A Review and Meta-analysis on Trastuzumab Resistance in Patients with HER2+ Breast Cancer.

BACKGROUND: Trastuzumab is a monoclonal antibody that revolutionized the treatment of HER2+ breast cancer. However, about 30% of patients demonstrate resistance to this drug. OBJECTIVE: The purpose of this study is to identify the mechanisms involved in resistance to treatment. with trastuzumab in women undergoing HER2+ breast cancer treatment. METHODS: A wide review and meta-analysis were performed in the PubMed and Scielo databases up to January 2022. All articles that analyzed the efficacy of the drug in HER2+ human patients treated with trastuzumab were selected, except reviews, meta-analyses, and reports. Egger's test was applied to verify publication bias. Forest plot and PRISMA flowchart were employed. RESULTS: 60 articles were selected for the review and 15 included in the meta-analysis. A total of 102 resistance mechanisms were identified, 73 of which are different from each other. The mechanisms have been classified into 5 different categories. The main resistance mechanisms found are in the PI3K/Akt/mTOR pathway or related to low HER2, often resulting from failure to assess HER2 status. Both groups presented statistical significance. The two groups were not significantly different from each other. CONCLUSION: Drug resistance is the main challenge of trastuzumab-based treatment. To overcome this challenge, it is important to continue efforts to understand the mechanisms of cancer drug resistance, identify therapies that can treat refractory cancer to current therapies, and possibly create a panel of genes that predict resistance, avoiding symptomatic and economic costs. The main limitation of this study was the selection and population bias.

Quanto você Sabe sobre Câncer de Mama? Avaliação do Nível de Conhecimento da População Brasileira / How Much do you Know about Breast Cancer? Assessing the Level of Knowledge of the Brazilian Population / ¿Cuánto Sabes sobre el Cáncer de Mama? Evaluación del Nivel de Conocimiento de la Población Brasileña Luiz

Introdução: Apesar dos esforços de conscientização da população, permanecem altas a incidência e a mortalidade decorrente de câncer de mama em mulheres brasileiras. Objetivo: Avaliar o nível de conhecimento da população brasileira sobre os fatores de risco que levam ao desenvolvimento dessa doença. Método: Foi utilizado um questionário estruturado on-line, enviado de setembro a dezembro de 2021, por meio das redes sociais e e-mail. Os participantes foram divididos em subgrupos (escolaridade, área de formação profissional, gênero, contato com indivíduos afetados pela doença e faixas de idade), e o teste de qui-quadrado foi realizado para verificar diferenças significativas entre eles. Resultados: Analisando as 200 respostas válidas da amostra como um todo, a taxa de acertos foi alta, ficando acima dos 70%. Ao contrapor os subgrupos, foram identificados resultados significativos para as análises relativas a escolaridade (p=0,016), área de formação (p=0,004), gênero (p=0,045) e proximidade com a doença (p=0,004), em que foi observado que as menores taxas de acertos foram de pessoas com o nível de escolaridade mais baixa, que não fazem parte da área de saúde, do sexo masculino e que não tiveram contato com pessoas próximas portadoras da doença. Conclusão: Foi possível avaliar o conhecimento dos participantes sobre o tema, entretanto, as ações atuais tomadas por grupos de extensão e divulgação científica e instituições de combate ao câncer de mama são válidas para alguns subgrupos, mas precisam atingir com mais qualidade pessoas de menor escolaridade, pessoas que não possuem formação na área da saúde e pessoas do sexo masculino

Introduction: Despite efforts to raise awareness of the population, the incidence and mortality due to breast cancer in Brazilian women remain high. Objective: To assess the level of knowledge of the Brazilian population about the risk factors that lead to the development of this disease. Method: A structured online questionnaire was sent through social networks and e-mail from September to December 2021. Participants were divided into subgroups (education, profession, gender, proximity to individuals affected by the disease and age groups) and the chi-square test was performed to verify significant differences between them. Results: Analyzing the 200 valid responses from the sample as a whole, the hit rate was high, reaching over 70%. By comparing subgroups, significant results were identified for the analyzes related to education (p=0.016), profession (p=0.004), gender (p=0.045) and proximity to the disease (p=0.004), where it was found that the lowest rates of correct answers were from individuals with lowest level of education, not working in health-related activities, males and who had no contact with someone with the disease. Conclusion: It was possible to evaluate the knowledge of the participants on the subject. The current actions taken by scientific dissemination groups and institutions to combat breast cancer are valid for some subgroups, however, they need to improve outreaching to individuals with less education, who are not working in health-related activities and males

