Integration of Multi-Omics Data for the Classification of Glioma Types and Identification of Novel Biomarkers.

Glioma is currently one of the most prevalent types of primary brain cancer. Given its high level of heterogeneity along with the complex biological molecular markers, many efforts have been made to accurately classify the type of glioma in each patient, which, in turn, is critical to improve early diagnosis and increase survival. Nonetheless, as a result of the fast-growing technological advances in high-throughput sequencing and evolving molecular understanding of glioma biology, its classification has been recently subject to significant alterations. In this study, we integrate multiple glioma omics modalities (including mRNA, DNA methylation, and miRNA) from The Cancer Genome Atlas (TCGA), while using the revised glioma reclassified labels, with a supervised method based on sparse canonical correlation analysis (DIABLO) to discriminate between glioma types. We were able to find a set of highly correlated features distinguishing glioblastoma from lower-grade gliomas (LGGs) that were mainly associated with the disruption of receptor tyrosine kinases signaling pathways and extracellular matrix organization and remodeling. Concurrently, the discrimination of the LGG types was characterized primarily by features involved in ubiquitination and DNA transcription processes. Furthermore, we could identify several novel glioma biomarkers likely helpful in both diagnosis and prognosis of the patients, including the genes PPP1R8, GPBP1L1, KIAA1614, C14orf23, CCDC77, BVES, EXD3, CD300A, and HEPN1. Collectively, this comprehensive approach not only allowed a highly accurate discrimination of the different TCGA glioma patients but also presented a step forward in advancing our comprehension of the underlying molecular mechanisms driving glioma heterogeneity. Ultimately, our study also revealed novel candidate biomarkers that might constitute potential therapeutic targets, marking a significant stride toward personalized and more effective treatment strategies for patients with glioma.

Bioinspired and Photo-Clickable Thiol-Ene Bioinks for the Extrusion Bioprinting of Mechanically Tunable 3D Skin Models.

Bioinks play a fundamental role in skin bioprinting, dictating the printing fidelity, cell response, and function of bioprinted 3D constructs. However, the range of bioinks that support skin cells' function and aid in the bioprinting of 3D skin equivalents with tailorable properties and customized shapes is still limited. In this study, we describe a bioinspired design strategy for bioengineering double crosslinked pectin-based bioinks that recapitulate the mechanical properties and the presentation of cell-adhesive ligands and protease-sensitive domains of the dermal extracellular matrix, supporting the bioprinting of bilayer 3D skin models. Methacrylate-modified pectin was used as a base biomaterial enabling hydrogel formation via either chain-growth or step-growth photopolymerization and providing independent control over bioink rheology, as well as the mechanical and biochemical cues of cell environment. By tuning the concentrations of crosslinker and polymer in bioink formulation, dermal constructs were bioprinted with a physiologically relevant range of stiffnesses that resulted in strikingly site-specific differences in the morphology and spreading of dermal fibroblasts. We also demonstrated that the developed thiol-ene photo-clickable bioinks allow for the bioprinting of skin models of varying shapes that support dermis and epidermis reconstruction. Overall, the engineered bioinks expand the range of printable biomaterials for the extrusion bioprinting of 3D cell-laden hydrogels and provide a versatile platform to study the impact of material cues on cell fate, offering potential for in vitro skin modeling.

Depression Among Portuguese Pregnant Women During Covid-19 Lockdown: A Cross Sectional Study.

INTRODUCTION: Coronavirus disease 2019 was declared as a pandemic on March 2020. Research on its psychological effects is still lacking. Perinatal depression is a medical complication of pregnancy, especially in situations of stress. In this study, we aimed to investigate the presence of symptoms of depression in pregnant women during the lockdown period in Portugal. METHODS: This study consisted in a cross-sectional study among Portuguese pregnant women, who completed an online self-report questionnaire between 25th April and 30th April 2020. An anonymous online questionnaire was developed to assess depression and concerns related to COVID-19. This study was approved by the IRB of Hospital Dona Estefânia and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Eligibility criteria included pregnant women, ≥ 18 years and living in Portugal. The primary outcome was to evaluate the presence of depressive symptoms and its association to socio-demographic characteristics and to concerns related to COVID-19. RESULTS: A total of 1698 pregnant women were enrolled. The mean age was 31.9 years. 82.4% felt a negative impact of the pandemic in the surveillance of pregnancy and 43% felt insufficient support. 26.3% showed "possible depression" according to the EPDS. A regression analysis revealed the possibility of depression increased as the concerns about COVID increased and was lower for women with support. The possibility of depression was higher for women with psychiatric medical history. CONCLUSION: This study demonstrated a significant increase in clinically significant depressive symptoms in pregnant women during the lockdown. It also revealed some of the socio-demographic characteristics of women at risk for depression. If left untreated, depression tends to persist, affecting the woman and also the child. Our findings suggest that COVID-19 represents a serious challenge for this population and reinforce the urgent need for early detection and intervention on mental health issues during pregnancy, especially during the pandemic.

