Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Corrigendum: Enhancing performance: unveiling the physiological impact of submaximal and supramaximal tests on mixed martial arts athletes in the -61 kg and -66 kg weight divisions.

[This corrects the article DOI: 10.3389/fphys.2023.1257639.].

Understanding the Personal Barriers of Elderly Patients for Carrying out Teleconsultations During COVID-19 Pandemic: An Observational Study.

Introduction: The expansion of telehealth during the COVID-19 pandemic may widen digital divides. It is essential to better understand the use of telehealth by the elderly population for the development of equitable telehealth tools. Objectives: This study aimed to describe the socioeconomic, clinical, and functional characteristics of elderly patients who were supported by a COVID-19 telehealth program. It also investigated the characteristics associated with the need for support for teleconsultations, hospitalization, and mortality. Methods: >Elderly patients supported by the TeleCOVID-MG program, between June 2020 and December 2021, in two Brazilian municipalities (Divinópolis and Teófilo Otoni) were included. Data were collected from electronic records and through phone call interviews. Descriptive and multivariable analyses were performed. Results: Among the 237 patients,121 were women (51.1%), mean age was 70.8 years (±8.5), 121 (51.1%) had less than 4 years of formal education, 123 patients (51.9%) had two or more comorbidities, and 68 (29%) reported functional decline in activities of daily life. Age greater than 80 years (odds ratio [OR]:4.68, 95% confidence interval [CI] 1.93-11.37, p = 0.001), lower educational level (OR:3.85, 95% CI 1.8-8.21, p < 0.001), hearing (OR:5.46, 95% CI: 1.24-11.27, p = 0.019), and visual (OR:15.10, 95% CI: 3.21-71.04, p = 0.001) impairments were characteristics associated with the need for support for teleconsultations. The need for support was associated with hospitalization and mortality (OR:5.08, 95% CI: 2.35-10.98, p < 0.001). Conclusion: Older age, lower educational level, and sensory impairments may compromise the effectiveness and the safety of the telehealth assistance to the elderly population. Functional evaluation and frailty screening should be considered part of the telehealth assessment of elderly patients.

Memory complaint in a middle-income country: a four-year longitudinal study in a cohort with low-education.

BACKGROUND: Memory complaints are frequent in older adults and are associated with higher risk of cognitive decline. OBJECTIVE: To investigate the functional outcome of individuals with memory complaints followed up at primary care centers. METHODS: Data were collected between 2016 e 2020 in primary health care centers in Brazil. Patients underwent the Brief Cognitive Screening Battery, and the Functional Activities Questionnaire. RESULTS: The initial sample (2016) comprised 91 individuals classified into those with subjective cognitive decline (SCD, n = 15), mild cognitive impairment (MCI, n = 45), or dementia (n = 31). During follow-up, 8 individuals (8.8% of the initial sample) died and 26 (28.5% of the initial sample) were not found. Fifty-seven participants underwent clinical reassessment. Of 15 individuals with SCD, 7 were not found (46.7%), 4 (26.7%) progressed to MCI, and 4 (26.7%) remained stable. Of 45 individuals with MCI, 11 were not found (24.4%), 2 (4.4%) died, 6 (13.4%) progressed to dementia, 12 (26.7%) regressed to SCD, and 14 (31.1%) remained stable. Of 31 individuals with dementia, 8 were not found (25.8%), 6 (19.4%) died, 2 (6.5%) regressed to SCD, 7 (22.6%) regressed to MCI, and 8 remained stable (25.8%). Clinical improvement was due to the treatment of reversible causes, such as B12 hypovitaminosis and mood disorders. Older age, lower Mini-Mental State Examination, and higher scores of memory complaint, but not the use of benzodiazepines and of proton pump inhibitors, were predictors of functional status. CONCLUSION: Despite their limits (short sample size, missing data), these results support the idea that adequate screening, follow-up, and treatment of reversible causes of dementia in primary care are essential.

ANTECEDENTES: Queixas de memória são frequentes em idosos e estão associadas ao maior risco de declínio cognitivo. OBJETIVO: Investigar o desfecho funcional de indivíduos com queixas de memória acompanhados em centros atenção primária. MéTODOS: Os dados foram coletados entre 2016 e 2020 em centros de atenção primária à saúde no Brasil. Os pacientes foram submetidos à Bateria Cognitiva Breve e ao Questionário de Atividades Funcionais. RESULTADOS: A amostra inicial (2016) foi composta por 91 indivíduos, classificados como tendo declínio cognitivo subjetivo (DCS, n = 15), comprometimento cognitivo leve (CCL, n = 45), ou demência (n = 31). Durante o seguimento, 8 indivíduos (8,8% da amostra inicial) faleceram e 26 (28,5% da amostra inicial) não foram encontrados. Cinquenta e sete participantes foram submetidos à reavaliação clínica. Dos 15 indivíduos com DCS, 7 não foram encontrados (46,7%), 4 (26,7%) declinaram para CCL e 4 (26,7%) permaneceram estáveis. Dos 45 indivíduos com CCL, 11 não foram encontrados (24,4%), 2 (4,4%) morreram, 6 (13,4%) declinaram para demência, 12 (26,7%) evoluíram para DCS e 14 (31,1%) permaneceram estáveis. Dos 31 indivíduos com demência, 8 não foram encontrados, (25,8%), 6 (19,4%) morreram, 2 (6,5%) evoluíram para DCS e 7 (22,6%) para CCL; e 8 permaneceram estáveis (25,8%). A melhora clínica deveu-se ao tratamento de causas reversíveis, como hipovitaminose B12 e transtornos de humor. A idade avançada, a baixa pontuação no Mini-Exame do Estado Mental e os escores de queixa de memória mais altos, mas não o uso de benzodiazepínicos e inibidores da bomba de prótons, foram preditores de declínio funcional. CONCLUSãO: Apesar de suas limitações (amostra pequena, dados ausentes), esses resultados corroboram que a triagem adequada, o acompanhamento e o tratamento de causas reversíveis de demência na atenção primária são essenciais.

