Local delivery of accutox® synergises with immune-checkpoint inhibitors at disrupting tumor growth.

BACKGROUND: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. METHODS: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). RESULTS: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. CONCLUSIONS: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.

Cannabidivarin and cannabigerol induce unfolded protein response and angiogenesis dysregulation in placental trophoblast HTR-8/SVneo cells.

Cannabidivarin (CBDV) and cannabigerol (CBG) are minor phytocannabinoids from Cannabis sativa, whose health benefits have been reported. However, studies about the impact of these cannabinoids on fundamental cellular processes in placentation are scarce. Placental development involves physiological endoplasmic reticulum (ER) stress, however when exacerbated it can lead to altered angiogenesis and pregnancy disorders, such as intrauterine growth restriction and preeclampsia. In this work, the effects of CBDV and CBG (1-10 µM) on placental extravillous trophoblasts were studied, using the in vitro model HTR-8/SVneo cells. Both cannabinoids induced anti-proliferative effects and reactive oxygen/nitrogen species generation, which was dependent on transient receptor potential vanilloid 1 (TRPV1) activation. Moreover, CBDV and CBG significantly upregulated, in a TRPV-1 dependent manner, the gene expression of HSPA5/Glucose-regulated protein 78 (GRP78/BiP), a critical chaperone involved in ER stress and unfolded protein response (UPR) activation. Nevertheless, the UPR pathways were differentially activated. Both cannabinoids were able to recruit the IRE branch, while only CBDV enhanced the expression of downstream effectors of the PERK pathway, namely p-eIF2α, ATF4 and CHOP. It also augmented the activity of the apoptotic initiator caspases-8 and -9, though the effector caspases-3/-7 were not activated. TRB3 expression was increased by CBDV, which may hinder apoptosis termination. Moreover, both compounds upregulated the mRNA levels of the angiogenic factors VEGFA, PGF and sFLT1, and disrupted the endothelial-like behavior of HTR-8/SVneo cells, by reducing tube formation. Thus, CBDV and CBG treatment interferes with EVTs functions and may have a negative impact in placentation and in pregnancy outcome.

Costic acid, a sesquiterpene from Nectandra barbellata (Lauraceae), attenuates sponge implant-induced inflammation, angiogenesis and collagen deposition in vivo.

Sesquiterpenes are a class of metabolites derived from plant species with immunomodulatory activity. In this study, we evaluated the effects of treatment with costic acid on inflammation, angiogenesis, and fibrosis induced by subcutaneous sponge implants in mice. One sponge disc per animal was aseptically implanted in the dorsal region of the mice and treated daily with costic acid (at concentrations of 0.1, 1, and 10 µg diluted in 10 µL of 0.5% DMSO) or 0.5% DMSO (control group). After 9 days of treatment, the animals were euthanized, and the implants collected for further analysis. Treatment with costic acid resulted in the reduction of the inflammatory parameters evaluated compared to the control group, with a decrease in the levels of inflammatory cytokines and chemokines (TNF, CXCL-1, and CCL2) and in the activity of MPO and NAG enzymes. Costic acid administration altered the process of mast cell degranulation. We also observed a reduction in angiogenic parameters, such as a decrease in the number of blood vessels, the hemoglobin content, and the levels of VEGF and FGF cytokines. Finally, when assessing implant-induced fibrogenesis, we observed a reduction in the levels of the pro-fibrogenic cytokine TGF-ß1, and lower collagen deposition. The results of this study demonstrate, for the first time, the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of costic acid in an in vivo model of chronic inflammation and reinforce the therapeutic potential of costic acid.

A1-reprogrammed mesenchymal stromal cells prime potent antitumoral responses.

Mesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis, encompassing cross-presentation assays and molecular profiling, among other cellular investigations, elucidated A1's impact on endosomal escape, reactive oxygen species production, and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma, we observe significant therapeutic potency, particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall, this study introduces a strong target for developing an antigen-adaptable vaccination platform, capable of synergizing with immune checkpoint blockers to trigger tumor regression, supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine.

Lignans Isolated from Piper truncatum Act as New Potent Antitrypanosomal Compounds.

