The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

O Impacto das Políticas Públicas na Morbimortalidade por Neoplasias dos Brônquios e dos Pulmões / The Impact of Public Policies on Morbimortality from Bronchial and Lung Neoplasms

O artigo busca analisar as variações temporais na incidência de neoplasias malignas dos brônquios e pulmões na cidade de São Paulo, considerando intervenções e políticas públicas de combate à poluição e ao tabagismo. O estudo quantitativo, descritivo e transversal utilizou dados do DATASUS, Vigitel Brasil 2021, IBGE e BasePop do INCA. Entre 1996 e 2021, houve aumento na taxa de mortalidade feminina de 7,3 por 100 mil habitantes, enquanto a masculina sofreu uma queda de 2,5 por 100 mil habitantes. Apesar das políticas antitabaco, a mortalidade geral aumentou em 2,56 em cada 100 mil habitantes, enquanto a taxa de incidência caiu 12,63 para cada 100 mil habitantes. Apesar das políticas públicas relacionadas ao controle do tabaco desde 1950 e de outros fatores de risco como exposição ocupacional e poluição atmosférica, o câncer de pulmão continua sendo uma ameaça significativa, sugerindo a necessidade de revisão das estratégias implementadas. Além disso, historicamente o tabagismo feminino, mostra como mudanças sociais e culturais influenciaram o aumento do consumo entre as mulheres, apontando para a necessidade de políticas públicas mais rígidas e ações de conscientização. Reconhece-se ainda que a falta de dados detalhados sobre fatores de risco e a eficácia das medidas implementadas ressalta a complexidade do desafio de reduzir a incidência de câncer de pulmão e brônquios.

The article seeks to analyze temporal variations in the incidence of malignant neoplasms of the bronchi and lungs in the city of São Paulo, considering interventions and public policies to combat pollution and smoking. The quantitative, descriptive and cross-sectional study used data from DATASUS, Vigitel Brasil 2021, IBGE and BasePop from INCA. Between 1996 and 2021, there was an increase in the female mortality rate of 7.3 per 100 thousand inhabitants, while the male mortality rate suffered a drop of 2.5 per 100 thousand inhabitants. Despite anti-smoking policies, overall mortality increased by 2.56 per 100,000 inhabitants, while the incidence rate fell by 12.63 per 100,000 inhabitants. Despite public policies related to tobacco control since 1950 and other risk factors such as occupational exposure and air pollution, lung cancer continues to be a significant threat, suggesting the need to review implemented strategies. Furthermore, historically, female smoking shows how social and cultural changes have influenced the increase in consumption among women, pointing to the need for stricter public policies and awareness-raising actions. It is also recognized that the lack of detailed data on risk factors and the effectiveness of implemented measures highlights the complexity of the challenge of reducing the incidence of lung and bronchial cancer.

Antineoplastic effects of pharmacological inhibitors of aurora kinases in CSF3RT618I-driven cells.

Myeloproliferative neoplasms (MPN) are consolidated as a relevant group of diseases derived from the malfunction of the hematopoiesis process and have as a particular attribute the increased proliferation of myeloid lineage. Among these, chronic neutrophilic leukemia (CNL) is distinguished, caused by the T618I mutation of the CSF3R gene, a trait that generates ligand-independent receptor activation and downstream JAK2/STAT signaling. Previous studies reported that mutations in BCR::ABL1 and JAK2V617F increased the expression of the aurora kinase A (AURKA) and B (AURKB) in Ba/F3 cells and their pharmacological inhibition displays antineoplastic effects in human BCR::ABL1 and JAK2V617F positive cells. Delimiting the current scenario, aspects related to the AURKA and AURKB as a potential target in CSF3RT618I-driven models is little known. In the present study, the cellular and molecular effects of pharmacological inhibitors of aurora kinases, such as aurora A inhibitor I, AZD1152-HQPA, and reversine, were evaluated in Ba/F3 expressing the CSF3RT618I mutation. AZD1152-HQPA and reversine demonstrated antineoplastic potential, causing a decrease in cell viability, clonogenicity, and proliferative capacity. At molecular levels, all inhibitors reduced histone H3 phosphorylation, aurora A inhibitor I and reversine reduced STAT5 phosphorylation, and AZD1152-HQPA and reversine induced PARP1 cleavage and γH2AX expression. Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs. In summary, our findings shed new insights into the use of AURKB inhibitors in the context of CNL.

