Avaliação do impacto de uma intervenção em gestão do stress em pacientes sujeitos a radioterapia e em situação de fadiga oncológica : um estudo quase experimental

Dissertação de Doutoramento apresentada ao ISPA - Instituto UniversitárioRESUMO: A intervenção em gestão do stress cognitivo-comportamental (IGSCC) composta por reestruturação cognitiva, treino em estratégias de coping e relaxação muscular é apontada por parte da Comunidade Científica como eficaz na redução da fadiga oncológica (FO). No entanto, esta opinião não é consensual e parte da investigação argumenta que a terapia cognitivo-comportamental não reestrutura a experiência da crise, durante o tratamento de radioterapia. A FO, altamente debilitante, é suportada por parte dos doentes oncológicos e surge como resultado do processo oncológico (doença e tratamentos). Manifesta-se em exaustão física, mental, emocional e social, impactando a qualidade de vida. A sua etiologia é patopsicofisiológica, com vários factores correlacionados: crenças disfuncionais, estados emocionais com significativa ansiedade, depressão e stress, baixa percepção e satisfação com o suporte social, baixa qualidade de vida e limitada resiliência. Este estudo procura avaliar o impacto da IGSCC, durante a radioterapia, sobre a FO, contribuindo para uma maior compreensão deste constructo tão complexo. É um estudo longitudinal, comparativo e correlacional, recorre a 3 grupos avaliados em 3 momentos: antes da radioterapia (M1), logo após o fim da radioterapia (M2) e seis meses após o fim da radioterapia (M3). O grupo de intervenção é composto por 35 indivíduos com FO sujeitos a IGSCC, o grupo de controlo é composto por 35 sujeitos com FO e apenas sujeitos a radioterapia e o grupo sem FO é composto por 35 sujeitos sem FO e apenas sujeitos a radioterapia. Todos os sujeitos foram previamente seleccionados e colocados aleatoriamente no respectivo grupo depois de responderem ao Termómetro Emocional (Bizarro, Patrão, & Deep, 2012). Avaliou-se ainda a dinâmica emocional, social, cognitiva, a personalidade, a qualidade de vida e as características sociodemográficas e clínicas. Verificou-se que os resultados obtidos dependeram do tipo de tratamento (com ou sem IGSCC) e que quando um paciente tem intervenção psicológica o sofrimento emocional, a ansiedade, a depressão, o impacto e a necessidade de ajuda diminuem (p˂,05). Igualmente verificou-se que a IGSCC alterou as crenças do grupo de intervenção, ajudando-o a lidar com o cancro, reduzindo o sofrimento psicológico e incrementando o bem-estar (p˂,05). Quanto aos padrões de regulação emocional verificou-se o impacto positivo da IGSCC a curto e longo prazo: a IGSCC reestruturou a vivência de crise e reduziu a gravidade da sintomatologia, ainda que se tenha assistido à perda de resultados positivos no grupo de intervenção no M3. A satisfação com o suporte social, resiliência e qualidade de vida também confirmam o impacto positivo da IGSCC a curto e longo prazo (p˂,05). Este estudo demonstra correlações (r˂,05) entre factores estudados: os padrões de regulação emocional estão positivamente correlacionados com a baixa qualidade de vida, e negativamente correlacionados com a resiliência e a satisfação com o suporte social. A IGSCC contribuiu para um maior bem-estar: teve impacto positivo sobre a experiência psicossocial do GI reestruturando a experiência de crise e reduzindo a gravidade dos sintomas. A IGSCC permitiu a reestruturação cognitiva, estabeleceu estratégias de enfrentamento apropriadas e ensinou os pacientes a relaxar. Embora a FO tenha um caráter patopsicofisiológico, com a IGSCC é possível alcançar níveis mais baixos de ansiedade, depressão e stress, considerando-se esta intervenção eficaz na gestão da FO. As implicações clínicas do estudo referem-se a necessidade de detectar a FO e intervir terapeuticamente.ABSTRACT: A cognitive behavioural intervention in stress management (CBISM) composed by muscle relaxation, cognitive restructuring and training in coping strategies is pointed by some Scientific Community as effective in reducing Cancer Related Fatigue (CRF). However, this opinion is not consensual and part of the investigation argues that cognitive behavioral therapy does not restructures the experience of crisis, during radiotherapy treatment. CRF is a highly debilitating and supported by most cancer patients. It arises as a result of the oncological process (disease and treatment). It manifests itself through physical, mental, emotional and social exhaustion, impacting the quality of life. Its etiology is pathopsychophysiological with several correlated factors: dysfunctional beliefs, emotional states with significant anxiety, depression and stress, low perception and satisfaction with social support, poor quality of life and limited resilience. This study seeks to evaluate the impact of CBISM during radiotherapy, about the FO, contributing to a greater understanding of this complex construct. A longitudinal, comparative and correlational study was developed, using three groups evaluated in three different moments: before radiotherapy (M1), shortly after the end of radiotherapy (M2) and six months after the end of radiotherapy (M3). The intervention group is composed by 35 individuals with CRF subject to a CBISM; the control group is composed by 35 subjects with CRF and only subjected to radiotherapy; and the group without CRF is composed of 35 subjects without CRF and only subjected to radiotherapy. All subjects were previously selected and placed randomly within their group after responding to the Emotional Thermometer (Bizarro, Patrão, & Deep, 2012). We evaluated the emotional, social and cognitive dynamic, personality, quality of life and sociodemographic and clinical characteristics. We found that the results depended on the type of treatment (with or without CBISM), and that when a patient has psychological intervention the emotional distress, anxiety, depression, impact and need for help decrease (p˂,05). We further observed that the CBISM changed the beliefs of the intervention group, helping the participants deal with cancer, reducing psychological distress and increasing well-being (p˂,05). In terms of emotional regulation, there was a positive impact of CBISM in the short and long term: CBISM restructured the experience of crisis and reduced the symptoms’ severity, even if we observed a decrease in positive results for the intervention group in M3. Regarding satisfaction with social support, resilience and quality of life, the positive impact of CBISM was confirmed in the short and long term (p˂ ,05). This study demonstrates correlations (r˂,05) between the studied factors: patterns of emotional regulation are positively correlated with poor quality of life, and negatively correlated with resilience and satisfaction with social support. The CBISM contributed to a greater wellbeing: had a positive impact on the psychosocial experience of the intervention group, restructuring the crisis experience and reducing the symptoms’ severity. The CBISM allowed for a cognitive restructuration, established appropriate coping strategies and taught the patients to relax. Although the CRF has a pathopsychophysiological character, with CBISM it is possible to achieve lower levels of anxiety, depression and stress, being this intervention considered effective. The clinical implications of these results relate to the need to detect the FO and intervene therapeutically