Effects of primary health care and socioeconomic aspects on the dispersion of COVID-19 in the Brazilian Northeast: Ecological study of the first pandemic wave.

BACKGROUND: The COVID-19 pandemic has had a negative impact on socioeconomic and public health conditions of the population. AIM: To measure the temporal evolution of COVID-19 cases in cities near the countryside outside metropolitan areas of northeastern Brazil and the impact of the primary care organization in its containment. METHODS: This is a time-series study, based on the first three months of COVID-19 incidence in northeastern Brazil. Secondary data were used, the outcome was number of COVID-19 cases. Independent variables were time, coverage and quality score of basic health services, and demographic, socioeconomic and social isolation variables. Generalizable Linear Models with first order autoregression were applied. RESULTS: COVID-19 spreads heterogeneously in cities near the countryside of Northeastern Brazilian cities, showing associations with the city size, socioeconomic and organizational indicators of services. The Family Health Strategy seems to mitigate the speed of progression and burden of the disease, in addition to measures such as social isolation and closure of commercial activities. CONCLUSION: The spread of COVID-19 reveals multiple related factors, which require coordinated intersectoral actions in order to mitigate its problems, especially in biologically and socially vulnerable populations.

Applications of Mass Spectrometry in the Characterization, Screening, Diagnosis, and Prognosis of COVID-19.

Mass spectrometry (MS) is a powerful analytical technique that plays a central role in modern protein analysis and the study of proteostasis. In the field of advanced molecular technologies, MS-based proteomics has become a cornerstone that is making a significant impact in the post-genomic era and as precision medicine moves from the research laboratory to clinical practice. The global dissemination of COVID-19 has spurred collective efforts to develop effective diagnostics, vaccines, and therapeutic interventions. This chapter highlights how MS seamlessly integrates with established methods such as RT-PCR and ELISA to improve viral identification and disease progression assessment. In particular, matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) takes the center stage, unraveling intricate details of SARS-CoV-2 proteins, revealing modifications such as glycosylation, and providing insights critical to formulating therapies and assessing prognosis. However, high-throughput analysis of MALDI data presents challenges in manual interpretation, which has driven the development of programmatic pipelines and specialized packages such as MALDIquant. As we move forward, it becomes clear that integrating proteomic data with various omic findings is an effective strategy to gain a comprehensive understanding of the intricate biology of COVID-19 and ultimately develop targeted therapeutic paradigms.

Memory complaint in a middle-income country: a four-year longitudinal study in a cohort with low-education / Queixa de memória na comunidade em um país de renda média: um estudo longitudinal de quatro anos em uma coorte de baixa escolaridade

Abstract Background Memory complaints are frequent in older adults and are associated with higher risk of cognitive decline. Objective To investigate the functional outcome of individuals with memory complaints followed up at primary care centers. Methods Data were collected between 2016 e 2020 in primary health care centers in Brazil. Patients underwent the Brief Cognitive Screening Battery, and the Functional Activities Questionnaire. Results The initial sample (2016) comprised 91 individuals classified into those with subjective cognitive decline (SCD, n = 15), mild cognitive impairment (MCI, n = 45), or dementia (n = 31). During follow-up, 8 individuals (8.8% of the initial sample) died and 26 (28.5% of the initial sample) were not found. Fifty-seven participants underwent clinical reassessment. Of 15 individuals with SCD, 7 were not found (46.7%), 4 (26.7%) progressed to MCI, and 4 (26.7%) remained stable. Of 45 individuals with MCI, 11 were not found (24.4%), 2 (4.4%) died, 6 (13.4%) progressed to dementia, 12 (26.7%) regressed to SCD, and 14 (31.1%) remained stable. Of 31 individuals with dementia, 8 were not found (25.8%), 6 (19.4%) died, 2 (6.5%) regressed to SCD, 7 (22.6%) regressed to MCI, and 8 remained stable (25.8%). Clinical improvement was due to the treatment of reversible causes, such as B12 hypovitaminosis and mood disorders. Older age, lower Mini-Mental State Examination, and higher scores of memory complaint, but not the use of benzodiazepines and of proton pump inhibitors, were predictors of functional status. Conclusion Despite their limits (short sample size, missing data), these results support the idea that adequate screening, follow-up, and treatment of reversible causes of dementia in primary care are essential.