The hexane extract from twigs of Piper truncatum Vell (Piperaceae) displayed activity against Trypanosoma cruzi and was subjected to chromatographic steps to afford six dibenzylbutyrolactolic lignans, being four knowns: cubebin (1), (-)-9α-O-methylcubebin (2), (+)-9ß-O-methylcubebinin (3) and 3,4-dimethoxy-3,4-demethylenedioxycubebin (4) as well as two new, named truncatin A (5) and B (6). Initially, in vitro activity against trypomastigotes was evaluated and compounds 1, 4 and 6 exhibited EC50 values of 41.6, 21.0 and 39.6 µM, respectively. However, when tested against amastigotes, the relevant clinical form in the chronic phase of Chagas disease, compounds 1-6 displayed activities with EC50 values ranging from 1.6 to 13.7 µM. In addition, the mammalian cytotoxicity of compounds 1-6 was evaluated against murine fibroblasts (NCTC). Compounds 2, 3 and 4 exhibited reduced toxicity against NCTC cells (CC50>200 µM), resulting in SI values of>21.9,>14.5 and>121.9, respectively. Compound 4 showed the highest potency with an SI value twice superior to that determined by the standard drug benznidazole (SI>54.6) against the intracellular amastigotes. These data suggest that lignan 4 can be considered a possible scaffold for designing a new drug candidate for Chagas disease.

An engineered Accum-E7 protein-based vaccine with dual anti-cervical cancer activity.

Worldwide prevalence of cervical cancer decreased significantly with the use of human papilloma virus (HPV)-targeted prophylactic vaccines. However, these multivalent antiviral vaccines are inert against established tumors, which leave patients with surgical ablative options possibly resulting in long-term reproductive complications and morbidity. In an attempt to bypass this unmet medical need, we designed a new E7 protein-based vaccine formulation using Accum™, a technology platform designed to promote endosome-to-cytosol escape as a means to enhance protein accumulation in target cells. Prophylactic vaccination of immunocompetent mice using the Accum-E7 vaccine (aE7) leads to complete protection from cervical cancer despite multiple challenges conducted with ascending C3.43 cellular doses (0.5-, 1.0-, and 2.0 × 106 cells). Moreover, the humoral response induced by aE7 was higher in magnitude compared with naked E7 protein vaccination and displayed potent inhibitory effects on C3.43 proliferation in vitro. When administered therapeutically to animals with pre-established C3.43 or Tal3 tumors, the vaccine-induced response synergized with multiple immune checkpoint blockers (anti-PD-1, anti-CTLA4, and anti-CD47) to effectively control tumor growth. Mechanistically, the observed therapeutic effect requires cross-presenting dendritic cells as well as CD8 T cells predominantly, with a non-negligible role played by both CD4+ and CD19+ lymphocytes. good laboratory practice (GLP) studies revealed that aE7 is immunogenic and well tolerated by immunocompetent mice with no observed adverse effects despite the use of a fourfold exceeding dose. In a nutshell, aE7 represents an ideal vaccine candidate for further clinical development as it uses a single engineered protein capable of exhibiting both prophylactic and therapeutic activity.

Lignans isolated from Piper truncatum act as new potent Antitrypanosomal compounds

The hexane extract from twigs of Piper truncatum Vell (Piperaceae) displayed activity against Trypanosoma cruzi and was subjected to chromatographic steps to afford six dibenzylbutyrolactolic lignans, being four knowns: cubebin (1), (−)-9α-O-methylcubebin (2), (+)-9β-O-methylcubebinin (3) and 3,4-dimethoxy-3,4-demethylenedioxycubebin (4) as well as two new, named truncatin A (5) and B (6). Initially, in vitro activity against trypomastigotes was evaluated and compounds 1, 4 and 6 exhibited EC50 values of 41.6, 21.0 and 39.6 μM, respectively. However, when tested against amastigotes, the relevant clinical form in the chronic phase of Chagas disease, compounds 1–6 displayed activities with EC50 values ranging from 1.6 to 13.7 μM. In addition, the mammalian cytotoxicity of compounds 1–6 was evaluated against murine fibroblasts (NCTC). Compounds 2, 3 and 4 exhibited reduced toxicity against NCTC cells (CC50>200 μM), resulting in SI values of>21.9,>14.5 and>121.9, respectively. Compound 4 showed the highest potency with an SI value twice superior to that determined by the standard drug benznidazole (SI>54.6) against the intracellular amastigotes. These data suggest that lignan 4 can be considered a possible scaffold for designing a new drug candidate for Chagas disease.

Evaluating the Antischistosomal Activity of Dehydrodieugenol B and Its Methyl Ether Isolated from Nectandra leucantha-A Preclinical Study against Schistosoma mansoni Infection.