Rat liver extracellular matrix and perfusion bioreactor culture promote human amnion epithelial cell differentiation towards hepatocyte-like cells.

Congenital and chronic liver diseases have a substantial health burden worldwide. The most effective treatment available for these patients is whole organ transplantation; however, due to the severely limited supply of donor livers and the side effects associated with the immunosuppressive regimen required to accept allograft, the mortality rate in patients with end-stage liver disease is annually rising. Stem cell-based therapy aims to provide alternative treatments by either cell transplantation or bioengineered construct transplantation. Human amnion epithelial cells (AEC) are a widely available, ethically neutral source of cells with the plasticity and potential of multipotent stem cells and immunomodulatory properties of perinatal cells. AEC have been proven to be able to achieve functional improvement towards hepatocyte-like cells, capable of rescuing animals with metabolic disorders; however, they showed limited metabolic activities in vitro. Decellularised extracellular matrix (ECM) scaffolds have gained recognition as adjunct biological support. Decellularised scaffolds maintain native ECM components and the 3D architecture instrumental of the organ, necessary to support cells' maturation and function. We combined ECM-scaffold technology with primary human AEC, which we demonstrated being equipped with essential ECM-adhesion proteins, and evaluated the effects on AEC differentiation into functional hepatocyte-like cells (HLC). This novel approach included the use of a custom 4D bioreactor to provide constant oxygenation and media perfusion to cells in 3D cultures over time. We successfully generated HLC positive for hepatic markers such as ALB, CYP3A4 and CK18. AEC-derived HLC displayed early signs of hepatocyte phenotype, secreted albumin and urea, and expressed Phase-1 and -2 enzymes. The combination of liver-specific ECM and bioreactor provides a system able to aid differentiation into HLC, indicating that the innovative perfusion ECM-scaffold technology may support the functional improvement of multipotent and pluripotent stem cells, with important repercussions in the bioengineering of constructs for transplantation.

Paracoccidioides brasiliensis Induces α3 Integrin Lysosomal Degradation in Lung Epithelial Cells.

Studies on the pathogen-host interaction are crucial for the understanding of the mechanisms involved in the establishment, maintenance, and spread of infection. In recent years, our research group has observed that the P. brasiliensis species interact with integrin family receptors and increase the expression of α3 integrin in lung epithelial cells within 5 h of infection. Interestingly, α3 integrin levels were reduced by approximately 99% after 24 h of infection with P. brasiliensis compared to non-infected cells. In this work, we show that, during infection with this fungus, α3 integrin is increased in the late endosomes of A549 lung epithelial cells. We also observed that the inhibitor of the lysosomal activity bafilomycin A1 was able to inhibit the decrease in α3 integrin levels. In addition, the silencing of the charged multivesicular body protein 3 (CHMP3) inhibited the reduction in α3 integrin levels induced by P. brasiliensis in A549 cells. Thus, together, these results indicate that this fungus induces the degradation of α3 integrin in A549 lung epithelial cells by hijacking the host cell endolysosomal pathway.

Orofacial myofunctional therapy associated with the use of the stimulating palatal plate in children with trisomy 21: case studies. / Terapia miofuncional orofacial associada ao uso da placa palatina de memória em crianças com Trissomia do 21: estudo de casos.

Individuals with trisomy 21 may have muscle hypotonia of the speech articulation organs, an enlarged protruding tongue positioned on the floor of the mouth, and a lack of lip closure. The stimulating palatal plate is an intraoral appliance that, associated with myofunctional therapy, aims to improve these children's habitual lip and tongue posture. This study aimed to present the cases of four male children with trisomy 21, with a mean age of 6.7 and a standard deviation of 7.8 months, who used the stimulating palatal plate in association with myofunctional therapy. The children used the plate for 6 months and did exercises based on the orofacial regulation therapy, and their parents received instructions on feeding them and removing deleterious oral habits. In the first session and at the end of the treatment, each child's face was video-recorded for 5 minutes at rest, and two researchers analyzed independently their habitual tongue and lip posture. Participants who began the treatment earlier and had the most severe postural changes had greater tongue and lip posture improvement.