The Influence of Saliva pH on the Fracture Resistance of Three Complete Denture Base Acrylic Resins.

METHODS: Ten prosthesis bases prepared with each brand of resin were subjected to neutral and low pH conditions (pH 7 and pH 4) by submerging them in artificial saliva for 30 days. After exposure, the fatigue resistance of the resins was tested using a Dental CS® Testing Machine. Statistical Analysis Test. The data sets were described quantitatively in terms of mean (M) and standard deviation (SD). Shapiro-Wilk tests and unilateral analysis of variance (ANOVA) were performed and complemented by Tukey's multiple comparison tests. The effect size (η2), whose cohort points followed Cohen's recommendations: 0.01 (low), 0.06 (medium), and 0.14 (high), was calculated. The results were considered significant if p < 0.05 and marginally significant if p < 0.10. RESULTS: One-way ANOVA showed that Megacryl® had the highest fracture resistance at pH 7 (52.23 Kgf), compared with Triplex Hot® (p < 0.001) and RS Vertex® (p=0.034). Two-way ANOVA confirmed the interaction between brand and pH (p=0.022), also revealing that brands comparison is significant or marginally significant, when pH is not considered (Megacryl® versus Triplex Hot®, p < 0.001, and RS Vertex®, p=0.058; Triplex Hot® versus RS Vertex®, p=0.051), and pH 7 results were significantly higher (p=0.003), even when brands are not considered. Hence, Megacryl® at pH 7 was found to have the highest fracture resistance, detached from other brands and pH values. CONCLUSION: It can be concluded within the limitations of this study that there are differences in the fracture resistance among the three brands of acrylic resin. Megacryl® was found to have the highest fracture resistance, and Triplex Hot® was the lowest. The results also show that exposure to a low pH environment decreases the fracture resistance of the Megacryl® and RS Vertex® resins.

A Deformed Exponential Statistical Manifold.

Consider µ a probability measure and P µ the set of µ -equivalent strictly positive probability densities. To endow P µ with a structure of a C ∞ -Banach manifold we use the φ -connection by an open arc, where φ is a deformed exponential function which assumes zero until a certain point and from then on is strictly increasing. This deformed exponential function has as particular cases the q-deformed exponential and κ -exponential functions. Moreover, we find the tangent space of P µ at a point p, and as a consequence the tangent bundle of P µ . We define a divergence using the q-exponential function and we prove that this divergence is related to the q-divergence already known from the literature. We also show that q-exponential and κ -exponential functions can be used to generalize of Rényi divergence.

Prevalence of anxious and depressive symptoms in college students of a public institution.

OBJECTIVE: Identify the prevalence of anxious and depressive symptoms and their correlations with sociodemographic and occupational characteristics in university students. METHOD: This is census, cross-sectional and analytical study, developed with nursing students of a federal public university in the Northeast of Brazil in the months of September and October 2016. 205 university students of all the periods of the course attended the study. Beck's inventories for anxiety and depression were applied. RESULTS: Most of the participants were female, single, native of the state capital and living with his parents. The prevalence of depression was 30.2% and of anxiety, 62.9%. Association between the level of depressive symptoms, work, sex and leisure was identified. CONCLUSION: The prevalence of symptoms of anxiety and depression was quite expressive, lacking, thus, more attention to the promotion of mental health of nursing students.

Mixture and Exponential Arcs on Generalized Statistical Manifold.

In this paper, we investigate the mixture arc on generalized statistical manifolds. We ensure that the generalization of the mixture arc is well defined and we are able to provide a generalization of the open exponential arc and its properties. We consider the model of a φ -family of distributions to describe our general statistical model.

Synthesis and mechanistic investigation of iron(II) complexes of isoniazid and derivatives as a redox-mediated activation strategy for anti-tuberculosis therapy.

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB) represents a major threat to global health. Isoniazid (INH) is a prodrug used in the first-line treatment of tuberculosis. It undergoes oxidation by a catalase-peroxidase KatG, leading to generation of an isonicotinoyl radical that reacts with NAD(H) forming the INH-NADH adduct as the active metabolite. A redox-mediated activation of isoniazid using an iron metal complex was previously proposed as a strategy to overcome isoniazid resistance due to KatG mutations. Here, we have prepared a series of iron metal complexes with isoniazid and analogues, containing alkyl substituents at the hydrazide moiety, and also with pyrazinamide derivatives. These complexes were activated by H2O2 and studied by ESR and LC-MS. For the first time, the formation of the oxidized INH-NAD adduct from the pentacyano(isoniazid)ferrate(II) complex was detected by LC-MS, supporting a redox-mediated activation, for which a mechanistic proposition is reported. ESR data showed all alkylated hydrazides, in contrast to non-substituted hydrazides, only generated alkyl-based radicals. The structural modifications did not improve minimal inhibitory concentration (MIC) against MTB in comparison to isoniazid iron complex, providing support to isonicotinoyl radical formation as a requirement for activity. Nonetheless, the pyrazinoic acid hydrazide iron complex showed redox-mediated activation using H2O2 with generation of a pyrazinoyl radical intermediate and production of pyrazinoic acid, which is in fact the active metabolite of pyrazinamide prodrug. Thereby, this strategy can also unveil new opportunities for activation of this type of drug.