Schistosomiasis, a parasitic disease affecting nearly 250 million individuals globally, poses a significant health challenge. With praziquantel being the sole available treatment and its limited efficacy in early stage infections, the identification of novel bioactive compounds becomes imperative. This study examines the potential of dehydrodieugenol B (1) and its methyl ether (2), derived from the leaves of the Brazilian Nectandra leucantha plant (Lauraceae), in combatting Schistosoma mansoni infections through a preclinical approach. Initially, compound 1 displayed noteworthy in vitro antiparasitic activity with an EC50 of 31.9 µM, showcasing low toxicity in mammalian cells and an in vivo animal model (Caenorhabditis elegans). Conversely, compound 2 exhibited no activity. In silico predictions pointed to favorable oral bioavailability and the absence of PAINS similarities. Subsequently, a single oral dose of 400 mg/kg of compound 1 or praziquantel was administered to mice infected with adult (patent infection) or immature parasites (prepatent infection). Remarkably, in prepatent infections, 1 resulted in a significant reduction (approximately 50%) in both worm and egg burden, while praziquantel reduced worm and egg numbers by 30%. The superior efficacy of dehydrodieugenol B (1) compared to praziquantel in premature infections holds the potential to advance the development of new molecular prototypes for schistosomiasis treatment.

Antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, on Leishmania (Leishmania) amazonensis.

BACKGROUND: Leishmaniasis, a neglected disease caused by the parasite Leishmania, is treated with drugs associated with high toxicity and limited efficacy, in addition to constant reports of the emergence of resistant parasites. In this context, snake serums emerge as good candidates since they are natural sources with the potential to yield novel drugs. OBJECTIVES: We aimed to show the antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, against Leishmania (Leishmania) amazonensis. METHODS: Promastigotes forms were exposed to γCdcPLI, and we assessed the parasite viability and cell cycle, as well as invasion and proliferation assays. FINDINGS: Despite the low cytotoxicity effect on macrophages, our data indicate that γCdcPLI has a direct effect on parasites promoting an arrest in the G1 phase and reduction in the G2/M phase at the highest dose tested. Moreover, this PLA2 inhibitor reduced the parasite infectivity when promastigotes were pre-treated. Also, we demonstrated that the γCdcPLI treatment modulated the host cell environment impairing early and late steps of the parasitism. MAIN CONCLUSIONS: γCdcPLI is an interesting tool for the discovery of new essential targets on the parasite, as well as an alternative compound to improve the effectiveness of the leishmaniasis treatment.

Intratumoral administration of unconjugated Accum™ impairs the growth of pre-established solid lymphoma tumors.

The Accum™ technology was initially designed to enhance the bioaccumulation of a given molecule in target cells. It does so by triggering endosomal membrane damages allowing endocytosed products to enter the cytosol, escaping the harsh environmental cues of the endosomal lumen. In an attempt to minimize manufacturing hurdles associated with Accum™ conjugation, we tested whether free Accum™ admixed with antigens could lead to outcomes similar to those obtained with conjugated products. Surprisingly, unconjugated Accum™ was found to promote cell death in vitro, an observation further confirmed on various murine tumor cell lines (EL4, CT-26, B16, and 4 T1). At the molecular level, unconjugated Accum™ triggers the production of reactive oxygen species and elicits immunogenic cell death while retaining its innate ability to cause endosomal damages. When administered as a monotherapy to animals with pre-established EL4 T-cell lymphoma, Accum™ controlled tumor growth in a dose-dependent manner, and its therapeutic effect relies on CD4 and CD8 T cells. Although unconjugated Accum™ synergizes with various immune checkpoint inhibitors (anti-CTLA4, anti-PD-1, or anti-CD47) at controlling tumor growth, its therapeutic potency could not be further enhanced when combined with all three tested immune checkpoint inhibitors at once due to its dependency on a specific dosing regimen. In sum, we report in this study an unprecedented new function for unconjugated Accum™ as a novel anticancer molecule. These results could pave the path for a new line of investigation aimed at exploring the pro-killing properties of additional Accum™ variants as a mean to develop second-generation anticancer therapeutics.

Resilience, Life Satisfaction and Flourishing: Mediation of Positive and Negative Affects in the Covid-19 Pandemic / Resiliencia, satisfacción con la vida y florecimiento: mediación de los afectos positivos y negativos en la pandemia de Covid-19 / Resiliência, satisfação com a vida e florescimento: mediação de afetos positivos e negativos na pandemia de Covid-19

The Covid-19 pandemic generated mental health problems, which motivated this research to test the effect of resilience, mediated by positive and negative affects, on life satisfaction and flourishing. A total of 261 Brazilian university students participated; they had an average age of 24.38 ± 7.44 years old, and 63.9 % were female. They answered an online survey at the beginning of social isolation containing scales on resilience, life satisfaction, positive and negative affects, and flourishing, in addition to sociodemographic questions. In the mediation model, the results indicated sufficiently adequate fits [B-Sχ² (328) = 698.28; p = 0.001; B-Sχ² / df = 2.13; cfi= 0.91; tli= 0.90; rmsea= 0.066 p (rmsea<0.05) = 0.001], showing a mediating effect for positive affect, which corroborates previous stu-dies, suggesting the importance of resilience and po-sitive emotions even during the Covid-19 pandemic to preserve the mental health of university students. These results can contribute to the implementation of an intervention project using positive psychology va-riables to promote mental health in university students.

