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BACKGROUND: Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein 1 (LDLRAP1). However, approximately 40% of the FH patients clinically diagnosed (based on FH phenotypes) may not carry a causal variant in a FH-related gene. Variants located at 3' untranslated region (UTR) of FH-related genes could elucidate mechanisms involved in FH pathogenesis. This study used a computational approach to assess the effects of 3'UTR variants in FH-related genes on miRNAs molecular interactions and to explore the association of these variants with molecular diagnosis of FH. METHODS AND RESULTS: Exons and regulatory regions of FH-related genes were sequenced in 83 FH patients using an exon-target gene sequencing strategy. In silico prediction tools were used to study the effects of 3´UTR variants on interactions between miRNAs and target mRNAs. Pathogenic variants in FH-related genes (molecular diagnosis) were detected in 44.6% FH patients. Among 59 3'UTR variants identified, LDLR rs5742911 and PCSK9 rs17111557 were associated with molecular diagnosis of FH, whereas LDLR rs7258146 and rs7254521 and LDLRAP1 rs397860393 had an opposite effect (p < 0.05). 3´UTR variants in LDLR (rs5742911, rs7258146, rs7254521) and PCSK9 (rs17111557) disrupt interactions with several miRNAs, and more stable bindings were found with LDLR (miR-4435, miR-509-3 and miR-502) and PCSK9 (miR-4796). CONCLUSION: LDLR and PCSK9 3´UTR variants disturb miRNA:mRNA interactions that could affect gene expression and are potentially associated with molecular diagnosis of FH.

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BACKGROUND Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein 1 (LDLRAP1). However, approximately 40% of the FH patients clinically diagnosed (based on FH phenotypes) may not carry a causal variant in a FH-related gene. Variants located at 3' untranslated region (UTR) of FH-related genes could elucidate mechanisms involved in FH pathogenesis. This study used a computational approach to assess the effects of 3'UTR variants in FH-related genes on miRNAs molecular interactions and to explore the association of these variants with molecular diagnosis of FH. METHODS AND RESULTS Exons and regulatory regions of FH-related genes were sequenced in 83 FH patients using an exon-target gene sequencing strategy. In silico prediction tools were used to study the effects of 3´UTR variants on interactions between miRNAs and target mRNAs. Pathogenic variants in FH-related genes (molecular diagnosis) were detected in 44.6% FH patients. Among 59 3'UTR variants identified, LDLR rs5742911 and PCSK9 rs17111557 were associated with molecular diagnosis of FH, whereas LDLR rs7258146 and rs7254521 and LDLRAP1 rs397860393 had an opposite effect (p < 0.05). 3´UTR variants in LDLR (rs5742911, rs7258146, rs7254521) and PCSK9 (rs17111557) disrupt interactions with several miRNAs, and more stable bindings were found with LDLR (miR-4435, miR-509-3 and miR-502) and PCSK9 (miR-4796). CONCLUSION LDLR and PCSK9 3´UTR variants disturb miRNA:mRNA interactions that could affect gene expression and are potentially associated with molecular diagnosis of FH.

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Exposure to heavy metals in mining zones is a significant threat, which can affect ecosystem services and contribute to the decline of wild bat populations. The present study investigated the impacts caused by mining on two bat species in central Brazil, the nectarivorous Glossophaga soricina and the frugivorous Carollia perspicillata. The bats were collected from a nickel-mining zone (treatment) and a protected area (control). The leukocyte profile of each species was compiled and genotoxicity (comet assay) and mutagenicity (micronucleus test) were determined using the appropriate procedures. Glossophaga soricina presented significantly higher frequencies of eosinophils and monocytes in the mining zone in comparison with the protected area, whereas C. perspicillata presented higher frequencies of lymphocytes in the mining zone, but significantly lower frequencies of monocytes. Concomitantly, G. soricina also presented a higher frequency of DNA damage, although no variation was found in this parameter in C. perspicillata when comparing environments. We also found no significant differences between populations in terms of the frequency of micronuclei and other nuclear abnormalities. Overall, the results of the study indicate that bats are susceptible to immunological disorders and DNA damage in mining zones, with the nectarivorous G. soricina appearing to be relatively more susceptible and thus a potentially effective bioindicator of the impact of contamination in these environments.