Impact of Dermoscopy and Reflectance Confocal Microscopy on the Histopathologic Diagnosis of Lentigo Maligna/Lentigo Maligna Melanoma

BACKGROUND: Equivocal pigmented lesions of the head are usually biopsied to avoid inappropriate treatment. Clinical approach has evolved from simple visual examination to sophisticated techniques for selecting the biopsy sites. OBJECTIVE: This study aimed to retrospectively evaluate the efficiency of dermoscopy (DE) and reflectance confocal microscopy (RCM) in sampling a histopathologically representative focus of lentigo maligna/lentigo maligna melanoma. METHODS: Punch biopsies and surgical excisions of 72 patients, 37 men and 35 women (median age 70.6 years, range 39-90 years), affected by lentigo maligna/lentigo maligna melanoma of the head, sent from a single dermatology clinic, were reviewed for the presence of 5 histopathologic criteria: atypical junctional melanocytes, increased junctional melanocytes, follicular colonization, pagetoid spread and melanocytic junctional nests, plus other minor features. Forty-two patients were biopsied under DE and 30 under RCM guidance. RESULTS: Accuracy of the 2 techniques in sampling a representative tissue overlapped in most cases, although RCM selected sites to biopsy with more histopathologic criteria, in particular pagetoid spread and melanocytic nests. Interestingly, with RCM, inflammation and melanophages were observed more in biopsy than in excision. False positive cases were not registered. CONCLUSION: Compared with the sampling at naked eye, our results show that DE and RCM help selecting the most appropriate areas for biopsies, thus allowing not only more robust histopathologic diagnoses, but also a more accurate microstaging of tumor

Hidden Diversity Hampers Conservation Efforts in a Highly Impacted Neotropical River System.