Introducción: A pesar de los esfuerzos de sensibilización de la población, la incidencia y la mortalidad por cáncer de mama en mujeres brasileñas siguen siendo elevadas. Objetivo: Evaluar el nivel de conocimiento de la población brasileña sobre los factores de riesgo que conducen al desarrollo de esta enfermedad. Método: Se utilizó un cuestionario online estructurado, enviado de septiembre a diciembre de 2021, a través de redes sociales y correo electrónico. Los participantes se dividieron en subgrupos (educación, área de formación profesional, género, proximidad a los afectados por la enfermedad y grupos de edad) y se realizó la prueba de chi-cuadrado para verificar diferencias significativas entre ellos. Resultados: Analizando las 200 respuestas válidas de la muestra en su conjunto, la tasa de acierto fue alta, superando el 70%. Al contrastar subgrupos, se identificaron resultados significativos para los análisis relacionados con escolaridad (p=0,016), área de formación (p=0,004), género (p=0,045) y proximidad a la enfermedad (p=0,004), donde se observó que las tasas más bajas de aciertos fueron de las personas con menor nivel de instrucción, que no forman parte del área de salud, son del sexo masculino y no han tenido contacto con alguien con la enfermedad. Conclusión: Fue posible evaluar el conocimiento de los participantes sobre el tema. Las acciones actuales de los grupos de divulgación científica e instituciones para combatir el cáncer de mama son válidas para algunos subgrupos, pero necesitan llegar con más calidad a las personas con menor educación, a las personas que no tienen formación en el área de la salud y personas del sexo masculino

Blood groups in Native Americans: a look beyond ABO and Rh.

The study presents comparisons between blood group frequencies beyond ABO and Rh blood systems in Native American populations and previously published data from Brazilian blood donors. The frequencies of Diego (c.2561C>T, rs2285644), Kell (c.578C>T, rs8176058), Duffy (c.125A>G, rs12075, c.1-67T>C, rs2814778) and Kidd (c.838A>G, rs1058396) variants in Kaingang (n=72) and Guarani (n=234) populations from Brazil (1990-2000) were obtained and compared with data from these populations sampled during the 1960s and with individuals of different Brazilian regions. Data showed high frequencies of DI*01 and FY*01 alleles: 11.8% and 57.6% in Kaingang and 6.8% and 75.7% in Guarani groups, respectively. The main results indicated: (1) reduction in genetic distance over time of Kaingang and Guarani in relation to other Brazilian populations is suggestive of ongoing admixture; (2) significant differences in some frequencies of blood group markers (especially Diego, Kidd and Duffy) in relation to Native Americans and individuals from different geographical regions of Brazil. Our study shows that the frequency of red blood cell polymorphisms in two Native American groups is very different from that of blood donors, when we evaluated blood groups different from ABO and Rh systems, suggesting that a better ethnic characterization of blood unit receptors is necessary.

Association of TNFRSF1A and IFNLR1 Gene Polymorphisms with the Risk of Developing Breast Cancer and Clinical Pathologic Features.

Several genes have been associated with breast cancer (BC) susceptibility. The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and interferon lambda receptor 1 (IFNLR1) genes encode receptors that mediate the action of inflammatory cytokines. Previous studies have demonstrated the association of the variants rs1800693 (TNFRSF1A) and rs4649203 (IFNLR1) with some inflammatory diseases. The present study aimed to verify a possible association of these variants with BC, its clinical pathologic features, as well as epidemiological data in a Brazilian population. A total of 243 patients and 294 individuals without history of BC were genotyped for these polymorphisms through TaqMan® SNP genotyping assays by qPCR. For the TNFRSF1A gene, no significant results were found. For IFNLR1, the AA genotype (p = 0.008) and the A allele (p = 0.02) were significantly associated with a lower risk of developing BC. When analyzing the age, it was observed that each increase of one year contributes to the development of BC (p < 0.001). Also, the smoking habit (p < 0.001) and body mass index (p = 0.018) increase the risk of disease development. Analyzing progesterone receptor factor an association was found with the AA genotype of the IFNLR1 (p = 0.02). The findings suggest that polymorphism in the immune-related IFNLR1 gene contribute to BC susceptibility in a Brazilian population. These findings can contribute to the further understanding of the role this gene and pathways in BC development.

C-reactive protein gene rs1205 polymorphism is associated with low-grade chronic inflammation in postmenopausal women.