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Bats may serve as bioindicators of human impact on landscape ecology. This study aimed to evaluate the health condition of bats from different food guilds captured in two areas with different land use profiles in Brazil and to compare data on the oxidant-antioxidant balance and histopathological changes due to different anthropogenic pressures. Bats were collected from a protected area in Serra do Cipó National Park (SCNP), MG, Brazil, and an area with intense agricultural activity in the municipality of Uberaba (UB), MG, Brazil. Despite the differences in land use and occupation between the studied areas, bats showed similar responses. However, the trophic guilds were affected differently. Frugivorous bats in both areas showed lower activities of the enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) and concentrations of malondialdehyde (MDA) than other guilds, which can be explained by the greater intake of antioxidants from the diet in addition to the lower production of reactive oxygen species (ROS). Histopathological analysis of the livers revealed that the animals had a similar prevalence in the two areas, with some differences related to guilds. Compared with other bats, hematophagous bats from SCNP had a higher prevalence of steatosis and, together with frugivorous bats from Uberaba, had higher frequencies of ballooning degeneration, suggesting that these animals are subjected to anthropogenic factors capable of inducing disturbances in hepatic metabolism. Hematophagous bats from Uberaba had a higher prevalence of portal inflammation, while insectivorous bats from Uberaba had a higher prevalence of lobular and portal inflammation. The profiles of use and occupation of the areas are different; Uberaba bats seem to face worse conditions because they show more liver damage owing to lipoperoxidation.

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Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.

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OBJECTIVE: The study aimed to characterize the clinical, histological, and immunohistochemical profile of women with invasive breast cancer, according to the risk for Hereditary Predisposition Breast and Ovarian Cancer Syndrome in a Brazilian population. METHODS: This is a retrospective study performed from a hospital-based cohort of 522 women, diagnosed with breast cancer treated at an oncology referral center in the Southeast region of Brazil, between 2014 and 2016. RESULTS: Among the 430 women diagnosed with invasive breast cancer who composed the study population, 127 (29.5%) were classified as at increased risk for hereditary predisposition to breast and ovarian cancer syndrome. There was a lower level of education in patients at increased risk (34.6%) when compared with those at usual risk (46.0%). Regarding tumor characteristics, women at increased risk had higher percentages of the disease diagnosed at an advanced stage (32.3%), and with tumors > 2cm (63.0%), with increased prevalence for both characteristics, when compared with those at usual risk. Furthermore, we found higher percentages of HG3 (43.3%) and Ki-67 ≥ 25% (64.6%) in women at increased risk, with prevalence being about twice as high in this group. The presence of triple-negative tumors was observed as 25.2% in women at increased risk and 6.0% in women at usual risk, with the prevalence of absence of biomarkers being 2.5 times higher among women in the increased risk group. CONCLUSION: From the clinical criteria routinely used in the diagnosis of breast cancer, the care practice of genetic counseling for patients at increased risk of hereditary breast cancer in contexts such as Brazil is still scarce.

OBJETIVO: O presente estudo buscou caracterizar o perfil clínico, histológico e imunohistoquímico de mulheres com câncer de mama invasivo segundo o risco para a Síndrome de Predisposição Hereditária ao Câncer de Mama e Ovário em uma população brasileira. MéTODOS: Trata-se de um estudo retrospectivo realizado a partir de uma coorte hospitalar composta por 522 mulheres diagnosticadas com câncer de mama entre 2014 e 2016 assistidas em um centro de referência oncológica localizado na região sudeste brasileira. RESULTADOS: Entre as 430 mulheres diagnosticadas com câncer de mama invasivo que compuseram a população de estudo, 127 (29,5%) foram classificadas como de risco aumentado para a síndrome de predisposição hereditária ao câncer de mama e ovário. Verificou-se menor nível de escolaridade nas pacientes com risco aumentado (34,6%) quando comparadas àquelas consideradas como de risco habitual (46,0%). Quanto às características do tumor, as mulheres de risco aumentado apresentaram maiores percentuais de doença diagnosticada em estádio avançado (32,3%) e com tumores > 2cm (63,0%), com prevalência aumentada para ambas as características, quando comparadas àquelas de risco habitual. Ainda nas mulheres de risco aumentado, foram encontrados maiores percentuais de GH3 (43,3%) e Ki-67 ≥ 25% (64,6%), com prevalência cerca de duas vezes maior neste grupo. A presença de tumores triplo-negativos foi observada em 25,2% nas mulheres de risco aumentado e 6,0% nas mulheres de risco habitual, com prevalência de ausência de biomarcadores 2,5 vezes maior entre as mulheres do grupo de risco aumentado. CONCLUSãO: A partir dos critérios clínicos rotineiramente utilizados no diagnóstico do câncer de mama, a prática assistencial do aconselhamento genético para as pacientes com risco aumentado de câncer de mama hereditário em contextos como o do Brasil ainda é escarça.

