pharmacological interventions to recover functionality after a transient ischaemic attack or a minor stroke: the 'Back to Normal' trial

Introduction Transient ischaemic attack (TIA) and minor stroke are frequently assumed as temporary or non-disabling events. However, evidence suggests that these patients can experience relevant impairment and functional disability. Therefore, the present study aims to evaluate the feasibility and effectiveness of a 3-month multidomain intervention programme, composed of five non-pharmacological strategies, aimed at accelerating return to pre-event level of functionality in patients with TIA or minor stroke. Methods and analysis Patients diagnosed with a TIA or a minor stroke are being recruited at the emergency or neurology departments of the Hospital Pedro Hispano, located in Matosinhos, Portugal (n=70). Those who accept to participate will be randomly allocated to two groups (1:1): (a) Intervention-receives a 3 months combined approach, initiating early post-event, composed of cognitive training, physical exercise, nutrition, psychoeducation and assessment/correction of hearing loss; (b) Control-participants will not be subject to any intervention. Both groups will receive the usual standard of care provided to these diseases. Recruitment began in May 2022 and is expected to continue until March 2023. Socio-demographic characteristics, lifestyles, health status, cognitive function, symptoms of anxiety and depression and quality of life will be assessed; as well as anthropometry, blood pressure and physical condition. Time to complete or partial recovery of instrumental activities of daily living will be assessed using an adapted version of the Frenchay Activities Index. All participants will be evaluated before the intervention and after 3 months. Ethics and dissemination This study was approved by the Ethics Committee of the Local Health Unit of Matosinhos (Ref. 75/CES/JAS). Written informed consent will be required from all the participants; data protection and confidentiality will be also ensured. The findings of this project are expected to be submitted for publication in scientific articles, and the main results will be presented at relevant scientific meetings. Trial registration number NCT05369637.This work was financed by national funds through the FCT - Foundation for Science and Technology, I.P., within the scope of projects UIDB/04750/2020 and LA/P/0064/2020. It was also supported by the Portuguese Stroke Society under the research scholarship Prof. Castro Lopes in cerebrovascular disease. The MIND-Matosinhos project was supported by 'Portugal Inovacao Social' and co-funded by the Operational Program Social Inclusion and Employment, Portugal 2020 and European Union, through the European Social Fund (POISE-03-4639-FSE-000793). Funders will not have any influence on the study design, execution, interpretation of data, writing and publication of manuscripts

Dynamin-related protein 1 at the crossroads of cancer

Mitochondrial dynamics are known to have an important role in so-called age-related diseases, including cancer. Mitochondria is an organelle involved in many key cellular functions and responds to physiologic or stress stimuli by adapting its structure and function. Perhaps the most important structural changes involve mitochondrial dynamics (fission and fusion), which occur in normal cells as well as in cells under dysregulation, such as cancer cells. Dynamin-related protein 1 (DRP1), a member of the dynamin family of guanosine triphosphatases (GTPases), is the key component of mitochondrial fission machinery. Dynamin-related protein 1 is associated with different cell processes such as apoptosis, mitochondrial biogenesis, mitophagy, metabolism, and cell proliferation, differentiation, and transformation. The role of DRP1 in tumorigenesis may seem to be paradoxical, since mitochondrial fission is a key mediator of two very different processes, cellular apoptosis and cell mitosis. Dynamin-related protein 1 has been associated with the development of distinct human cancers, including changes in mitochondrial energetics and cellular metabolism, cell proliferation, and stem cell maintenance, invasion, and promotion of metastases. However, the underlying mechanism for this association is still being explored. Herein, we review the published knowledge on the role of DRP1 in cancer, exploring its interaction with different biological processes in the tumorigenesis context.Acknowledgments: The authors would like to acknowledge all the members of the Cancer Signalling and Metabolism research group at IPATIMUP/i3S for their input on different topics of the manuscript. This work was supported by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia—in the framework of project UID/BIM/04293/2013. It was also financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Further funding was obtained from the project “Advancing cancer research: from basic knowledgment to application” NORTE-01-0145-FEDER-000029: “Projetos Estruturados de I & D & I”, funded by Norte 2020—Programa Operacional Regional do Norte