El Covid-19 ha generado problemas de salud mental, lo que motivó esta investigación. El objetivo es pro-bar el efecto de la resiliencia en la satisfacción con la vida y el florecimiento, mediado por afectos positivos y negativos. Participaron 261 universitarios brasileros, el 63.9 % eran mujeres, con edad promedio de 24.38 ± 7.44 años. Al comienzo del aislamiento social, respondieron en línea cuestionarios que contenían escalas de resiliencia, satisfacción con la vida, afectos positivos y negativos, y florecimientos, además de cuestiones sociodemográficas. En el modelo de mediación, los resultados indicaron ajustes suficientemente adecuados [B-Sχ² (328) = 698.28; p = 0.001; B-Sχ² / gl = 2.13; cfi= 0.91; tli= 0.90; rmsea= 0.066; p (rmsea<0.05) = 0.001], mostrando un efecto mediador de afecto positivo, lo que corrobora estudios previos, sugiriendo la importancia de la resiliencia y de las emociones positivas durante la pandemia de Covid-19 para mantener la salud mental. Los resultados de este estudio pueden contribuir a la implementación de un proyecto de intervención utilizando variables de psicología positiva para promover la salud mental en estudiantes universitarios.

A Covid-19 gerou problemas de saúde mental, o que motivou esta pesquisa. O objetivo é testar o efeito da resiliência na satisfação com a vida e no florescimento, mediado por afetos positivos e negativos. Participaram 261 universitários brasileiros, 63.9 % eram mulhe-res, com idade média de 24.38 ± 7.44 anos. No início do isolamento social, eles responderam questionários on-line contendo escalas de resiliência, satisfação com a vida, afetos positivos e negativos e florescimento, além de questões sociodemográficas. No modelo de mediação, os resultados indicaram ajustes suficiente-mente adequados [B-Sχ² (328) = 698.28; p = 0.001; B-Sχ²/gl = 2,13; cfi= 0.91; tli= 0.90; rmsea= 0.066; p (rmsea<0.05) = 0.001], mostrando efeito mediador do afeto positivo, o que corrobora estudos anteriores, su-gerindo a importância da resiliência e das emoções posi-tivas durante a pandemia de Covid-19 para a manutenção da saúde mental. Os resultados deste estudo podem contribuir para a implementação de um projeto de inter-venção utilizando variáveis da psicologia positiva para promoção de saúde mental em estudantes universitários.

Psychometric properties of The Maastricht Upper Extremity Questionnaire: systematic review and meta-analysis / Propriedades psicométricas do The Maastricht Upper Extremity Questionnaire: revisão sistemática e meta-análise

ABSTRACT BACKGROUND AND OBJECTIVES: With the necessity to assess musculoskeletal complaints caused by computer use, The Maastricht Upper Extremity Questionnaire (MUEQ) was created, which aims to assess musculoskeletal complaints of the upper limbs, shoulder complex and cervical spine in computer users. However, there is currently no comprehensive summary in the scientific literature on the psychometric properties of the MUEQ. The objective of this study was to conduct a synthesis of all available scientific evidence that has analyzed the psychometric properties of the MUEQ. CONTENTS: This study followed the PRISMA recommendations. The bibliographic search was carried out in the following databases: MEDLINE (via VHL), Embase, LILACS (via VHL), Pubmed, PsycINFO, Scielo, Academic Search Premier, CINAHL, Rehabilitation & Sports Medicine Source, MEDLINE Complete, Web of Science CENTRAL, Scopus and SPORTDiscus. Studies that addressed the psychometric properties of the MUEQ were included, as long as they were original articles of research carried out with human beings and indexed in the databases used. The studies were selected in two phases, with two independent reviewers. A total of 6 articles were included in the analysis. The evidence based on internal structure showed acceptable results. The reliability indexes ranged from α=0.52 to α=0.84, and ICC/composite reliability > 0.70 in the analyzed studies, classified as "good" and "excellent," respectively. CONCLUSION: In general, this research found a lack of detail on the process of content validity and evidence related to external variables and the description of the sample. These problems extended to the evidence based on the internal structure and reliability of the MUEQ, which did not reach levels considered acceptable to ensure its adequacy and accuracy.