Resumo Antecedentes Queixas de memória são frequentes em idosos e estão associadas ao maior risco de declínio cognitivo. Objetivo Investigar o desfecho funcional de indivíduos com queixas de memória acompanhados em centros atenção primária. Métodos Os dados foram coletados entre 2016 e 2020 em centros de atenção primária à saúde no Brasil. Os pacientes foram submetidos à Bateria Cognitiva Breve e ao Questionário de Atividades Funcionais. Resultados A amostra inicial (2016) foi composta por 91 indivíduos, classificados como tendo declínio cognitivo subjetivo (DCS, n = 15), comprometimento cognitivo leve (CCL, n = 45), ou demência (n = 31). Durante o seguimento, 8 indivíduos (8,8% da amostra inicial) faleceram e 26 (28,5% da amostra inicial) não foram encontrados. Cinquenta e sete participantes foram submetidos à reavaliação clínica. Dos 15 indivíduos com DCS, 7 não foram encontrados (46,7%), 4 (26,7%) declinaram para CCL e 4 (26,7%) permaneceram estáveis. Dos 45 indivíduos com CCL, 11 não foram encontrados (24,4%), 2 (4,4%) morreram, 6 (13,4%) declinaram para demência, 12 (26,7%) evoluíram para DCS e 14 (31,1%) permaneceram estáveis. Dos 31 indivíduos com demência, 8 não foram encontrados, (25,8%), 6 (19,4%) morreram, 2 (6,5%) evoluíram para DCS e 7 (22,6%) para CCL; e 8 permaneceram estáveis (25,8%). A melhora clínica deveu-se ao tratamento de causas reversíveis, como hipovitaminose B12 e transtornos de humor. A idade avançada, a baixa pontuação no Mini-Exame do Estado Mental e os escores de queixa de memória mais altos, mas não o uso de benzodiazepínicos e inibidores da bomba de prótons, foram preditores de declínio funcional. Conclusão Apesar de suas limitações (amostra pequena, dados ausentes), esses resultados corroboram que a triagem adequada, o acompanhamento e o tratamento de causas reversíveis de demência na atenção primária são essenciais.

Some new insights into the biological activities of carboxymethylated polysaccharides from Lasiodiplodia theobromae.

BACKGROUND: Carboxymethylated Lasiodiplodan (LaEPS-C), Lasiodiplodia theobromae ß-glucan exopolysaccharide derivative, has a well-known range of biological activities. Compared to LaEPS-C, its fractions, Linear (LLaEPS-C) and Branched (BLaEPS-C), have biological potentialities scarcely described in the literature. So, in this study, we investigate the immunomodulatory, antiviral, antiproliferative, and anticoagulant activities of LLaEPS-C and BLaEPS-C and compare them to the LaEPS-C. METHODS: LaEPS was obtained from L. theobromae MMBJ. After carboxymethylation, LaEPS-C structural characteristics were confirmed by Elementary Composition Analysis by Energy Dispersive X-Ray Detector (EDS), Fourier Transform Infrared (FTIR), and Nuclear Magnetic Resonance (NMR). The immunomodulatory activity on cytokine secretion was evaluated in human monocyte-derived macrophage cultures. The antiviral activity was evaluated by Hep-2 cell viability in the presence or absence of hRSV (human respiratory syncytial virus). In vitro antiproliferative activity was tested by sulforhodamine B assay. The anticoagulant activity was determined by APTT (Activated Partial Thromboplastin Time) and PT (Prothrombin Time). RESULTS: LaEPS-C showed low macrophage cell viability only at 100 µg/mL (52.84 ± 24.06, 48 h), and LLaEPS-C presented no effect. Conversely, BLaEPS-C showed cytotoxicity from 25 to 100 µg/mL (44.36 ± 20.16, 40.64 ± 25.55, 33.87 ± 25.16; 48 h). LaEPS-C and LLaEPS-C showed anti-inflammatory activity. LaEPS-C presented this at 100 µg/mL (36.75 ± 5.53, 48 h) for IL-10, and LLaEPS-C reduces TNF-α cytokine productions at 100 µg/mL (18.27 ± 5.80, 48 h). LLaEPS-C showed an anti-hRSV activity (0.7 µg/ml) plus a low cytotoxic activity for Hep-2 cells (1.4 µg/ml). LaEPS-C presented an antiproliferative activity for NCI-ADR/RES (GI50 65.3 µg/mL). A better PT was achieved for LLaEPS-C at 5.0 µg/mL (11.85 ± 0.87s). CONCLUSIONS: These findings demonstrated that carboxymethylation effectively improves the biological potential of the LaEPS-C and their fractions. From those polysaccharides tested, LLaEPS provided the best results with low toxicity for anti-inflammatory, antiviral, and anticoagulant activities.