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OBJECTIVE: To assess the frequency and factors associated of the provision of nutrition support (NS) in the last 30 days of life in patients with advanced cancer in the palliative or non-palliative setting. METHODS: Retrospective cohort study in palliative and non-palliative care units at a specialized cancer center for oncology in Brazil. The use of oral nutrition supplements (ONS) and enteral (EN) and parenteral (PN) nutrition in the 30 days before death were assessed. RESULTS: The 239 patients included were predominantly older (>60 years; 63.2%) and female (61.1%). The use of ONS was lower in palliative than non-palliative care during the last 30 (52% vs. 6%), 7 (42% vs. 4%), and 3 (23% vs. 2%) days before death (all P < .001). The use of EN and PN was lower in palliative care, decreasing with the approach of death. The independent factors associated with ONS in non-palliative care were (odds ratio): breast tumor (3.03), hypoalbuminemia (1.10), and nutrition risk (16.98); in palliative care, only the Karnofsky Performance Status (KPS) ≥40% (1.24) was associated to the use of ONS. The use of EN and PN was associated with head-neck (HN) tumor in both settings (5.41) in non-palliative and (8.74) in palliative. Others independent factors were: hypoalbuminemia (3.12) in non-palliative care and KPS (1.31) in palliative care. CONCLUSIONS: The use of NS near the end of life was high in the non-palliative and less frequent in palliative care setting. The factors associated with NS differed according to the clinical oncology setting, with one of the factors in palliative care being a better prognosis.

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OBJECTIVE: Yacon flour is rich in bioactive compounds (phenolic compounds and fructooligosaccharides (FOS)), and may therefore reduce the risk of diseases associated with excess body weight. However, its effect on fecal short chain fatty acids (SCFA), intestinal permeability, oxidative stress and inflammation markers has not been studied in adult humans with excess body weight. Thus, we evaluated the effect of the consumption of yacon flour on these variables. METHODS: Twenty-six excess body weight (30.4 ± 2.4 kg/m2) adults (31.3 ± 8.5y) were randomized to one of two groups (yacon flour or control; n = 13) on a double blind clinical trial. Subjects received a breakfast drink containing or not yacon flour (25g) associated with an energy restricted diet, for six weeks. The flour chemical characterization, FOS and total phenolics contents were evaluated. Antioxidant capacity was evaluated in vitro and in vivo (plasma). Intestinal permeability, fecal SCFA, oxidative stress and inflammatory markers also were evaluated in vivo. RESULTS: Yacon flour was well tolerated. It presented an in vitro and in vivo antioxidant capacity, increased plasma total antioxidant capacity (ΔYAC: 49.16 (-4.20; 156.63)) and reduced protein carbonyl concentrations (ΔYAC: -0.98 (-1.54; -0.42)). A reduction in SCFAs was observed in both groups (Δacetic: -3.16 (-5.07; -0.95) vs. -1.05 (-2.65; 1.11); Δpropionic: -1.05 (-2.60;-0.38) vs. -0.41 (-2.08; 0.09); Δbutyric -0.75 (-1.38; -0.04) vs. -0.28 (-0.98; 0.11), for YAC and CON, respectively). Other variables did not change. CONCLUSION: The yacon flour increased the plasma antioxidant capacity, decreased oxidative stress and SCFAs in adults with obesity or overweight.

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OBJECTIVE: To describe overall survival (OS) in 90 days and to evaluate the prognostic factors in patients with advanced cancer and COVID-19. METHODS: This is a retrospective cohort study carried out at the Palliative Care Unit of the Brazilian National Cancer Institute. Patients with advanced cancer and COVID-19 confirmed by Reverse Transcription Polymerase Chain Reaction were included. Kaplan-Meier's curves, log-rank test, and Cox regression were performed. RESULTS: Eighty-three inpatients were selected. The average age was 61.4 (±12.6) years, with a higher proportion of women (73.4%). The most prevalent tumor type was breast (36.7%), followed by gastrointestinal tract (20.3%). The OS was 32 [interquartile range (IQR): 6-70] days, and at the end of the follow-up period, 17 patients (20.5%) were alive and 66 (79.5%) had died. Patients with advanced cancer and COVID-19 and who were 60-74 years old [hazard ratio (HR): 2.03; 95% confidence interval (CI): 1.09-3.78], with lung tumors (HR: 17.50; 95% CI: 1.70-28.34), with lung metastasis (HR: 4.21; 95% CI: 2.17-8.15), and with chronic obstructive pulmonary disease (HR: 4.92; 95% CI: 1.01-24.69) had higher risk of death in 90 days. CONCLUSION: The age of 60-74 years old, lung tumors (primary or metastases), and the presence of chronic obstructive pulmonary disease were considered independent prognostic factors in patients with advanced cancer and COVID-19.

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Aim: To explore the association of circulating miRNAs with adiposity, metabolic status and inflammatory biomarkers in patients with metabolic syndrome (MetS). Methods: Serum levels of 372 miRNAs were measured in patients with (n = 6) and without MetS (n = 6) by quantitative PCR array, and dysregulated miRNAs were validated in a larger cohort (MetS, n = 89; non-MetS, n = 144). Results: In the screening study, seven miRNAs were dysregulated in patients with MetS, and miR-421 remained increased in the validation study. miR-421 was associated with a high risk of MetS and insulin resistance and hypertension and correlated with glycated hemoglobin, triacylglycerols, high-sensitivity CRP, IL-6, resistin and adiponectin (p < 0.05). Conclusion: Circulating miR-421 is a potential biomarker for insulin resistance, metabolic dysregulation and inflammatory status in patients with MetS.

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