RESUMO JUSTIFICATIVA E OBJETIVOS: Com a necessidade de avaliar as queixas musculoesqueléticas ocasionadas pelo uso de computadores, foi criado o The Maastricht Upper Extremity Questionnaire (MUEQ), cujo objetivo foi avaliar as queixas musculoesqueléticas relativas aos membros superiores, ao complexo do ombro e à cervical em usuários de computadores. No entanto, atualmente não existe uma sumarização abrangente, na literatura científica, sobre as propriedades psicométricas do MUEQ. O objetivo deste estudo foi realizar uma síntese de evidências científicas disponíveis que analisaram as propriedades psicométricas do MUEQ. CONTEÚDO: Este estudo seguiu as recomendações do PRISMA. A busca bibliográfica foi realizada nas bases de dados Medline (via BVS), Embase, LILACS (via BVS), Pubmed, PsycINFO, Scielo, Academic Search Premier, CINAHL, Rehabilitation & Sports Medicine Source, MEDLINE Complete, Web of Science CENTRAL, Scopus e SPORTDiscus. Foram incluídos estudos que abordaram as propriedades psicométricas do MUEQ, desde que fossem artigos originais de pesquisas desenvolvidas com seres humanos e indexados nas bases utilizadas. A seleção dos estudos ocorreu em duas fases, com dois revisores independentes. Foram incluídos 6 artigos/publicações na análise. A evidência baseada na estrutura interna apresentou resultados aceitáveis. Os índices de fidedignidade variaram de α=0,52 a α=0,84 e ICC/confiabilidade composta foram maiores que 0,70 nos estudos selecionados, classificados como "bom" e "excelente", respectivamente. CONCLUSÃO: De um modo geral, esta pesquisa constatou a falta de detalhamento sobre o processo de validade de conteúdo e de evidências relacionados a variáveis externas e à descrição da amostra. Esses problemas se estenderam à evidência baseada na estrutura interna e à confiabilidade do MUEQ, que não alcançaram níveis considerados aceitáveis para garantir sua adequação e precisão.

Parámetros psicométricos de la escala International Fitness Scale–versión brasileña-online e impreso / Parâmetros psicométricos do International Fitness Scale –versão brasileira via on-line e impresso / Psychometric parameters of the International Fitness Scale –brazilian version -online and print

Con los avances tecnológicos, las encuestas en línea se han vuelto cada vez más comunes, lo que hace viable la evaluación del estado físico en línea. Nuestro objetivo fue evaluar la validez de construto y probar la confiabilidad de la International Fitness Scale - versión brasileña (IFIS - BRA) en el formato en línea en comparación con la versión impresa. Participaron en el estudio adolescentes (n = 294), con edades comprendidas entre 12 y 17 años, de ambos sexos. Los adolescentes respondieron la versión impresa y en línea del IFIS - BRA en dos momentos, con un intervalo de dos semanas entre aplicaciones. La confiabilidad de todos los elementos se clasificó como "sustancial". Se encontró una concordancia media para todos los ítems, clasificados como “perfecto” (69,7%) y “perfectamente aceptable” (97,1%). Podemos afirmar que la versión online del IFIS - BRA, alcanzó niveles adecuados de desempeño psicométrico, asegurando así el uso, por parte de profesionales del área de la salud e investigadores, como medio alterno confiable para la evaluación de la aptitud física de los adolescentes brasileños. (AU)

With technological advances, online surveys have become increasingly common, which makes online fitness assessment feasible. We aimed to evaluate the evidence based on the internal structure, to verify the factorial invariance of the model between the online format and the printed version (paper and pen), as well as to test the reliability of the International Fitness Scale-Brazilian version(IFIS-BRA). Participants were adolescents (n=294), aged between 12 to 17 years, of both sexes. Adolescents answered the printed and online version of the IFIS–BRA in two moments, with an interval of two weeks between applications. Reliability of all items was classified as “substantial”. A mean agreement was found for all items, classifiedas “perfect” (69.7%) and “perfectly acceptable” (97.1%). We can affirm that the online version of the IFIS–BRA, reached adequate levels of psychometric performance, thus assuring its use by health professionals and researchers as a reliable alternative means of assessing physical fitnessin Brazilian adolescents. (AU)