Assessment of the correlation between mandibular radiomorphometric patterns and dual-energy X-ray absorptiometry measurements for screening bone mineral density.

The objective of this study was to investigate the correlation between scores for femoral and lumbar spine bone mineral density (dual-energy X-ray absorptiometry [DXA]) and visual, qualitative mandibular bone pattern assess¬ments (mandibular cortical index, trabecular bone pattern, and visual mandibular cortical width) as well as age and body mass index. Three trained observers evaluated 200 panoramic radiographs and 200 femoral and lumbar spine DXA measurements from 100 male and 100 female participants. The κ test showed an acceptable agreement among observers (0.73; P = 0.003). The Shapiro-Wilk test revealed that the variables were not normally distributed, so the Spearman correlation test was used. The mean age of the sample was 60.7 (13.9) years, and 86.0% of the patients were White. There were inverse correlations between the mandibular cortical index and the spine T-score in men, women, and the total sample as well as between the spine Z-score in the total sample. An inverse correlation was observed between the trabecular bone pattern and the spine T- and Z-scores in women and the total sample. The results also showed inverse correlations between the visual mandibular cortical width and all parameters analyzed in men, women, and the total sample except for the femur T-score and spine T- and Z-scores in men. Body mass index was correlated with all DXA parameters. Age was inversely correlated with femur T-scores in men and women but not with spine DXA values in men. The results suggest that qualitative assessments of radiomorphometric patterns on panoramic radiographs correlate with DXA values and therefore are suitable for screening patients at risk of developing low bone mineral density.

Monitoring health as an opportunity to categorize preventative and early-treatment actions in a self-care journey: our experience with a Healthcare Magenta Scorecard.

Background: Applying a digital health intervention to measure health and wellbeing status offers opportunities to guide and augment healthcare and promotion. In our scenario, we consider mainly digital-native patients and present an evaluation of a new Healthcare Magenta Scorecard towards this end. Methods: Grounded in the six domains of health and promotion (physical activity; sleep quality; nutrition; habits/lifestyle; mental health; quality of life) we developed a health Magenta Scorecard (Magenta Score), a mobile based Electronic Patient Reported Outcomes (e-PRO) that measures patients health and wellbeing every 3-5 months. The Magenta Scorecard was derived from previously published evidence-based instruments. We collected data as patients were onboarded into our healthcare system (T0 and T1, time span between measurements, 141 days) and provided correlations among our domains of care. Results: A total of 1,622 participants responded to T0 and T1 our Magenta Scorecard. Participants mean age was 31.3 [95% confidence interval (CI): 31.2-31.5] years and female (63.4%). Fifty-five percent (n=892) of our sample were categorized as relating to Health and Wellbeing promotion, 8.5% (n=138) disease management, 35.7% (n=579) self-care care support and only 0.8% (n=13) pertained to case management. From our care coordination guided approach, our Magenta Scorecards reported mean improvement across the study cohort of 26 ± standard deviation (SD) points, from T0 (649, 95% CI: 643-656) to T1 (675, 95% CI: 668-682). Our Magenta Scorecard domains had significant, albeit weak spearman correlations. Conclusions: We demonstrated our Magenta Scorecard rationale and its guided approach. The Magenta Scorecard displayed adequate responsiveness and was significantly correlated across all of the domains investigated. Further prospective research is needed to validate our results in the long term.

LC-MS Analysis and Antifungal Activity of Turnera subulata Sm.

Fungi of the Candida genus are responsible for invasive candidiasis, which affects people all over the world and has high mortality rates. This is due to their virulence factors, which give them great resistance and pathogenicity. In addition, the emergence of multidrug-resistant strains makes it difficult to treat these infections. In this way, natural products have emerged as an alternative to standard drugs, where plants known for their medicinal properties such as Turnera subulata become attractive to research. The present work aimed to analyze the ethanol extract of Turnera subulata leaves against standard strains of Candida albicans, Candida krusei and Candida tropicalis using broth microdilution techniques. The identification of the compounds in T. subulata leaves by LC-MS revealed the presence of a wide variety of substances such as carboxylic acids and terpenes, with flavonoids and fatty acids being more evident. The antifungal assays showed that the extract was not able to inhibit the growth of the tested strains at concentrations with a clinical relevance. However, at higher concentrations, it was able to inhibit the fungal dimorphism of C. albicans and C. tropicalis. It is possible that the T. subulata extract has potential as an inhibitor of fungal virulence factors without affecting the cell viability. Further research should be carried out in order to assess its inhibitory potential for other fungal virulence factors.

Cancer Stem Cells and Chemoresistance in Ewing Sarcoma.