Indivíduos com Trissomia do 21 podem apresentar hipotonia muscular dos órgãos fonoarticulatórios, língua alargada, posicionada no assoalho oral e protrusa e ausência de selamento labial. A placa palatina de memória é um dispositivo intraoral que, associado à terapia miofuncional, visa à melhora da postura habitual dos lábios e da língua dessas crianças. O objetivo deste trabalho foi apresentar os casos de quatro crianças com Trissomia do 21, do sexo masculino, com média de idade de 6,7 e desvio-padrão de 7,8 meses, que fizeram uso da placa palatina de memória de forma associada à terapia miofuncional. As crianças utilizaram a placa por seis meses, realizaram exercícios baseados na terapia de regulação orofacial e receberam orientações quanto à alimentação e retirada de hábitos orais deletérios. Na primeira sessão e ao final do tratamento, foi realizada a gravação de 5 minutos da face de cada criança em repouso e a análise da postura habitual de língua e de lábios foi realizada por dois pesquisadores independentes. Observou-se maior melhora da postura de língua e de lábios dos participantes que iniciaram o tratamento mais precocemente e que apresentavam as alterações posturais mais severas.

Characterizing wine terroir using strontium isotope ratios: a review.

This paper presents a detailed review of the use of 87Sr/86Sr isotope systematics for wine provenance studies. The method is based on the principle that the Sr isotope ratio in wine reflects that of the labile fraction of the vineyard soil from which the wine is produced. The review encompasses 87Sr/86Sr data from wine samples published between 1993 and 2021 from terroirs in 22 different countries. The analytical procedures and techniques adopted by the different authors and the range of isotope ratios obtained in the different studies are discussed and evaluated. This study provides a bibliometric analysis of the 87Sr/86Sr isotope approach for wine authentication at different scales. Although limitations are evident when implemented at large (global) scales, we demonstrate that the 87Sr/86Sr isotope tracing technique remains a powerful and reliable tool for determining the geographical origin of wine when combined with detailed knowledge of the geological and soil characteristics of the substrata. For example, this combination of data allows the wines grown in the volcanic soils of Central and Southern Italy to be unambiguously fingerprinted. We present a detailed protocol for the application of the Sr isotope technique to wine authentication.

The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells.

Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced γH2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease.

Influência da idade e do tempo de uso da Placa Palatina de Memória por crianças com Trissomia do 21 nas mudanças miofuncionais orofaciais percebidas pelos pais, na adaptação e satisfação da família após quatro meses de tratamento / nfluence of age and time of use of the Stimulating Palatal Plate by children with Trisomy 21 on orofacial myofunctional changes perceived by parents, children's adaptation, and family's satisfaction after four months of treatment / Influencia de la edad y el tiempo de uso de la placa de memoria palatina por niños con trisomía 21 sobre los cambios miofuncionales orofaciales percibidos por los padres, adaptación y satisfacción familiar después de cuatro meses de tratamiento

Objetivo: verificar se a idade das crianças com Trissomia do 21 e o tempo de uso por dia da placa palatina de memória influenciam a adaptação da criança à placa, as mudanças miofuncionais orofaciais percebidas pelos pais e a satisfação da família, após quatro meses de tratamento. Métodos: participaram do estudo14 pais ou responsáveis legais de crianças com Trissomia do 21, com idades de 3 a 20 meses. O tratamento com a placa palatina de memória foi realizado durante quatro meses. A adaptação da criança à placa, as mudanças miofuncionais orofaciais percebidas pelos pais e a satisfação das famílias em relação ao tratamento foram investigadas por meio de questionário elaborado pelos autores da pesquisa e respondido pelas mães após quatro meses de tratamento. Resultados: a média de idade das crianças que participaram do estudo foi 10 meses e o desvio-padrão de 4,9 meses. O resultado do questionário indicou associação entre idade e postura de lábios relatada pelos pais com o uso da placa palatina de memória, sendo que todas as crianças menores de 10 meses mantiveram o selamento labial, de acordo com os pais, durante o uso da placa; bem como entre idade e satisfação com o tratamento, sendo que as mães das crianças menores mostraram-se mais satisfeitas. Conclusão: os resultados do estudo indicam que houve associação entre idade e postura de lábios relatada pelos pais com o uso da placa, bem como entre idade e satisfação com o tratamento e sugerem que o tratamento precoce com a placa palatina de memória beneficia as crianças com Trissomia do 21. (AU)