Com os avanços tecnológicos as pesquisas on-line tornaram-se cada vez mais comuns, o que torna a avaliação da aptidão física on-line viável. Objetivamos avaliar a evidência baseada na estrutura interna, verificar a invariância fatorial do modelo entre o formato on-line e à versão impressa (papel e caneta), bem como testar a confiabilidade do International Fitness Scale–versão brasileira (IFIS-BRA). Participaram do estudo adolescentes (n=294), na faixa etária entre 12 e 17 anos, de ambos os sexos. Os adolescentes responderam à versão impressa e on-line do IFIS–BRA em dois momentos, como intervalo de duas semanas entre as aplicações. A confiabilidade, de todos os itens, foi classificada como “substancial”. Foi encontrada uma concordância média, de todos os itens, classificada como “perfeita” (69,7%), e “perfeitamente aceitável” (97,1%). Podemos afirmar que a versão on-line do IFIS–BRA, atingiu níveis adequados de desempenho psicométrico, assim assegurando a utilização, por profissionais da área da saúde e pesquisadores, como meio alterativo confiável para a avaliação da aptidão física de adolescentes brasileiros. (AU)

Cytotoxic effects of neolignans from Saururus cernuus (Saururaceae) against prostate cancer cells.

In this study, five neolignans were isolated from Saururus cernuus-threo-dihydroguaiaretic acid (1), threo-austrobailignan-6 (2), threo-austrobailignan-5 (3), verrucosin (4), and saucernetin (5)-and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood-brain barrier and did not show any alert in PAINS (pan-assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 µmol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 µmol/L and compound 2 showed effects at 100 µmol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.

Prognostic Value of Bladder Involvement in the Outcome of Upper Tract Urothelial Carcinoma.

Accurately predicting the clinical prognosis of upper tract urothelial carcinoma (UTUC) seems crucial. We evaluated the effect of the involvement of urothelial bladder carcinoma (UBC) as a potential prognostic factor for overall survival (OS) and progression-free survival (PFS). The cohort included 115 patients with UTUC, subgrouped between January 2009 and December 2019 as follows: (1) only UTUC and (2) UTUC with synchronous or metachronous UBC (UTUC + UBC). Univariate and multivariate analyses were performed to identify independent prognostic factors for OS and PFS. Synchronous or metachronous UBC diagnosis in UTUC patients was an independent predictor of worse PFS (HR 3.326 CI 95% 1.474−7.503, p = 0.004), but it was not identified as a prognostic factor for OS (p > 0.05). Lymphovascular invasion (LVI) was associated with decreased PFS (HR 2.687 CI 95%1.172−6.163, p = 0.020) and OS (HR 4.980 CI 95%1.763−14.064, p = 0.002). This study indicates that concomitant or later UBC could predict a poor PFS, but it is not associated with a significantly worse OS in UTUC patients. The prognostic impact of LVI underlines its inclusion in the tumor staging system of UTUC.

Evidências de Validade da Sportsmanship Coaching Behaviors Scale (SCBS)para o contexto brasileiro / Evidencias de Validez de la Sportsmanship Coaching Behaviors Scale (SCBS)para el Contexto Brasileño / Validity Evidence of Sportsmanship Coaching Behaviors Scale (SCBS) for the Brazilian Context

El entrenador deportivo es considerado una de las figuras más influyentes para los atletas, siendo importante contar con medidas que puedan evaluar su comportamiento de juego limpio. En este sentido, el presente estudio pretendió adaptar y verificar la evidencia de de validez con base en la estructura interna de la Sportsmanship Coaching Behavior Scale (SCBS) para el contexto deportivo brasileño. Inicialmente, se realizaron traducciones, adaptaciones culturales y validez de contenido del SCBS, con la participación de 20 jóvenes atletas (edad promedio 15.44 ± 2.53) y cinco médicos especialistas en el campo de la psicología del deporte. La validez de contenido demostró que los ítems del instrumento eran claros y pertinentes (CVC entre 0.80 y 1.00) y que estaban evaluando las dimensiones correctas (Kappa ≥ 0.70). Para verificación de evidencia de validez con base en la estructura interna del SCBS,, participaron 302 atletas jóvenes de ambos sexos (edad media 16.1 ± 3.61; 64.7% hombres). Usando el programa estadístico FACTOR, un análisis factorial exploratorio identificó una estructura factorial con cuatro factores, explicando el 69% de la varianza total, que consta de 20 elementos distribuidos en los factores: Prioriza la victoria sobre el buen espíritu deportivo - PV (α = 0.85, ω = 0.87); Enseña buen espíritu deportivo - EBEE (α = 0.83, ω = 0.85); Es un modelo de buena deportividad- MBEE (α = 0.72, ω = 0.77), y Castiga la mala deportividad - PPEE (α = 0.70, ω = 0,74). Son necesarios futuros estúdios para confirmar esta estructura factorial y ampliar la evidencia de validez de SCBS para el contexto brasileño, llevando a cabo análisis basados ​​en variables externas, por ejemplo. (AU)