Low-energy electron collisions with C4H6 isomers

We report integral, differential, and momentum-transfer cross sections for elastic scattering of low-energy electrons by C4H6 isomers, namely, 1,3-butadiene, 2-butyne, and cyclobutene. We use the Schwinger multichannel method with pseudopotentials [M. H. F. Bettega, L. G. Ferreira, and M. A. P. Lima, Phys. Rev. A-47, 1111 (1993)] at the static-exchange approximation to compute the cross sections for energies from 10 to 60 eV. In particular, we discuss the isomer effect, reported by experimental studies for isomers Of C3H4 and C4H6. We also calculate the total ionization cross section using the binary-encounter-Bethe model for 2-butyne and 1,3-butadiene, and estimate the inelastic cross section for these two isomers.69

Elevated arousal at time of decision-making is not the arbiter of risk avoidance in chickens

The somatic marker hypothesis proposes that humans recall previously experienced physiological responses to aid decision-making under uncertainty. However, little is known about the mechanisms used by non-human animals to integrate risk perception with predicted gains and losses. We monitored the behaviour and physiology of chickens when the choice between a high-gain (large food quantity), high-risk (1 in 4 probability of receiving an air-puff) option (HGRAP) or a low-gain (small food quantity), no-risk (of an air-puff) (LGNAP) option. We assessed when arousal increased by considering different stages of the decision-making process (baseline, viewing, anticipation, reward periods) and investigated whether autonomic responses influenced choice outcome both immediately and in the subsequent trial. Chickens were faster to choose and their heart-rate significantly increased between the viewing and anticipation (post-decision, pre-outcome) periods when selecting the HGRAP option. This suggests that they responded physiologically to the impending risk. Additionally, arousal was greater following a HGRAP choice that resulted in an air-puff, but this did not deter chickens from subsequently choosing HGRAP. In contrast to human studies, we did not find evidence that somatic markers were activated during the viewing period, suggesting that arousal is not a good measure of avoidance in non-human animals

Os efeitos do cigarro e do consumo de café sobre a formação óssea e a integração óssea de implantes de hidroxiapatita

The present study aims to assess the effects of cigarette smoke inhalation and/or coffee consumption on bone formation and osseous integration of a dense hydroxyapatite (DHA) implant in rats. For this study, 20 male rats were divided into four groups (n = 5): CT (control) group, CE (coffee) group, CI (cigarette) group and CC (coffee + cigarette) group. During 16 weeks, animals in the CI group were exposed to cigarette smoke inhalation equivalent to 6 cigarettes per day; specimens in the CE group drank coffee as liquid diet; and rats in the CC group were submitted to both substances. In the 6th week a 5 mm slit in the parietal bone and a 4 mm slit in the tibia were performed on the left side: the former was left open while the latter received a DHA implant. As soon as surgeries were finished, the animals returned to their original protocols and after 10 weeks of exposure they were euthanised (ethically sacrificed) and the mentioned bones collected for histological processing. Data showed that exposure to cigarette smoke inhalation and coffee consumption did not interfere in weight gain and that solid and liquid diet consumption was satisfactory. Rats in the CC group showed a decrease in bone neoformation around the tibial DHA implant (31.8 ± 2.8) as well as in bone formation in the parietal slit (28.6 ± 2.2). On their own, cigarette smoke inhalation or coffee consumption also led to diminished bone neoformation around the implant and delayed the bone repair process in relation to the CT group. However, reduction in the bone repair process was accentuated with exposure to both cigarette smoke inhalation and coffee consumption in this study.O presente estudo teve como objetivo avaliar os efeitos do tabagismo e do consumo de café, isolada ou concomitantemente, sobre a formação óssea e a osseointegração de implantes hidroxiapatita densa. Foram utilizados 20 ratos machos, divididos em quatro grupos (n = 5): grupo CT (controle); grupo CA (café); grupo CI (cigarro), e grupo CC (cigarro + café). Durante 16 semanas, os animais do grupo CI foram expostos à fumaça de seis cigarros/dia; os animais do grupo CA consumiram café como dieta líquida, e os animais do grupo CC, ambas as substâncias. Após seis semanas de exposição, uma falha óssea de 5 mm foi produzida no osso parietal esquerdo e de 4 mm, na tíbia esquerda dos animais. A falha do parietal foi mantida aberta, enquanto na tíbia corpos cerâmicos de hidroxiapatita densa (HAD) foram implantados em cavidade produzida cirurgicamente. Após as cirurgias, os animais retornaram aos protocolos experimentais e, ao término de dez semanas, foram eutanasiados, sendo as tíbias e os parietais coletados para processamento histológico. A exposição à fumaça do cigarro e o consumo de café não interferiram no ganho de peso dos animais, e os consumos de dieta líquida e sólida foram satisfatórios entre os grupos. Os animais do grupo CC apresentaram menor volume de osso neoformado ao redor do implante de HAD na tíbia (31,8 ± 2,8) e menor osteogênese na falha produzida no osso parietal (28,6 ± 2,2). O café e o cigarro consumidos isoladamente provocam a diminuição do volume de osso ao redor do implante e o atraso no processo de reparação óssea. Observou-se que o consumo de café associado à exposição à fumaça do cigarro reduziu de forma acentuada o processo de reparação óssea, no presente estudo.17317