Resistance to chemotherapy poses a major challenge for cancer treatment. Reactivating a stem cell program resembling that seen in embryonic development can lead cancer cells to acquire a stem-cell phenotype characterized by expression of stemness genes, pluripotency, high self-renewal ability, and tumor-initiating capability. These cancer stem cells (CSCs) are usually resistant to anticancer drugs and are likely involved in treatment failure in many cancer types. Ewing sarcoma (ES) is a pediatric cancer type typically resulting from a typical genetic alteration affecting bone or soft tissues. Despite advances in treatment, survival prognostic remains poor for patients with refractory or recurrent disease. Here, we review the increasing evidence indicating that ES tumors contain a CSC subpopulation expressing stem cell genes, including BM1, OCT3/4, NANOG, and SOX2, that plays a role in resistance to drug treatment, and current experimental strategies that successfully counteract chemoresistance mediated by CSCs in ES.

Toll-like Receptors 2, 3, and 4 in Childhood Acute Lymphocytic Leukemia / Receptores do Tipo Toll 2, 3 e 4 em Leucemia Linfocítica Aguda Infanti / Receptores Tipo Toll 2, 3 y 4 en la Leucemia Linfocítica Aguda Infantil

Introduction: Acute lymphocytic leukemia (ALL) is the most common cancer type in children and accounts for 80% of pediatric leukemias. Novel targets are necessary to improve survival rates for refractory and relapsed disease. There is accumulating evidence that Toll-like Receptor (TLR) signaling may be associated with outcomes in cancer however little has been described in leukemias. Objective: Analyze the expression and contribution of TLRs to the development of childhood ALL. Method: To evaluate the effect of specific TLR2, TLR3, and TLR4 agonists on the viability and proliferation of childhood ALL cell lines and to analyzed the mRNA expression of these types of TLR in bone marrow blast cells at diagnosis (D0) and induction (D35) in pediatric ALL patients. Results: Treatment with TLR agonists reduced the cell viability of Jurkat and Sup-B15 cell lines. Cell cycle distribution in Jurkat was altered, reducing polyploid cells and increasing sub-G1 phase. Conclusion: It was observed that the cell viability of the cell lines responded with different sensitivities to the agonists. The polyploidy associated with tumor malignancy was reduced, in addition to the increase in the sub-G1 phase indicating an increase in apoptosis. There were differences in TLR expression at D35 between groups at risk of the disease. Patients with high expression of TLR2 and low expression of TLR4 on D35 demonstrated a worse prognosis

Introdução: A leucemia linfoblástica aguda (LLA) é o tipo de câncer mais comum em crianças e representa 80% das leucemias pediátricas. Novos alvos são necessários para melhorar as taxas de sobrevivência para doença refratária e recidivante. Há evidências acumuladas de que a sinalização de receptores Toll-Like (TLR) pode estar associada a resultados em câncer, embora pouco tenha sido descrito em leucemias. Objetivo: Analisar a expressão e a contribuição dos TLR para o desenvolvimento da LLA infantil. Método: Avaliar o efeito de agonistas específicos de TLR2, TLR3 e TLR4 na viabilidade e proliferação de linhagens celulares de LLA infantil e analisar a expressão do RNAm desses tipos de TLR em células blásticas da medula óssea no diagnóstico (D0) e na indução (D35) em pacientes LLA pediátricos. Resultados: O tratamento com agonistas de TLR reduziu a viabilidade celular das linhagens celulares Jurkat e Sup-B15. A distribuição do ciclo celular em Jurkat foi alterada, reduzindo as células poliploides e aumentando a fase sub-G1. Houve aumento na expressão dos receptores entre D0 e D35 em amostras de pacientes. Conclusão: Observou-se que a viabilidade celular das linhagens celulares respondeu com diferentes sensibilidades aos agonistas. A poliploidia associada à malignidade tumoral foi reduzida, além de o aumento da fase sub-G1 indicar aumento da apoptose. Houve diferenças na expressão de TLR em D35 entre os grupos de risco da doença. Pacientes com alta expressão de TLR2 e baixa expressão de TLR4 no D35 demonstraram pior prognóstico.

Introducción: La leucemia linfocítica aguda (LLA) es el tipo de cáncer más común en los niños y representa el 80 % de las leucemias pediátricas. Se necesitan nuevos objetivos para mejorar las tasas de supervivencia de la enfermedad refractaria y recidivante. Cada vez hay más pruebas de que la señalización del receptor Toll-Like (TLR) puede estar asociada con resultados en el cáncer, aunque se ha descrito poco en las leucemias. Objetivo: Analizar la expresión y la contribución de los TLR al desarrollo de la LLA infantil. Método: Evaluar el efecto de agonistas específicos de TLR2, TLR3 y TLR4 en la viabilidad y proliferación de líneas celulares de LLA infantil y analizar la expresión de ARNm de estos tipos de TLR en células blásticas de médula ósea en el momento del diagnóstico (D0) y la inducción (D35) en pacientes pediátricos con LLA. Resultados: El tratamiento con agonistas de TLR redujo la viabilidad celular de las líneas celulares Jurkat y sup-B15. Se alteró la distribución del ciclo celular en Jurkat, reduciendo las células poliploides y aumentando la fase sub-G1. Hubo un aumento en la expresión de los receptores entre D0 y D35 en muestras de pacientes. Conclusión: Se observó que la viabilidad celular de las líneas celulares respondía con distintas sensibilidades a los agonistas. Se redujo la poliploidía asociada con la malignidad del tumor, además de un aumento de la fase sub-G1 que indica un aumento de la apoptosis. Hubo diferencias en la expresión de TLR en D35 entre los grupos de riesgo de enfermedad. Los pacientes con alta expresión de TLR2 y baja expresión de TLR4 en D35 mostraron peor pronóstico