The present study aimed to adapt and verify validity evidence based on the internal structure of the Sportsmanship Coaching Behavior Scale (SCBS) for the Brazilian sports context. Initially, translations, cultural adaptations and content validity of the SCBS were performed. The content validity demonstrated that the items of the instrument were clear and relevant (CVCs between 0.80 and 1.00) and that they were evaluating the correct dimensions (Kappa ≥ 0.70). Em seguida, 302 young athletes of both sexes participated (mean age 16.1 ± 3.61). Anexploratory factor analysis using FACTOR identified a factorial structure with four factors, explaining 69% of the total variance, composed of 20 items distributed in the factors: Prioritizes winning over good sportsmanship(α = 0.85, ω = 0.87); Teaches good sportsmanship(α = 0.83, ω = 0.85); Isa model of good sportsmanship(α = 0.72, ω = 0.77); and Punishes the poor sportsmanship(α = 0.70, ω = 0.74). Future studies are necessary to confirm this factorial structure and expand the evidence of validity of SCBS for the Brazilian context, carrying out analyzes based on external variables, for example. (AU)

O estudo objetivou adaptar e verificar evidências de validade baseada na estrutura interna da Sportsmanship Coaching Behavior Scale(SCBS) para o contexto brasileiro. Os resultados indicaram que os itens estavam claros e pertinentes (CVCs entre 0.80 e 1.00) e avaliando as dimensões corretas (Kappa ≥ 0.70). Em seguida, participaram 302 jovens atletas de ambos os sexos (idade média 16,1±3,61). Uma análise fatorial exploratoria realizada no FACTOR,identificou quatro fatores, explicando 69% da variância total, composta por 20 itens distribuídos nos fatores: Prioriza a vitória acima do bom espírito esportivo(α = 0.85, ω = 0.87); Ensina o bom espírito esportivo (α = 0.83, ω = 0.85); É modelo de bom espírito esportivo(α = 0.72, ω = 0.77); e Pune o pobre espírito esportivo(α = 0.70, ω = 0.74). Estudos futuros são necessários para confirmar esta estrutura fatorial e ampliar evidênciasde validade da SCBS no contexto brasileiro. (AU)

Antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, on Leishmania (Leishmania) amazonensis

BACKGROUND Leishmaniasis, a neglected disease caused by the parasite Leishmania, is treated with drugs associated with high toxicity and limited efficacy, in addition to constant reports of the emergence of resistant parasites. In this context, snake serums emerge as good candidates since they are natural sources with the potential to yield novel drugs. OBJECTIVES We aimed to show the antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, against Leishmania (Leishmania) amazonensis. METHODS Promastigotes forms were exposed to γCdcPLI, and we assessed the parasite viability and cell cycle, as well as invasion and proliferation assays. FINDINGS Despite the low cytotoxicity effect on macrophages, our data indicate that γCdcPLI has a direct effect on parasites promoting an arrest in the G1 phase and reduction in the G2/M phase at the highest dose tested. Moreover, this PLA2 inhibitor reduced the parasite infectivity when promastigotes were pre-treated. Also, we demonstrated that the γCdcPLI treatment modulated the host cell environment impairing early and late steps of the parasitism. MAIN CONCLUSIONS γCdcPLI is an interesting tool for the discovery of new essential targets on the parasite, as well as an alternative compound to improve the effectiveness of the leishmaniasis treatment.

Antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, on Leishmania (Leishmania) amazonensis

BACKGROUND Leishmaniasis, a neglected disease caused by the parasite Leishmania, is treated with drugs associated with high toxicity and limited efficacy, in addition to constant reports of the emergence of resistant parasites. In this context, snake serums emerge as good candidates since they are natural sources with the potential to yield novel drugs. OBJECTIVES We aimed to show the antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, against Leishmania (Leishmania) amazonensis. METHODS Promastigotes forms were exposed to γCdcPLI, and we assessed the parasite viability and cell cycle, as well as invasion and proliferation assays. FINDINGS Despite the low cytotoxicity effect on macrophages, our data indicate that γCdcPLI has a direct effect on parasites promoting an arrest in the G1 phase and reduction in the G2/M phase at the highest dose tested. Moreover, this PLA2 inhibitor reduced the parasite infectivity when promastigotes were pre-treated. Also, we demonstrated that the γCdcPLI treatment modulated the host cell environment impairing early and late steps of the parasitism. MAIN CONCLUSIONS γCdcPLI is an interesting tool for the discovery of new essential targets on the parasite, as well as an alternative compound to improve the effectiveness of the leishmaniasis treatment.