Purpose: to verify if the age of children with Trisomy 21 and the time of use per day of the stimulating palatal plate influence the child's adaptation to the plate, the orofacial myofunctional changes perceived by the parents, and the family's satisfaction, after four months of treatment. Methods: 14 parents or legal guardians of children with Trisomy 21, aged between 3 and 20 months, participated in the study. Treatment with the stimulating palatal plate was carried out for four months. The child's adaptation to the plate, the orofacial myofunctional changes perceived by the parents, and the families' satisfaction with the treatment were investigated through a questionnaire prepared by the research authors and answered by the mothers after four months of treatment. Results: The mean age of the children who participated in the study was 10 months and the standard deviation was 4.9 months. The results of the questionnaire indicated an association between age and lip posture, reported by parents, during the use of the stimulating palatal plate, and all children under 10 months maintained lip closure, according to the parents, during the use of the plate. Age was also associated with satisfaction with the service, as the mothers of younger children were more satisfied. Conclusion: The study results indicate an association between age and lip posture, reported by the parents, during the use of the plate, and between age and satisfaction with the service. Thus, it suggests that early treatment with the stimulating palatal plate benefits children with Trisomy 21. (AU)

Objetivo: verificar si la edad de los niños con Trisomía 21 y el tiempo de uso por día de la placa palatina de memoria influyen en la adaptación del niño a la placa, los cambios miofuncionales orofaciales percibidos por los padres y la satisfacción de la familia, después de cuatro meses de tratamiento. Métodos: Participaron en el estudio 14 padres o tutores legales de niños con trisomía 21, con edades comprendidas entre los 3 y los 20 meses. El tratamiento con la placa de memoria palatina se llevó a cabo durante cuatro meses. La adaptación del niño al plato, los cambios miofuncionales orofaciales percibidos por los padres y la satisfacción de las familias con el tratamiento fueron investigados a través de un cuestionario elaborado por los autores y respondido por las madres, después de cuatro meses de tratamiento. Resultados: La edad media de los niños que participaron en el estudio fue de 10 meses y la desviación estándar fue de 4,9. El resultado del cuestionario indicó una asociación entre la edad y la postura de los labios, reportada por los padres, con el uso de la placa de memoria palatina, y todos los niños menores de 10 meses mantuvieron el sello de los labios, según los padres, durante el uso de la placa de memoria palatina, así como entre la edad y la satisfacción con el servicio. Las madres de niños más pequeños estaban más satisfechas. Conclusión: Los resultados del estudio indican que hubo asociación entre la edad y la postura de los labios, reportada por los padres, con el uso de la placa, así como entre la edad y la satisfacción con el servicio, y sugieren que el tratamiento temprano con la placa de memoria palatina beneficia a los niños con trisomía 21. (AU)

Chlamydia trachomatis, Neisseria gonorrhoeae and human papillomavirus infections of lower genital tract of Indigenous women from Xingu Indigenous Park.