Neotropical Rivers host a highly diverse ichthyofauna, but taxonomic uncertainty prevents appropriate conservation measures. The Doce River Basin (DRB), lying within two Brazilian threatened hotspots (Atlantic Forest and Brazilian Savanna) in south-east Brazil, faced the worst ever environmental accident reported for South American catchments, due to a dam collapse that spread toxic mining tailings along the course of its main river. Its ichthyofauna was known to comprise 71 native freshwater fish species, of which 13 endemic. Here, we build a DNA barcode library for the DRB ichthyofauna, using samples obtained before the 2015 mining disaster, in order to provide a more robust biodiversity record for this basin, as a baseline for future management actions. Throughout the whole DRB, we obtained a total of 306 barcodes, assigned to 69 putative species (with a mean of 4.54 barcodes per species), belonging to 45 genera, 18 families, and 5 orders. Average genetic distances within species, genus, and families were 2.59, 11.4, and 20.5%, respectively. The 69 species identified represent over 76% of the known DRB ichthyofauna, comprising 43 native (five endemic, of which three threatened by extinction), 13 already known introduced species, and 13 unknown species (such as Characidium sp., Neoplecostomus sp., and specimens identified only at the sub-family level Neoplecostominae, according to morphological identification provided by the museum collections). Over one fifth of all analyzed species (N = 16) had a mean intraspecific genetic divergence higher than 2%. An integrative approach, combining NND (nearest neighbor distance), BIN (barcode index number), ABGD (automatic barcode gap discovery), and bPTP (Bayesian Poisson Tree Processes model) analyses, suggested the occurrence of potential cryptic species, species complex, or historical errors in morphological identification. The evidence presented calls for a more robust, DNA-assisted cataloging of biodiversity-rich ecosystems, in order to enable effective monitoring and informed actions to preserve and restore these delicate habitats

Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production

BACKGROUND: Disseminated leishmaniasis is an emerging infectious disease, mostly due to L. braziliensis, which has clinical and histopathological features distinct from cutaneous leishmaniasis. METHODS: In the current study we evaluated the in vitro production of the cytokines IFN-γ, TNF-α, IL-5 and IL-10 by peripheral blood mononuclear cells (PBMC) from 15 disseminated leishmaniasis and 24 cutaneous leishmaniasis patients upon stimulation with L. braziliensis antigens genotyped as disseminated leishmaniasis or cutaneous leishmaniasis isolates. RESULTS: Regardless of the source of L. braziliensis antigens, PBMC from cutaneous leishmaniasis patients produced significantly higher IFN-γ than PBMC from disseminated leishmaniasis patients. Levels of TNF-α by PBMC from cutaneous leishmaniasis patients were significantly higher than disseminated leishmaniasis patients only when stimulated by genotyped cutaneous leishmaniasis antigens. The levels of IL-5 and IL-10 production by PBMC were very low and similar in PBMCs from both disseminated leishmaniasis and cutaneous leishmaniasis patients. The immune response of each patient evaluated by the two L. braziliensis antigens was assessed in a paired analysis in which we showed that L. braziliensis genotyped as disseminated leishmaniasis isolate was more potent than L. braziliensis genotyped as cutaneous leishmaniasis isolate in triggering IFN-γ and TNF-α production in both diseases and IL-5 only in cutaneous leishmaniasis patients. CONCLUSION: This study provides evidence that antigens prepared from genotypically distinct strains of L. braziliensis induce different degrees of immune response. It also indicates that both parasite and host play a role in the outcome of L. braziliensis infection

The C Allele of rs5743836 Polymorphism in the Human TLR9 Promoter Links IL-6 and TLR9 Up-Regulation and Confers Increased B-Cell Proliferation

In humans, allelic variants in Toll-like receptors (TLRs) associate with several pathologies. However, the underlying cellular and molecular mechanisms of this association remain largely unknown. Analysis of the human TLR9 promoter revealed that the C allele of the rs5743836 polymorphism generates several regulatory sites, including an IL-6-responding element. Here, we show that, in mononuclear cells carrying the TC genotype of rs5743836, IL-6 up-regulates TLR9 expression, leading to exacerbated cellular responses to CpG, including IL-6 production and B-cell proliferation. Our study uncovers a role for the rs5743836 polymorphism in B-cell biology with implications on TLR9-mediated diseases and on the therapeutic usage of TLR9 agonists/antagonists