BACKGROUND: Cardiovascular disease is the leading cause of death in postmenopausal women, and inflammation is a key mechanism involved in the pathogenesis of atherosclerosis. High-sensitivity C-reactive protein (hs-CRP) has been used as a biomarker of inflammation. Considering that CRP gene rs1205 polymorphism has been associated with hs-CRP circulating levels, we evaluated whether rs1205 genotypes influence the presence of low-grade chronic inflammation, acting as a marker of cardiovascular risk. METHODS: We performed a cross-sectional study with biobanked blood samples from 327 postmenopausal women with no evidence of clinical disease. Genotyping for rs1205 C > T SNP of the CRP gene was done by real-time polymerase chain reaction with allelic discrimination assays. RESULTS: Mean age was 55.6 ± 5.6 years. Mean body mass index (BMI) was 27.3 ± 4.7. Participants were divided according to hs-CRP levels: ≥3 mg/l (low-grade chronic inflammation) or < 3 mg/l. The frequency of allele C at rs1205 was 74.2% in the hs-CRP ≥ 3 mg/l group vs. 59% in the hs-CRP < 3 mg/l. In a multivariable model, higher prevalence of hs-CRP ≥ 3 mg/l was associated with CC genotype (PR 1.53; 95%CI 1.07-2.18; p = 0.018) and waist circumference ≥ 88 cm (PR 2.45; 95%CI 1.66-3.60; p < 0.001). CONCLUSIONS: CRP rs1205 CC homozygotes may be at higher risk of a low-grade chronic inflammatory status compared to individuals carrying the T allele.

Genetic variability of blood groups in southern Brazil.

We evaluated genetic variability among the blood groups Kell (c.578C > T and c.1790T > C), Kidd (c.838A > G), Duffy (c.125A > G, c.265C > T and c.1-67T > C), Diego (c.2561C > T), MNS (c.143T > C) and Rh (c.676G > C) in Rio Grande do Sul in southern Brazil. Genetic profiling from 382 volunteer blood donors was performed through allelic discrimination assays using a hydrolysis probe (TaqMan®) with a real-time PCR system. The sample was divided into two groups: Euro-Brazilian and Afro-Brazilian. A comparison with studies from other regions of Brazil and the 1000 Genomes Database showed significant differences for almost all polymorphisms evaluated in our population. Population differentiation between the Euro- and Afro-Brazilian groups was low (FST value 0.055). However, when each locus was evaluated individually, KEL*06 and FY*02N.01 allele frequencies were significantly higher in the Afro-Brazilian group than in the Euro-Brazilian group. Ethnic classification that uses phenotypic criteria to find blood units with rare antigens may be important when there is a need to detect blood units with an absence of Duffy antigens. There is also a greater probability of finding donors in the Afro-Brazilian group. Taken together, the data indicate strong European and African contributions to the gene pool, with intense admixture.

Genetic risk score based on fat mass and obesity-associated, transmembrane protein 18 and fibronectin type III domain containing 5 polymorphisms is associated with anthropometric characteristics in South Brazilian children and adolescents.

The prevalence of childhood obesity has increased worldwide. Although it is considered a polygenic inheritance disease, little is known about its susceptibility when the additive effect is considered. The aim of this study is to investigate whether the genetic risk score (GRS) based on previously associated obesity polymorphisms (SNP) rs9939609 (fat mass and obesity-associated (FTO)), rs6548238 (transmembrane protein 18 (TMEM18)) and rs16835198 (fibronectin type III domain containing 5 (FNDC5)) could serve as a predictor for anthropometric characteristics in a sample of Brazilian children and adolescents. This is a cross-sectional study with 1471 children and adolescents aged 6-17 years. BMI, waist circumference (WC) and percentage of body fat and metabolic parameters were verified. In all, three SNP were genotyped by TaqMan™ allelic discrimination. The metabolic and anthropometric parameters were compared between the genotypes, and the unweighted and weighted GRS (GRS and wGRS, respectively) were created to test the additive effect of these genetic polymorphisms on anthropometric parameters. The prevalence of overweight plus obesity was 41 %. Significant associations were identified for FTO rs9939609, TMEM18 rs6548238 and FNDC5 rs16835198 and for GRS and wGRS with anthropometric phenotypes. The higher score of wGRS was associated with obesity (OR: 2·65, 95 % CI 1·40, 5·04, P=0·003) and with greater WC (OR: 2·91, 95 % CI 1·57, 5·40, P=0·001). Our results suggest that these genetic variants contribute to obesity susceptibility in children and adolescents and reinforce the idea that the additive effect may be useful to elucidate the genetic component of obesity.