INTRODUCTION: Xingu Indigenous Park (XIP) currently protects 16 ethnic Indigenous groups and is located in the central area of Brazil. XIP is the first and the largest Indigenous land to be recognized in the country. Community access is limited and restricted for the non-Indigenous population, and the Indigenous women are constantly dealing with shortages of medical care. High-risk human papillomavirus (HR-HPV) is the most common cause of cervical cancer and is detected in 99% of cervical precancers. HPV infections may be associated with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoeae, which are also important causative agents of sexually transmitted infections and are responsible for the most frequent bacterial infections in the world. The present study evaluated the frequency and potential impact of Chlamydia trachomatis, Neisseria gonorrhoeae, and HR-HPV in the Indigenous women of XIP. METHODS: In this cross-sectional study, 992 cervical-vaginal samples were collected from Indigenous women, using a Cervex-Brush, and were immediately placed in a SurePath medium. All samples were submitted to the cobas® 4800 detection system for the identification of 14 different types of HR-HPV, and the multiplex Abbott RealTime CT/NG assay for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. RESULTS: HR-HPV was detected in 18.2% of women; 6% were positive for HPV16, 5% for HPV18, and 81% for other types of HR-HPV. Co-infections of HPV16 and other types was observed in 5% of women, and 3% had co-infections of HPV18 and other types. Moreover, 1.8% of women were positive for Chlamydia trachomatis, while Neisseria gonorrhoeae was not detected. In women with HR-HPV, 33% had Chlamydia trachomatis infections, 28% were positive for HR-HPV other than HPV16 or HPV18, and 5% had co-infections of HPV16 and the other types of HPV. Younger women were found to be more susceptible to HPV infections. CONCLUSION: The findings indicate a high frequency of HR-HPV and a considerable frequency of Chlamydia trachomatis in the Indigenous women of XIP. The detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and/or HR-HPV does not present evidence of a potential interrelationship for a combined pathogenic action in these women.

Body mass index and abdominal waist values are related to increased cardiometabolic risk in schoolchildren aged five to ten years.

OBJECTIVE: To evaluate the frequency of obesity and cardiometabolic risk in schoolchildren under ten years old. METHODS: This is a cross-sectional study with schoolchildren (n=639) aged five to ten years in a municipally of southern of Brazil. The cardiometabolic risk was calculated from values of body mass index (BMI), waist circumference (WC), diastolic (DBP) and systolic blood pressure (SBP), blood glucose levels, triglycerides and total cholesterol (TC). Odds ratio (OR), Spearman correlation and principal component analysis (PCA) were analyzed. RESULTS: Independent of sex, elevated WC and BMI were related to higher values of SBP, DBP, and TC in schoolchildren. The frequency of cardiometabolic risk was 6.0% in girls and 9.9% in boys. Schoolchildren with elevated values of SBP, triglycerides and TC presented high OR for cardiometabolic risk. PCA indicated that schoolchildren with high WC (p>80) presented more frequently altered glucose levels, triglycerides, and TC. CONCLUSIONS: Obesity, especially when associated with elevated WC, is related to metabolic dysfunctions and cardiometabolic risk in schoolchildren under ten years of age. These findings indicate the urgency of stablishing metabolic risk for this age group, enabling early diagnosis and adequate treatment, to prevent the development of diabetes and cardiovascular dysfunction throughout life.

Gene Expression Profile of Uterine Leiomyoma from Women Exposed to Different Air Pollution Levels in Metropolitan Cities of Sao Paulo, Brazil.

Leiomyomas (LMs) are the most frequent uterine benign tumors, representing the leading cause of hysterectomy indications worldwide. They are highly associated with women's reproductive complications, and endocrine disruptors may influence their etiology. In this sense, air pollution represents a relevant hormonal disruptor that acts on key signaling pathways, resulting in tumor development and infertility. Our goal was to evaluate submucosal LM samples from patients living in the metropolitan and Sao Paulo city regions, focusing on genes involved in tumor development and infertility features. Twenty-four patients were selected based on their region of residence and clinical information availability. Several genes were differentially expressed between women living in metropolitan areas and Sao Paulo city. Significant associations were observed between BCL-2, DVL1, FGFR3, and WNT5b downregulation and contraceptive use in the samples from women living in Sao Paulo city. ESR1 and HHAT downregulation was associated with ethnicity. WNT5b and GREM were associated with LM treatment and related pathologies, respectively. In the samples from women living in other cities of the metropolitan region, abortion occurrence was associated with BMP4 upregulation. Although further studies may be necessary, our results showed that air pollution exposure influences the expression of genes related to LM development and female reproductive features.