Prevalence of anxious and depressive symptoms in college students of a public institution / Prevalencia de síntomas ansiosos y depresivos en universitarios de una institución pública / Prevalência de sintomas ansiosos e depressivos em universitários de uma instituição pública

ABSTRACT Objective: Identify the prevalence of anxious and depressive symptoms and their correlations with sociodemographic and occupational characteristics in university students. Method: This is census, cross-sectional and analytical study, developed with nursing students of a federal public university in the Northeast of Brazil in the months of September and October 2016. 205 university students of all the periods of the course attended the study. Beck's inventories for anxiety and depression were applied. Results: Most of the participants were female, single, native of the state capital and living with his parents. The prevalence of depression was 30.2% and of anxiety, 62.9%. Association between the level of depressive symptoms, work, sex and leisure was identified. Conclusion: The prevalence of symptoms of anxiety and depression was quite expressive, lacking, thus, more attention to the promotion of mental health of nursing students.

RESUMEN Objetivo: Identificar la prevalencia de síntomas ansiosos y depresivos y sus correlaciones con características sociodemográficas y ocupacionales en universitarios. Método: Se trata de un estudio censal, transversal, y analítico, desarrollado con estudiantes de enfermería de una universidad pública federal del Nordeste de Brasil en los meses de septiembre y octubre de 2016. Participaron 205 universitarios de todos los períodos del curso. Se aplicaron los inventarios de Beck para la ansiedad y la depresión. Resultados: La mayoría de los participantes era del género femenino, soltera, natural de la capital del estado y vivía con los padres. La prevalencia de depresión fue del 30,2%, y de ansiedad el 62,9%. Se identificó asociación entre el nivel de síntomas depresivos, trabajo, sexo y ocio. Conclusión: La prevalencia de los síntomas de ansiedad y depresión fue bastante expresiva, necesitando, por lo tanto, de más atención y promoción a la salud mental de los estudiantes de enfermería.

RESUMO Objetivo: Identificar a prevalência de sintomas ansiosos e depressivos e suas correlações com características sociodemográficas e ocupacionais em universitários. Método: Trata-se de estudo censitário, transversal, e analítico, desenvolvido com estudantes de enfermagem de uma universidade pública federal do Nordeste do Brasil nos meses de setembro e outubro de 2016. Participaram 205 universitários de todos os períodos do curso. Foram aplicados os inventários de Beck para ansiedade e depressão. Resultados: A maioria dos participantes era do sexo feminino, solteira, natural da capital do estado e morava com os pais. A prevalência de depressão foi de 30,2% e de ansiedade, 62,9%. Identificou-se associação entre o nível de sintomas depressivos, trabalho, sexo e lazer. Conclusão: A prevalência dos sintomas de ansiedade e depressão foi bastante expressiva, carecendo, portanto, de mais atenção e promoção à saúde mental dos estudantes de enfermagem.

Colaboração interprofissional no Projeto Saúde e Prevenção na Escola / Inter-professional collaboration in the ‘Health and Prevention in Schools’ Project

Resumo A colaboração interprofissional sugere compartilhamento de ação orientada por objetivos comuns. Analisá-la no Projeto Saúde e Prevenção na Escola (PSPE) enquanto dispositivo da promoção da saúde é relevante pelo estímulo à responsabilidade partilhada e à intersetorialidade, valor e princípio da Política Nacional de Promoção da Saúde (PNPS). Estudo de caso realizado em uma cidade de médio porte, no Nordeste brasileiro, cujas fontes foram documentos e questionários aplicados a participantes, subsidiado pelo Modelo de Colaboração interprofissional de D’Amour et al. Com base nas dimensões e indicadores avaliados, identificou-se que os articuladores do PSPE orientam-se por objetivos comuns; o planejamento das ações não se orienta pelas necessidades dos escolares; existem poucas oportunidades para que os integrantes interajam; evidencia-se confiança na capacidade dos outros em assumirem responsabilidades; a infraestrutura não é usada adequadamente; a liderança é pouco impactante; existem processos de capacitação para os integrantes; os encontros dos integrantes do PSPE priorizam discussões específicas e os acordos formais estão em processos de negociação. Resultados que expressam um nível de colaboração interprofissional do tipo “em desenvolvimento”.