Impact of cross-sex hormone therapy on bone mineral density and body composition in transwomen.

OBJECTIVE: Cross-sex hormone therapy (CSHT) has been associated with changes in bone and lean/fat mass. This study assessed bone mineral density (BMD), appendicular lean mass (ALM), and total fat mass in transwomen undergoing CSHT. PATIENTS AND DESIGN: We evaluated 142 transwomen (mean age: 33.7 ± 10.3 years; BMI: 25.4 ± 4.6; 86.6% with previous CSHT) during the first 3 months of regular oestrogen treatment (with or without anti-androgens). A reference group including 22 men and 17 cis women was also studied. MEASUREMENTS: Clinical and hormonal evaluation and dual-energy X-ray absorptiometry (DXA). RESULTS: Bone mineral density was similar in trans and reference women, and lower at all sites in transwomen vs men. Low bone mass for age was observed in 18% of transwomen at baseline vs none of the reference women or men. Appendicular lean mass and total fat mass were positively correlated with L1-L4 BMD, explaining 14.9% of the observed variation in lumbar spine BMD and 20.6% of the variation in total femur BMD. Appendicular lean mass was similar in trans and reference women, and lower in transwomen vs men. Total fat mass was lower in trans vs reference women. Densitometry was repeated after a mean of 31.3 ± 6.5 months in 46 transwomen. There was a significant increase in total fat mass and a significant decrease in ALM. Bone mineral density remained stable over time. CONCLUSIONS: The fairly high prevalence of low bone mass in this sample of transwomen from southern Brazil seems to be related to lower ALM. Non-pharmacological lifestyle-related strategies for preventing bone loss could be beneficial for transgender women receiving long-term CSHT.

Variability of innate immune system genes in Native American populations-relationship with history and epidemiology.

OBJECTIVES: The immune system of a host, defending him/her against invading pathogens, has two main subsystems: innate immunity and acquired immunity. There are several evidences showing that Native American populations are immunologically different from non-Native populations. Our aim was to describe the variability of innate immune system genes in Native American populations. MATERIALS AND METHODS: We investigated heterozygozities and patterns of population differentiation (FST ) of 14 polymorphisms related to the innate immune response in five Native American populations (Aché, Guarani-Kaiowá, Guarani-Ñandeva, Kaingang, and Xavante) and the results were compared with the three major world population data (YRI, CEU, and CHB) available at the 1,000 genomes database. RESULTS: Mean heterozygosities ranged between 0.241 ± 0.057 (Aché) and 0.343 ± 0.033 (Kaingang), but no significant differences were observed (Friedman test, P = 0.197). Mean heterozygosities were also not significantly different when Amerindians were pooled and compared with the 1000 genomes populations (Friedman test, P = 0.506). When the Native American populations were grouped as Amerindians, a significantly higher FST value (0.194) was observed between the Amerindian and African populations. The Ewens-Watterson neutrality test showed that these markers are not under strong selective pressure. DISCUSSION: Native American populations present similar levels of heterozygosity as those of other continents, but are different from Africans in the frequency of polymorphisms of innate immune genes. This higher differentiation is probably due to demographic processes that occurred during the out-of-Africa event.

Calculando o tamanho de efeito no SPSS / Calculating the Effect Size in SPSS

O tamanho de efeito é uma estatística descritiva que serve como complemento aoteste de significância estatística. Cada vez mais esse tipo de abordagem vem sendoestimulada, em alguns casos até exigida, pelas publicações da área científica.Foram escolhidas algumas medidas de tamanho de efeito para uma explicaçãomais detalhada: o tamanho de efeito de d de Cohen, g de Hedges, D de Glass paracomparação das médias de dois grupos e o f2 de Cohen utilizado na análise demedidas correlacionadas. Esses tamanhos de efeito foram calculados em exemplosobtidos a partir de simulação usando o SPSS v.18.0.0.

Effect size is a descriptive statistic that complements the statistical significancetest. The use of this type of approach has been increasingly stimulated, or evenrequired, in scientific publications. We selected some measures of effect size inorder to provide a more detailed explanation: the effect size of Cohen’s d, Hedges’g, Δ of Glass for comparison of the means of two groups, and Cohen’s f² was used inthe analysis of correlated measures. These effect sizes were calculated in samplesobtained from simulation using the SPSS v.18.