Volatile constituents and behavioral change induced by Cymbopogon winterianus leaf essential oil in rodents

Cymbopogon winterianus Jowitt (‘Java citronella’) is an important essential oil yielding aromatic grass cultivated in India and Brazil and its volatile essential oils extracted from its leaves are used in perfumery, cosmetics, pharmaceuticals and flavoring industries. However, there is no report on any psychopharmacological study of C. winterianus leaf essential oil (LEO) available to date. In this study, the pharmacological effects of the LEO were investigated in animal models and its phytochemical analyses. GC-MS analysis showed a mixture of monoterpenes, as citronellal (36.19%), geraniol (32.82%) and citronellol (11.37%). LEO exhibited an inhibitory effect on the locomotor activity of mice, an antinociceptive effect by increasing the reaction time in the writhing and capsaicin tests. All doses induced a significant increase in the sleeping time of animals not having modified however, the latency. The LEO did not alter the remaining time of the animals on the rota-rod apparatus. These results suggest a possible central effect.Key words: Cymbopogon winterianus, essential oil, CNS, behavioral effects, analgesic

Automatic construction of rule-based ICD-9-CM coding systems

Background: In this paper we focus on the problem of automatically constructing ICD-9-CM coding systems for radiology reports. ICD-9-CM codes are used for billing purposes by health institutes and are assigned to clinical records manually following clinical treatment. Since this labeling task requires expert knowledge in the field of medicine, the process itself is costly and is prone to errors as human annotators have to consider thousands of possible codes when assigning the right ICD-9-CM labels to a document. In this study we use the datasets made available for training and testing automated ICD-9-CM coding systems by the organisers of an International Challenge on Classifying Clinical Free Text Using Natural Language Processing in spring 2007. The challenge itself was dominated by entirely or partly rule-based systems that solve the coding task using a set of hand crafted expert rules. Since the feasibility of the construction of such systems for thousands of ICD codes is indeed questionable, we decided to examine the problem of automatically constructing similar rule sets that turned out to achieve a remarkable accuracy in the shared task challenge. Results: Our results are very promising in the sense that we managed to achieve comparable results with purely hand-crafted ICD-9-CM classifiers. Our best model got a 90.26 % F measure on the training dataset and an 88.93 % F measure on the challenge test dataset, using the micro-averaged Fβ=1 measure, the official evaluatio

Two Separate Effects Contribute to Regulatory T Cell Defect in Systemic Lupus Erythematosus Patients and Their Unaffected Relatives

Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.info:eu-repo/semantics/publishedVersio