Body mass index and abdominal waist values are related to increased cardiometabolic risk in schoolchildren aged five to ten years / Valores do índice de massa corpórea e circunferência abdominal estão relacionados a elevado risco cardiometabólico em escolares com idade de cinco a dez anos

ABSTRACT Objective: To evaluate the frequency of obesity and cardiometabolic risk in schoolchildren under ten years old. Methods: This is a cross-sectional study with schoolchildren (n=639) aged five to ten years in a municipally of southern of Brazil. The cardiometabolic risk was calculated from values of body mass index (BMI), waist circumference (WC), diastolic (DBP) and systolic blood pressure (SBP), blood glucose levels, triglycerides and total cholesterol (TC). Odds ratio (OR), Spearman correlation and principal component analysis (PCA) were analyzed. Results: Independent of sex, elevated WC and BMI were related to higher values of SBP, DBP, and TC in schoolchildren. The frequency of cardiometabolic risk was 6.0% in girls and 9.9% in boys. Schoolchildren with elevated values of SBP, triglycerides and TC presented high OR for cardiometabolic risk. PCA indicated that schoolchildren with high WC (p>80) presented more frequently altered glucose levels, triglycerides, and TC. Conclusions: Obesity, especially when associated with elevated WC, is related to metabolic dysfunctions and cardiometabolic risk in schoolchildren under ten years of age. These findings indicate the urgency of stablishing metabolic risk for this age group, enabling early diagnosis and adequate treatment, to prevent the development of diabetes and cardiovascular dysfunction throughout life.

RESUMO Objetivo: Avaliar a frequência de obesidade e risco cardiometabólico em escolares menores de dez anos de idade. Métodos: Este é um estudo transversal com escolares (n=639) com idade de cinco a dez anos de um município do Sul do Brasil. O risco cardiometabólico foi calculado com base nos valores do índice de massa corpórea (IMC), circunferência da cintura (CC), pressão arterial sistólica (PAS) e diastólica (PAD), valores sanguíneos de glicose, triglicerídeos e colesterol total. Odds ratio (OR), correlação de Spearman e análise de componentes principais (PCA) foram obtidos. Resultados: Independentemente do sexo, CC e IMC aumentados foram relacionados com maiores valores de PAS, PAD e colesterol total. A frequência de risco cardiometabólico foi de 6,0% nas meninas e 9,9% nos meninos. Escolares com elevados valores de PAS, triglicerídeos e colesterol total tinham alto OR para risco cardiometabólico. A PCA mostrou que escolares com alta CC (p>80) apresentam mais frequentemente alterações nos níveis sanguíneos de glicose, triglicerídeos e colesterol total. Conclusões: A obesidade, especialmente quando associada a elevados valores de CC, está relacionada com disfunções metabólicas e risco cardiometabólico em escolares menores de dez anos de idade. Estes achados indicam a urgência de estabelecer o risco metabólico para essa faixa etária, possibilitando o diagnóstico precoce, o adequado tratamento para evitar o desenvolvimento de diabetes e disfunções cardiovasculares ao longo da vida.

Terapia miofuncional orofacial associada ao uso da placa palatina de memória em crianças com Trissomia do 21: estudo de casos / Orofacial myofunctional therapy associated with the use of the stimulating palatal plate in children with trisomy 21: case studies

RESUMO Indivíduos com Trissomia do 21 podem apresentar hipotonia muscular dos órgãos fonoarticulatórios, língua alargada, posicionada no assoalho oral e protrusa e ausência de selamento labial. A placa palatina de memória é um dispositivo intraoral que, associado à terapia miofuncional, visa à melhora da postura habitual dos lábios e da língua dessas crianças. O objetivo deste trabalho foi apresentar os casos de quatro crianças com Trissomia do 21, do sexo masculino, com média de idade de 6,7 e desvio-padrão de 7,8 meses, que fizeram uso da placa palatina de memória de forma associada à terapia miofuncional. As crianças utilizaram a placa por seis meses, realizaram exercícios baseados na terapia de regulação orofacial e receberam orientações quanto à alimentação e retirada de hábitos orais deletérios. Na primeira sessão e ao final do tratamento, foi realizada a gravação de 5 minutos da face de cada criança em repouso e a análise da postura habitual de língua e de lábios foi realizada por dois pesquisadores independentes. Observou-se maior melhora da postura de língua e de lábios dos participantes que iniciaram o tratamento mais precocemente e que apresentavam as alterações posturais mais severas.