Avaliação do impacto de uma intervenção em gestão de stress em pacientes com fadiga oncológica a realizar radioterapia: Resultados preliminares

Objetivo: Este trabalho apresenta os resultados preliminares da avaliação do impacto de uma intervenção em gestão do stress cognitivo-comportamental (IGSCC) sobre padrões de regulação emocional (ansiedade, depressão e stress) e resiliência em pacientes com fadiga oncológica e em radioterapia. Método: Comparam-se os resultados entre um grupo de controlo (20 participantes submetidos ao tratamento convencional de radioterapia sem IGSCC) e um grupo experimental (20 participantes submetidos ao tratamento de radioterapia convencional e com IGSCC) em dois momentos: no início e no fim da radioterapia. Recorreu-se a um questionário demográfico, à Escala de Ansiedade, Depressão e Stress, à Escala de Resiliência e ao Termómetro da Emoção. Resultados: No grupo experimental, após IGSCC, assistiu-se à descida significativa da ansiedade, da depressão e do stress, (p ˂ .005), bem como à subida significativa da resiliência global (p ˂ .005) e seus constituintes. Tal não aconteceu no grupo de controlo. Conclusão: Os resultados apontam para diferenças significativas entre ambos os grupos e ambos os momentos nas variáveis em estudo, salientando a eficácia da IGSCC. ------ ABSTRACT ------ Aim: We present the preliminary results of the assessment of the impact of cognitive-behavioral intervention on stress management (CBISM) on patterns of emotional regulation (anxiety, depression and stress) and resilience in patients with cancer fatigue and in radiotherapy. Method: We compare the results between the control group (20 participants subject to the conventional treatment of radiotherapy without CBISM) and the experimental group (20 participants subjected to the treatment of conventional radiotherapy with CBISM) in 2 times: at the beginning and end of radiotherapy. We used: a Demographic Questionnaire, a Scale of Anxiety, Depression and Stress, a Scale of Resilience as well as the Emotion Thermometers. Results: There is a significant fall of anxiety, depression and stress, (p ˂ .005) in the experimental group (not in the control group), as well as the significant rise of global resilience (p ˂ .005) and its constituents. Conclusion: The results indicate significant differences between both groups and both times, stressing the effectiveness of CBISM

Circulating tumour cell associated microRNA profiles change during chemoradiation and are predictive of response in locally advanced rectal cancer

Locally advanced rectal cancer (LARC) has traditionally been treated with trimodality therapy consisting of neoadjuvant radiation +/− chemotherapy, surgery, and adjuvant chemotherapy. There is currently a clinical need for biomarkers to predict treatment response and outcomes, especially during neoadjuvant therapy. Liquid biopsies in the form of circulating tumour cells (CTCs) and circulating nucleic acids in particular microRNAs (miRNA) are novel, the latter also being highly stable and clinically relevant regulators of disease. We studied a prospective cohort of 52 patients with LARC, and obtained samples at baseline, during treatment, and post-treatment. We enumerated CTCs during chemoradiation at these three time-points, using the IsofluxTM (Fluxion Biosciences Inc., Alameda, CA, USA) CTC Isolation and detection platform. We then subjected the isolated CTCs to miRNA expression analyses, using a panel of 106 miRNA candidates. We identified CTCs in 73% of patients at baseline; numbers fell and miRNA expression profiles also changed during treatment. Between baseline and during treatment (week 3) time-points, three microRNAs (hsa-miR-95, hsa-miR-10a, and hsa-miR-16-1*) were highly differentially expressed. Importantly, hsa-miR-19b-3p and hsa-miR-483-5p were found to correlate with good response to treatment. The latter (hsa-miR-483-5p) was also found to be differentially expressed between good responders and poor responders. These miRNAs represent potential predictive biomarkers, and thus a potential miRNA-based treatment strategy. In this study, we demonstrate that CTCs are present and can be isolated in the non-metastatic early-stage cancer setting, and their associated miRNA profiles can potentially be utilized to predict treatment response

Paleo-Drainage Basin Connectivity Predicts Evolutionary Relationships across Three Southeast Asian Biodiversity Hotspots