Idade, ansiedade, estresse e depressão associados a problemas alimentares durante a Covid-19 / Age, anxiety, stress, and depression associated with eating problems during Covid-19 / Edad, ansiedad, estrés y depresión asociados con problemas alimentarios durante la Covid-19

Este estudio transversal basado en la web investigó la asociación de edad, sexo y los síntomas de depre-sión, ansiedad y estrés con los problemas alimentarios (PAs) en adultos brasileños durante la pandemia del coronavirus disease 2019 (COVID-19). Se reclutó un total de 715 participantes (237 hombres y 478 mujeres) de todas las regiones de Brasil. Los instrumentos utilizados fueron la Escala de Depresión, Ansiedad y Estrés ­ 21 (Depression, Anxiety and Stress Scale-21 [DASS-21]) y el Teste de Actitudes Alimentarias ­ 26 (Eating Attitudes Test ­ 26 [EAT-26]). El análisis de los datos se realizó mediante la prueba t independiente, la correlación de Pearson y el análisis de regresión múltiple. La regresión múltiple mostró que la puntua-ción total en DASS-21 contribuyó positivamente a los PAs en hombres (ß = 0.17, p < 0.01) y mujeres (ß = 0.22, p < 0.001). Los datos mostraron que las mujeres tenían más síntomas en todas las variables (p < 0.001). Los síntomas de DASS-21 se asocian con conductas de riesgo para PAs en adultos brasileños durante la pandemia de COVID-19

Este estudo transversal baseado na web investigou a associação de idade, sexo e sintomas de depressão, ansiedade e estresse com problemas alimentares (PAs) em adultos brasileiros durante a pandemia da co-ronavirus disease 2019 (Covid-19). Um total de 715 participantes (237 homens e 478 mulheres) foram recru-tados em todas as regiões do Brasil. Os instrumentos utilizados foram a Escala de Depressão, Ansiedade e Estresse ­ 21 (Depression, Anxiety and Stress Scale-21 [Dass-21]) e o Teste de Atitudes Alimentares ­ 26 (Eating Attitudes Test ­ 26 [EAT-26]). A análise dos dados foi realizada por meio de teste t independente, correlação de Pearson e análise de regressão múltipla. A regressão múltipla mostrou que a pontuação total na Dass-21 contribuiu positivamente para PAs em homens (ß = 0,17, p < 0,01) e mulheres (ß = 0,22, p < 0,001). Os dados mostraram que as mulheres apresentaram mais sintomas em todas as variáveis (p < 0.001). Assim, os sintomas da Dass-21 foram associados a comportamentos de risco para PAs em adultos brasileiros durante a pandemia da Covid-19

This cross-sectional web-based study investigated the association of age, gender, and symptoms of depression, anxiety, and stress with eating problems in Brazilian adults during the COVID-19 pandemic. A total of 715 participants (237 men and 478 women) were recruited from all regions of Brazil. The instruments used were the Depression, Anxiety and Stress Scale-21 (DASS-21) and the Eating Attitudes Test ­ 26 (EAT-26). Data analysis was conducted through the independent t test, Pearson's correlation, and multiple regression analysis. Multiple regression showed that DASS total score made the largest positive contribution to EP for men (ß = .17, p < .01) and women (ß = .22, p < .001). The data showed significant differences between men and women for all variables (p < .001), indicating that women presented more symptoms in all variables. Our findings show that symptoms of depression, anxiety, and stress were associated whit risky behavior for EP in Brazilian adults during the COVID-19 pandemic.

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni.

Schistosomiasis, a parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, especially in developing countries. Despite the significant economic and public health consequences, only one drug is currently available for treatment of schistosomiasis, praziquantel. Thus, there is an urgent demand for new anthelmintic agents. Based on our continuous studies involving the chemical prospection of floristic biodiversity aiming to discover new bioactive compounds, this work reports the in vitro antiparasitic activity against Schistosoma mansoni adult worms of neolignans threo-austrobailignan-6 and verrucosin, both isolated from Saururus cernuus L. (Saururaceae). These neolignans showed a significant in vitro schistosomicidal activity, with EC50 values of 12.6-28.1 µM. Further analysis revealed a pronounced reduction in the number of S. mansoni eggs. Scanning electron microscopy analysis revealed morphological alterations when schistosomes were exposed to either threo-austrobailignan-6 or verrucosin. These relevant antischistosomal properties were accompanied by low cytotoxicity potential against the animal (Vero) and human (HaCaT) cell lines, resulting in a high selectivity index. Considering the promising chemical and biological properties of threo-austrobailignan-6 and verrucosin, this research should be of interest to those in the area of neglected diseases and in particular antischistosomal drug discovery.