Trk Inhibition Reduces Tumorsphere Formation and Changes Expression of Stemness Markers in SK-ES-1 Ewing Sarcoma Cells / Inibição de Trk Reduz a Formação de Tumoresferas e Modifica a Expressão de Marcadores Tronco Tumorais em Células de Sarcoma de Ewing SK-ES-1 / Inhibición de Trk Reduce la Formación de Esferoides Tumorales y Cambia la Expresión de Marcadores de Stemness en Células de Sarcoma de Ewing SK-ES-1

Introduction: Ewing sarcoma (ES) is a highly aggressive type of childhood cancer characterized by a chromosomal translocation resulting in fusions between the gene encoding EWS RNA Binding Protein 1 (EWSR1) and one gene of the ETS family, most frequently FLI-1, resulting in the EWS-FLI1 aberrant transcription factor. ES tumors can contain a subpopulation of cells showing cancer stem cell (CSC) features, which express stemness markers including CD133, OCT4 (Octamer-binding transcription factor 4), and NANOG, and display capacity to form tumorspheres likely enriched in CSCs. Neurotrophin (NT) receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) may play a role in stimulating ES progression, but their possible role in CSCs remains unknown. Objective: To verify the effect of Trks inhibition on the formation of tumorspheres as well as the gene expression of stem markers. Method: The cells were dissociated and the formation of spheres was induced with supplemented culture medium and the K252a treatment was performed. After RNA extraction, mRNA expression levels of target genes Prom1 (CD133), OCT4 (POU5F1), SOX2, and Musashi-1 (MSI1) were analyzed by qPCR. Results: The pan-Trk inhibitor K252a (100 or 500 mM) hindered tumorsphere formation in human SK-ES-1 ES cell cultures. K252a also reduced mRNA expression of Prom1 (CD133-coding gene) while enhancing expression of OCT4. No changes in mRNA levels of SOX2 or Musashi-1 were observed. Conclusion: These findings provide the first evidence suggesting that Trk activity can influence stemness in ES cells

Introdução: O sarcoma de Ewing (SE) é um tipo altamente agressivo de câncer infantil caracterizado por uma translocação cromossômica que resulta em fusões entre o gene que codifica a proteína de ligação a RNA EWS 1 (EWSR1) e um gene da família ETS, mais frequentemente o FLI-1, resultando no fator de transcrição aberrante EWS-FLI1. Os tumores de SE podem conter uma subpopulação de células com características de células-tronco tumorais (CTT), que expressam marcadores de pluripotência como CD133, OCT4 e NANOG, e têm a capacidade de formar esferas tumorais provavelmente enriquecidas em CTT. Os receptores de neurotrofinas (NT) da família de receptor de quinase de tropomiosina (Trk) (TrkA, TrkB e TrkC) podem desempenhar um papel no estímulo à progressão do SE, mas seu possível papel nas CTT permanece desconhecido. Objetivo: Verificar o efeito da inibição dos Trk na formação de tumoresferas, bem como na expressão gênica de marcadores de pluripotência. Método: As células foram dissociadas, a formação de esferas com meio de cultura suplementado foi induzida e realizou-se o tratamento com K252a. Após a extração de RNA, os níveis de expressão de mRNA dos genes-alvo Prom1 (CD133), OCT4 (POU5F1), SOX2 e Musashi-1 (MSI1) foram analisados por qPCR. Resultados: O inibidor pan-Trk K252a (100 ou 500 mM) impediu a formação de esferas tumorais em culturas de células de SE humanas SK-ES-1. O K252a também reduziu a expressão de mRNA de Prom1 (o gene que codifica CD133), enquanto aumentou a expressão de OCT4. Não foram observadas mudanças nos níveis de mRNA de SOX2 ou Musashi-1. Conclusão: Essas descobertas fornecem as primeiras evidências, sugerindo que a atividade dos Trk possa influenciar a pluripotência nas células de SE