Understanding factors driving diversity across biodiversity hotspots is critical for formulating conservation priorities in the face of ongoing and escalating environmental deterioration. While biodiversity hotspots encompass a small fraction of Earth's land surface, more than half the world's plants and two-thirds of terrestrial vertebrate species are endemic to these hotspots. Tropical Southeast (SE) Asia displays extraordinary species richness, encompassing four biodiversity hotspots, though disentangling multiple potential drivers of species richness is confounded by the region's dynamic geological and climatic history. Here, we use multilocus molecular genetic data from dense multispecies sampling of freshwater fishes across three biodiversity hotspots, to test the effect of Quaternary climate change and resulting drainage rearrangements on aquatic faunal diversification. While Cenozoic geological processes have clearly shaped evolutionary history in SE Asian halfbeak fishes, we show that paleo-drainage re-arrangements resulting from Quaternary climate change played a significant role in the spatiotemporal evolution of lowland aquatic taxa, and provide priorities for conservation efforts. [Freshwater; geology; halfbeak; island radiation; Miocene; Pleistocene; river; Southeast Asia.

Gas sensors based on localized surface plasmon resonances: synthesis of oxide films with embedded metal nanoparticles, theory and simulation, and sensitivity enhancement strategies

This work presents a comprehensive review on gas sensors based on localized surface plasmon resonance (LSPR) phenomenon, including the theory of LSPR, the synthesis of nanoparticle-embedded oxide thin films, and strategies to enhance the sensitivity of these optical sensors, supported by simulations of the electromagnetic properties. The LSPR phenomenon is known to be responsible for the unique colour effects observed in the ancient Roman Lycurgus Cup and at the windows of the medieval cathedrals. In both cases, the optical effects result from the interaction of the visible light (scattering and absorption) with the conduction band electrons of noble metal nanoparticles (gold, silver, and gold–silver alloys). These nanoparticles are dispersed in a dielectric matrix with a relatively high refractive index in order to push the resonance to the visible spectral range. At the same time, they have to be located at the surface to make LSPR sensitive to changes in the local dielectric environment, the property that is very attractive for sensing applications. Hence, an overview of gas sensors is presented, including electronic-nose systems, followed by a description of the surface plasmons that arise in noble metal thin films and nanoparticles. Afterwards, metal oxides are explored as robust and sensitive materials to host nanoparticles, followed by preparation methods of nanocomposite plasmonic thin films with sustainable techniques. Finally, several optical properties simulation methods are described, and the optical LSPR sensitivity of gold nanoparticles with different shapes, sensing volumes, and surroundings is calculated using the discrete dipole approximation method.This research was funded by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UIDB/04650/2020; and by the project NANO4BIO POCI-01-0145-FEDER-032299, with FCT reference PTDC/FISMAC/32299/2017. Marco S. Rodrigues acknowledges FCT for his PhD Scholarship, SFRH/BD/118684/2016

Space-time dynamics in monitoring neotropical fish communities using eDNA metabarcoding.

The biodiverse Neotropical ecoregion remains insufficiently assessed, poorly managed, and threatened by unregulated human activities. Novel, rapid and cost-effective DNA-based approaches are valuable to improve understanding of the biological communities and for biomonitoring in remote areas. Here, we evaluate the potential of environmental DNA (eDNA) metabarcoding for assessing the structure and distribution of fish communities by analysing water and sediment from 11 locations along the Jequitinhonha River catchment (Brazil). Each site was sampled twice, before and after a major rain event in a five-week period and fish diversity was estimated using high-throughput sequencing of 12S rRNA amplicons. In total, 252 Molecular Operational Taxonomic Units (MOTUs) and 34 fish species were recovered, including endemic, introduced, and previously unrecorded species for this basin. Spatio-temporal variation of eDNA from fish assemblages was observed and species richness was nearly twice as high before the major rain event compared to afterwards. Yet, peaks of diversity were primarily associated with only four of the locations. No correlation between β-diversity and longitudinal distance or presence of dams was detected, but low species richness observed at sites located near dams might that these anthropogenic barriers may have an impact on local fish diversity. Unexpectedly high α-diversity levels recorded at the river mouth suggest that these sections should be further evaluated as putative "eDNA reservoirs" for rapid monitoring. By uncovering spatio-temporal changes, unrecorded biodiversity components, and putative anthropogenic impacts on fish assemblages, we further strengthen the potential of eDNA metabarcoding as a biomonitoring tool, especially in regions often neglected or difficult to access