ABSTRACT Individuals with trisomy 21 may have muscle hypotonia of the speech articulation organs, an enlarged protruding tongue positioned on the floor of the mouth, and a lack of lip closure. The stimulating palatal plate is an intraoral appliance that, associated with myofunctional therapy, aims to improve these children's habitual lip and tongue posture. This study aimed to present the cases of four male children with trisomy 21, with a mean age of 6.7 and a standard deviation of 7.8 months, who used the stimulating palatal plate in association with myofunctional therapy. The children used the plate for 6 months and did exercises based on the orofacial regulation therapy, and their parents received instructions on feeding them and removing deleterious oral habits. In the first session and at the end of the treatment, each child's face was video-recorded for 5 minutes at rest, and two researchers analyzed independently their habitual tongue and lip posture. Participants who began the treatment earlier and had the most severe postural changes had greater tongue and lip posture improvement.

Efeitos da pandemia: percepção de estresse e apoio em famílias com filhos com desenvolvimento atípico / Pandemic' effects: perception of stress and support in families with children with atypical development

A pandemia da COVID-19 exigiu medidas de proteção que repercutiram no modo de vida das famílias. Os impactos podem ter sido mais intensos em famílias com crianças com deficiência ou transtorno global do desenvolvimento (TGD) que necessitam de cuidados e estímulos específicos. O objetivo deste estudo foi analisar o impacto do isolamento social na percepção de estresse, estresse parental e apoio social percebido por mães e pais de crianças com deficiência/TGD. Trata-se de um estudo transversal com 37 participantes, em duas fases independentes de coleta de dados (F1; F2). Utilizou-se instrumentos autoaplicáveis disponibilizados em um Formulário Google: Questionário Sociodemográfico; Questionário sobre percepção da influência do isolamento social na dinâmica familiar; Escala de Estresse Percebido; Escala de Estresse Parental e Escala de Apoio Social. Observou-se que a percepção de estresse em F2 foi significativamente maior que em F1 e em famílias com mais de um filho (p

The COVID-19 pandemic required protect actions with quarantine and social distancing, which had an impact on families' lifestyle. The impacts of the pandemic may have been even more intense in families of children with disabilities or pervasive developmental disorder (PDD) who need specific care. This study aims to analyze the impact of the social distancing situation on the perception of stress, parental stress and perceived social support by mothers and fathers of children with disabilities/PDD with 11 years old or more, and associations between these variables. This is a cross-sectional study with 37 participants in two independent phases. The following self-administered instruments were available in a Google Form: Sociodemographic Questionnaire; Questionnaire on the perception of the influence of social distancing resulting from the pandemic on family dynamics; Perceived Stress Scale; Parental Stress Scale and Social Support Scale. There was a significatively higher stress perception between mothers in Phase 2 (P2>P1) and higher stress among families with more than one child. Most mothers referred social support, an increase in the stress perception with children care and stress comparing the phases. This study demonstrated the importance of social support to parents' adaptation in stress increasing related to pandemic situation

Comprehensive analysis of the HCK gene in myeloid neoplasms: Insights into biological functions, prognosis, and response to antineoplastic agents.

Myeloid neoplasms result from molecular alterations in hematopoietic stem cells, with acute myeloid leukemia (AML) being one of the most aggressive and with a poor prognosis. Hematopoietic cell kinase (HCK) is a proto-oncogene that encodes a protein-tyrosine kinase of the Scr family, and it is highly expressed in AML. The present study investigated HCK expression in normal hematopoietic cells across myeloid differentiation stages and myeloid neoplasm patients. Within the AML cohort, we explored the impact of HCK expression on clinical outcomes and its correlation with clinical, genetic, and laboratory characteristics. Furthermore, we evaluated the association between HCK expression and the response to antineoplastic agents using ex vivo assay data from AML patients. HCK expression is higher in differentiated subpopulations of myeloid cells. High HCK expression was observed in patients with chronic myelomonocytic leukemia, chronic myeloid leukemia, and AML. In patients with AML, high levels of HCK negatively impacted overall and disease-free survival. High HCK expression was also associated with worse molecular risk groups and white blood cell count; however, it was not an independent prognostic factor. In functional genomic analyses, high HCK expression was associated with several biological and molecular processes relevant to leukemogenesis. HCK expression was also associated with sensitivity and resistance to several drugs currently used in the clinic. In conclusion, our analysis confirmed the differential expression of HCK in myeloid neoplasms and its potential association with unfavorable molecular risks in AML. We also provide new insights into HCK biological functions, prognosis, and response to antineoplastic agents.