Introducción: El sarcoma de Ewing (SE) es un tipo de cáncer infantil altamente agresivo caracterizado por una translocación cromosómica que resulta en fusiones entre el gen que codifica la proteína de unión a RNA EWS 1 (EWSR1) y un gen de la familia ETS, más frecuentemente FLI-1, lo que resulta en el factor de transcripción aberrante EWS-FLI1. Los tumores del SE pueden contener una subpoblación de células que presentan características de células madre cancerosas (CMC), las cuales expresan marcadores de pluripotencia como CD133, OCT4 y NANOG, y muestran la capacidad de formar esferas tumorales probablemente enriquecidas en CMC. Los receptores de neurotrofinas (NT) de la familia del receptor de quinasa de tropomiosina (Trk) (TrkA, TrkB y TrkC) podrían desempeñar un papel en el estímulo de la progresión del SE, pero su posible papel en las CMC aún es desconocido. Objetivo: Verificar el efecto de la inhibición de los Trk en la formación de esferoides tumorales, así como en la expresión génica de marcadores de pluripotencia. Método: Las células fueron disociadas e inducidas a formar esferas con un medio de cultivo suplementado y se realizó el tratamiento con K252a. Después de la extracción de ARN, los niveles de expresión de ARNm de los genes objetivo Prom1 (CD133), OCT4 (POU5F1), SOX2 y Musashi-1 (MSI1) se analizaron mediante qPCR. Resultados: El inhibidor pan-Trk K252a (100 o 500 mM) evitó la formación de esferas tumorales en cultivos de células de SE humanas SK-ES-1. El K252a también redujo la expresión de ARNm de Prom1 (el gen que codifica CD133), mientras que aumentaba la expresión de OCT4. No se observaron cambios en los niveles de ARNm de SOX2 o Musashi-1. Conclusión: Estos hallazgos proporcionan las primeras evidencias que sugieren que la actividad de Trk puede influir en la pluripotencia en las células del SE

Enhancing performance: unveiling the physiological impact of submaximal and supramaximal tests on mixed martial arts athletes in the -61 kg and -66 kg weight divisions.

This study delves into the intricate details of Mixed Martial Arts (MMA) by examining key variables such as maximal oxygen uptake (VO2 peak), aerobic energy (EAER), anaerobic energy (EAN), and accumulated O2 deficit (DOA). By investigating associations and comparing athletes in the -61 kg bantamweight and -66 kg featherweight weight divisions, we aim to shed light on their physiological characteristics. The sample consisted of 20 male volunteers separated into two paired groups: ten athletes in the category up to 61 kg (age: 27.7 ± 5.9 years old, height: 170.9 ± 3.4 cm, body mass: 72.8 ± 1.4 kg, fat percentage: 9.5% ± 3.0%, professional experience: 7.5 ± 7.1 years) and ten athletes up to 66 kg (age: 27.6 ± 2.9 years old, height: 176.0 ± 5.5 cm, body mass: 77.0 ± 1.5 kg, fat percentage: 7.85% ± 0.3%, professional experience: 5.5 ± 1.5 years). Remarkably, our findings revealed striking similarities between the two weight divisions. Furthermore, we discovered a negative correlation between VO2 peak and the number of MMA fights, indicating a potential impact of professional experience on aerobic capacity (r = -0.65, p < 0.01). Additionally, the number of fights exhibited negative correlations with anaerobic energy (r = -0.53, p < 0.05) and total energy cost (r = -0.54, p < 0.05). These results provide valuable insights for designing training programs in the context of MMA. While training both weight divisions together can be beneficial, it is equally crucial to incorporate specific weight-class-focused training to address each division's unique physical demands and requirements.

Poor Agreement between Responses to the International Physical Activity Questionnaire and Objective ActiGraph® Data among Persons with Major Depressive or Bipolar Disorders.

The purpose of this research was to investigate the degree of agreement between data from the International Physical Activity Questionnaire-Short Form (IPAQ) and accelerometer (ActiGraph®) readings for physical activity (PA), classified as moderate, vigorous, and moderate-vigorous PA, and sedentary behavior (SB) in participants with major depressive or bipolar disorder. Following a cross-sectional observational design (n = 30), participants used an accelerometer for 4 to 7 days (minimum of 10 h per day) and answered the IPAQ (for the same period as accelerometer use). Our results suggest significant differences (p < 0.05) when comparing the ActiGraph® and IPAQ data: for moderate PA, 155 min vs. 25 min per week; for moderate-vigorous PA, 157 min vs. 50 min per week; and for SB, 8 h vs. 3 h per day. Spearman's correlation coefficients (ActiGraph® and IPAQ) were low for moderate PA, vigorous PA, and moderate-vigorous PA (rho = 0.03 to 0.13). The Bland-Altman plot showed a bias of -75 min for moderate PA, 9 min for vigorous PA, -66 min for moderate-vigorous PA, and -5 h for SB. Considering the differences observed and the objectivity of the ActiGraph® measurements, whenever possible, we recommend ActiGraph® measurements of PA and SB for these clinical groups.

Chemical Composition and Antimicrobial Potential of Essential Oil of Acritopappus confertus (Gardner) R.M.King & H.Rob. (Asteraceae).