Abstract Inter-professional collaboration implies that there is a sharing of activities with a view to meeting a common goal. This theme was analyzed in the ‘Health and Prevention in Schools’ project (known as PSPE in the Portuguese) as a health promotion device. The aim was to encourage the sharing of ideas and information as well as intersectoral responsibilities and values in adherence to the principles of the National Policy for Health Promotion (PNPS). This was a case study conducted in a medium-sized city, in the northeast of Brazil. Our sources of information came from documents and questionnaires that had been applied to and taken from participants. We used the Inter-professional Collaboration Model designed by D’Amour et al. Based on the dimensions and indicators that were assessed, we identified that the project workers in the PSPE were guided by common goals. We noted that: their planning of actions was not guided by the needs of students, there were few opportunities for members to interact, there was evidence of their having confidence in the ability of others to take on responsibilities, infrastructures were not used properly and the leadership that we studied had little impact. We also noted that there were training processes for members. Our results showed that the level of inter-professional collaboration was at the level of “in development”.

[Fe(CN)5(isoniazid)](3-): an iron isoniazid complex with redox behavior implicated in tuberculosis therapy.

Tuberculosis has re-emerged as a worldwide threat, which has motivated the development of new drugs. The antituberculosis complex Na3[Fe(CN)5(isoniazid)] (IQG607) in particular is of interest on account of its ability to overcome resistance. IQG607 has the potential for redox-mediated-activation, in which an acylpyridine (isonicotinoyl) radical could be generated without assistance from the mycobacterial KatG enzyme. Here, we have investigated the reactivity of IQG607 toward hydrogen peroxide and superoxide, well-known intracellular oxidizing agents that could play a key role in the redox-mediated-activation of this compound. HPLC, NMR and electronic spectroscopy studies showed a very fast oxidation rate for bound isoniazid, over 460-fold faster than free isoniazid oxidation. A series of EPR spin traps were used for detection of isonicotinoyl and derived radicals bound to iron. This is the first report for an isonicotinoyl radical bound to a metal complex, supported by (14)N and (1)H hyperfine splittings for the POBN and PBN trapped radicals. POBN and PBN exhibited average hyperfine coupling constants of aN=15.6, aH=2.8 and aN=15.4, aH=4.7, respectively, which are in close agreement to the isonicotinoyl radical. Radical generation is thought to play a major role in the mechanism of action of isoniazid and this work provides strong evidence for its production within IQG607, which, along with biological and chemical oxidation data, support a redox-mediated activation mechanism. More generally the concept of redox activation of metallo prodrugs could be applied more widely for the design of therapeutic agents with novel mechanisms of action.

Trimetazidina e resposta inflamatória em cirurgia de revascularização do miocárdio / Trimetazidine and inflammatory response in coronary artery bypass grafting

FUNDAMENTO: A resposta inflamatória orgânica constitui um mecanismo fisiopatológico presente em todas as cirurgias de revascularização do miocárdio com circulação extracorpórea (CRVM-CEC), e a liberação de mediadores inflamatórios constitui um de seus mecanismos de defesa. OBJETIVO: Avaliar, em estudo prospectivo duplo-cego randomizado e controlado com placebo, os efeitos da trimetazidina (Tmz) sobre a resposta inflamatória, por meio da variação nas interleucinas 6 e 8; TNF-α; complementos C3 e C5, e na proteína C reativa ultrassensível (PCR-us), em dois momentos, pré e pós-operatório. MÉTODOS: Foram estudados 30 pacientes submetidos a CRVM-CEC utilizando cardioplegia hipotérmica intermitente, e com no máximo disfunção ventricular leve, divididos em dois grupos (placebo e Tmz), estratificados por ecocardiografia e recebendo medicação/placebo na dose de 60mg/dia. As amostras foram dosadas no pré-operatório sem medicação, no dia da cirurgia com 12 a 15 dias de medicação/placebo e, seguidamente, 5 min após o desclampeamento aórtico, 12 e 24h, para interleucinas e complementos, e 48h para PCR. RESULTADOS: Não ocorreram diferenças significativas entre os níveis de interleucina 8, Tnf-α, complementos C3 e C5, e PCR-us. No entanto, no grupo tratado, os níveis de interleucina 6 foram significativamente inferiores aos do grupo controle, em todos os momentos analisados. CONCLUSÃO: A trimetazidina mostrou-se eficaz apenas na redução da interleucina 6 nos pacientes submetidos à CRVM.

BACKGROUND: Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. OBJECTIVE: To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. METHODS: This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. RESULTS: No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. CONCLUSION: Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.

Trimetazidine and inflammatory response in coronary artery bypass grafting.

BACKGROUND: Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. OBJECTIVE: To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. METHODS: This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. RESULTS: No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. CONCLUSION: Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.