Factors Associated with Motivation in Medical Students: A 30-Month Longitudinal Study.

This longitudinal study aimed to assess the factors associated with motivation in 303 Brazilian medical students after a 30-month follow-up. Their demographics, study habits, sleep quality, motivation (Brazilian version of the Academic Motivation Scale-BAMS), learning approaches (R-SPQ-2F scale), and stressors (MSSF-Medical Student Stress Factor scale) were examined. We found an increase in amotivation and extrinsic motivation through external regulation (e.g., "I come to school to earn a degree") and a decrease in intrinsic motivation and extrinsic motivation through integrated regulation (e.g., "because studying broadens our horizons") in medical students after the 30-month follow-up. Students in earlier stages of medical training showed greater increases in amotivation. Factors such as the learning approach, hours spent studying, sex, stressors, studying just before examinations, and sleep problems were predictors of the different dimensions of motivation. Medical students' motivation changed negatively as medical training progressed.

Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature.

There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of "pure" uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.

DNGR-1-tracing marks an ependymal cell subset with damage-responsive neural stem cell potential.

Cells with latent stem ability can contribute to mammalian tissue regeneration after damage. Whether the central nervous system (CNS) harbors such cells remains controversial. Here, we report that DNGR-1 lineage tracing in mice identifies an ependymal cell subset, wherein resides latent regenerative potential. We demonstrate that DNGR-1-lineage-traced ependymal cells arise early in embryogenesis (E11.5) and subsequently spread across the lining of cerebrospinal fluid (CSF)-filled compartments to form a contiguous sheet from the brain to the end of the spinal cord. In the steady state, these DNGR-1-traced cells are quiescent, committed to their ependymal cell fate, and do not contribute to neuronal or glial lineages. However, trans-differentiation can be induced in adult mice by CNS injury or in vitro by culture with suitable factors. Our findings highlight previously unappreciated ependymal cell heterogeneity and identify across the entire CNS an ependymal cell subset wherein resides damage-responsive neural stem cell potential.

Reactive oxygen and nitrogen species are crucial for the antifungal activity of amorolfine and ciclopirox olamine against the dermatophyte Trichophyton interdigitale.

Onychomycosis is a nail infection caused by Trichophyton interdigitale and other fungi, which can be treated with topical amorolfine (AMR) and ciclopirox olamine (CPX). Although these drugs are widely used, little is known about the role of reactive oxygen (ROS) and nitrogen (RNS) in their mechanism of action. To better understand the effects of AMR and CPX in dermatophytes, we evaluated whether they act through the production of ROS and peroxynitrite (PRN). We tested a set of strains, all susceptible to AMR and CPX, and these antifungals significantly reduced T. interdigitale viability within 24 h. This effect occurred concomitantly with reduced ergosterol, increased production of ROS and PRN, and consequently increased lipid peroxidation. Together, these mechanisms lead to cell damage and fungal death. These fungicidal effects were abolished when PRN and superoxide scavengers were used in the assays, demonstrating the role of these species in the mechanism of action. We also studied the antioxidant system when T. interdigitale was exposed to AMR and CPX. Interestingly, superoxide dismutase and catalase inhibition lead to altered ROS and PRN production, lipid peroxidation, and ergosterol levels. In fact, the combination of AMR or CPX with a superoxide dismutase inhibitor was antagonistic. Together, these data demonstrate the importance of ROS and PRN in the antifungal action of AMR and CPX against the evaluated T. interdigitale strains. LAY SUMMARY: Onychomycosis is a nail infection, which can be treated with amorolfine and ciclopirox olamine. Here we demonstrate that these drugs exhibit antifungal activity also through the production of oxidative and nitrosative radicals.