Microbial resistance has become a worrying problem in recent decades after the abusive use of antibiotics causing the selection of resistant microorganisms. In order to circumvent such resistance, researchers have invested efforts in the search for promising natural substances, such as essential oils. Thus, the objective of this work was to determine the chemical composition of the essential oil of Acritopappus confertus leaves, to evaluate its intrinsic effect and its effects in combination with drugs against pathogenic fungi and bacteria, in addition to verifying the inhibition of virulence in Candida strains. To this end, the oil was verified by gas chromatography coupled with mass spectrometry (GC/MS). Candida strains were used for antifungal assays by means of the serial microdilution technique, in order to determine the average inhibitory concentration (IC50), and for the modification assays, sub-inhibitory concentrations (MIC/8) were used. Finally, the natural product's ability to inhibit the formation of filamentous structures was evaluated. In antibacterial tests, the MIC of the oil against strains of Staphylococcus aureus and Escherichia coli and its modifying effects in association with gentamicin, erythromycin, and norfloxacin were determined. The major constituent of the essential oil was the monoterpene myrcene (54.71%). The results show that the essential oil has an antifungal effect, with C. albicans strains being the most susceptible. Furthermore, the oil can potentiate the effect of fluconazole against strains of C. tropicalis and C. albicans. Regarding its effect on micromorphology, the oil was also able to inhibit the filaments in all strains. In combination with antibiotics, the oil potentiated the drug's action by reducing the MIC against E. coli and S. aureus. It can be concluded that the essential oil of A. confertus has potential against pathogenic fungi and bacteria, making it a target for the development of an antimicrobial drug.

Influence of Advancing Biological Maturation on Aerobic and Anaerobic Power and on Sport Performance of Junior Rowers: A Longitudinal Study.

Background: Researches are linking Biological Maturation (BM) with the performance of adolescent rowers from both genders. Despite this, there is still not enough information about the influence of BM advancement correlating to sports, aerobic and anaerobic performance in adolescent athletes at the sport modality rowing. Objective: Investigate the influence of Biological Maturation on sports performance and aerobic and anaerobic power in adolescent rowing athletes. Methods: A longitudinal observational study, developed over 3 years, with a sample of 52 adolescents, rowing athletes, of both genders (61% male and 39% female) mean age of 16.0 ± 0.5 years old at the start and 18.4 ± 0.5 years old at the end of the study. Analysis was performed once a year. BM was evaluated through maturational groups generated from Age Peak Height Velocity; maximum aerobic power [VO2Max (ml/kg/min)] and mean anaerobic power (Watts) through the ergometer test (indoor rowing); peak anaerobic power (Watts) through a mathematical model derived from competition time, to determine sports performance analyzed the race time during world championship tryouts. Results: The advancement of BM influenced the reduction of the test time and increase of the mean anaerobic power (Watts) in indoor rowing (η2p > 0.36, p < 0.05), as well as an improvement in performance in sports competition (η2p > 0.35, p < 0.05). However, the advancement of BM did not affect VO2Max (ml/kg/min) in young elite rowing athletes of both sexes (p > 0.05). Conclusion: Advances in biological maturation have been shown to influence the anaerobic and sports performance (reduction of the execution time in 2,000-m) of adolescent rowing athletes of both genders.

Proteomic analysis reveals stage-specific reprogramed metabolism for the primary breast cancer cell lines MGSO-3 and MACL-1.

Breast cancer is the most prevalent cancer in women worldwide. Its molecular subtypes are based on the presence/absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). MACL-1 and MGSO-3 are cell lines derived from primary tumor sites of patients diagnosed with luminal A subtype carcinoma (ER+/PR+/HER2-) and ductal carcinoma in situ (ER-/PR-/HER2+), respectively. However, these cell lines lost the expression of these markers over cell culturing, and both have triple-negative phenotypes (ER-/PR-/HER2-), which has the poorest prognosis. Here, we sought to study the proteome signature of MGSO-3 and MACL-1, comparing them with the epithelial cell line MCF-10A and the well-established metastatic-derived breast cancer cell line MDA-MB-231. Our results showed that proteins associated with the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) were upregulated in MGSO-3 and MACL-1 cells. These cell lines also showed upregulation of pro-apoptotic proteins when compared with MDA-MB-231. The molecular differences highlighted in this study may clarify the molecular basis behind cancer cells functioning and may reveal novel signatures across the breast cancer cell models.

Prognostic factors and management of colorectal gastrointestinal stromal tumors

Introduction: The gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Even though it can be found in any location of the digestive tract, the colorectal GIST is rare. With this study, we aim to review the current knowledge regarding the prognosis and management of colorectal GIST. Methods: A literature search was conducted in PubMed, and 717 articles were collected. After analyzing these studies, 60 articles were selected to use in this review. Results: The mitotic index, as well as tumor size and location were identified as good discriminators of prognosis in various studies. Surgery remains the only curative therapy for potentially resectable tumors. However, even after surgical resection, some patients develop disease recurrence and metastasis, especially those with highrisk tumors. Therefore, surgical resection alone might be inadequate for the management of all colorectal GISTs. The discovery of GIST's molecular pathway led to a shift in its therapy, insofar as tyrosine kinase inhibitors became part of the treatment schemes for this tumor, revolutionizing the treatment's outcome and prognosis. Discussion/Conclusion: The controversy concerning colorectal GIST prognosis and treatment can be, in part, attributed to the limited number of studies in the literature. In this review, we gathered the most recent knowledge about the prognosis and management of GIST in this rare location and propose two algorithms for its approach. Lastly, we highlight the importance of an individualized approach in the setting of a multidisciplinary team. (AU)