Unlocking the complete blood count as a risk stratification tool for breast cancer using machine learning: a large scale retrospective study.

Optimizing early breast cancer (BC) detection requires effective risk assessment tools. This retrospective study from Brazil showcases the efficacy of machine learning in discerning complex patterns within routine blood tests, presenting a globally accessible and cost-effective approach for risk evaluation. We analyzed complete blood count (CBC) tests from 396,848 women aged 40-70, who underwent breast imaging or biopsies within six months after their CBC test. Of these, 2861 (0.72%) were identified as cases: 1882 with BC confirmed by anatomopathological tests, and 979 with highly suspicious imaging (BI-RADS 5). The remaining 393,987 participants (99.28%), with BI-RADS 1 or 2 results, were classified as controls. The database was divided into modeling (including training and validation) and testing sets based on diagnostic certainty. The testing set comprised cases confirmed by anatomopathology and controls cancer-free for 4.5-6.5 years post-CBC. Our ridge regression model, incorporating neutrophil-lymphocyte ratio, red blood cells, and age, achieved an AUC of 0.64 (95% CI 0.64-0.65). We also demonstrate that these results are slightly better than those from a boosting machine learning model, LightGBM, plus having the benefit of being fully interpretable. Using the probabilistic output from this model, we divided the study population into four risk groups: high, moderate, average, and low risk, which obtained relative ratios of BC of 1.99, 1.32, 1.02, and 0.42, respectively. The aim of this stratification was to streamline prioritization, potentially improving the early detection of breast cancer, particularly in resource-limited environments. As a risk stratification tool, this model offers the potential for personalized breast cancer screening by prioritizing women based on their individual risk, thereby indicating a shift from a broad population strategy.

Novos Biomarcadores Cardiovasculares em Pacientes com Câncer de Mama Submetidas a Quimioterapia à Base de Doxorrubicina / New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy

Resumo Fundamento As doenças cardiovasculares (DCV) são relevantes para o manejo do tratamento do câncer de mama, uma vez que um número significativo de pacientes desenvolve essas complicações após a quimioterapia. Objetivo Este estudo teve como objetivo avaliar novos biomarcadores cardiovasculares, sendo eles CXCL-16 (ligante de motivo C-X-C 16), FABP3 (proteína de ligação a ácidos graxos 3), FABP4 (proteína de ligação a ácidos graxos 4), LIGHT (membro da superfamília do fator de necrose tumoral 14/TNFS14), GDF-15 (fator de crescimento/diferenciação 15) , sCD4 (forma solúvel de CD14) e ucMGP (matriz Gla-proteína não carboxilada) em pacientes com câncer de mama tratadas com doxorrubicina (DOXO). Métodos Este estudo de caso-controle foi realizado em uma clínica oncológica, incluindo 34 mulheres com diagnóstico de câncer de mama tratadas com quimioterapia com DOXO e 34 mulheres controle, sem câncer ou DCV. Os marcadores foram determinados imediatamente após o último ciclo de quimioterapia. O nível de significância estatística adotado foi de 5%. Resultados O grupo com câncer de mama apresentou níveis mais elevados de GDF-15 (p<0,001), enquanto os indivíduos controle apresentaram níveis mais elevados de FABP3 (p=0,038), FABP4 (p=0003), sCD14 e ucMGP (p<0,001 para ambos). Correlações positivas foram observadas entre FABPs e IMC no grupo com câncer. Conclusão GDF15 é um biomarcador emergente com potencial aplicabilidade clínica neste cenário. FABPs são proteínas relacionadas à adiposidade, potencialmente envolvidas na biologia do câncer de mama. sCD14 e ucMGP estão envolvidos na calcificação inflamatória e vascular. Acima de tudo, a avaliação destes novos biomarcadores cardiovasculares pode ser útil no tratamento da quimioterapia do câncer de mama com DOXO.

Abstract Background Cardiovascular diseases (CVDs) are relevant to the management of breast cancer treatment since a substantial number of patients develop these complications after chemotherapy. Objective This study aims to evaluate new cardiovascular biomarkers, namely CXCL-16 (C-X-C motif ligand 16), FABP3 (fatty acid binding protein 3), FABP4 (fatty acid binding protein 4), LIGHT (tumor necrosis factor superfamily member 14/TNFS14), GDF-15 (Growth/differentiation factor 15), sCD4 (soluble form of CD14), and ucMGP (uncarboxylated Matrix Gla-Protein) in breast cancer patients treated with doxorubicin (DOXO). Methods This case-control study was conducted in an oncology clinic that included 34 women diagnosed with breast cancer and chemotherapy with DOXO and 34 control women without cancer and CVD. The markers were determined immediately after the last cycle of chemotherapy. The statistical significance level adopted was 5%. Results The breast cancer group presented higher levels of GDF-15 (p<0.001), while control subjects had higher levels of FABP3 (p=0.038), FABP4 (p=0003), sCD14, and ucMGP (p<0.001 for both). Positive correlations were observed between FABPs and BMI in the cancer group. Conclusion GDF15 is an emerging biomarker with potential clinical applicability in this scenario. FABPs are proteins related to adiposity, which are potentially involved in breast cancer biology. sCD14 and ucMGP engage in inflammatory and vascular calcification. The evaluation of these novel cardiovascular biomarkers could be useful in the management of breast cancer chemotherapy with DOXO.

Evaluation of the RDW Index (Red Cell Distribution Width) in Women with Breast Cancer Treated with Doxorubicin in a One-Year Follow-Up Study.

Breast cancer is the most common cancer and the most frequent cause of death in women. Doxorubicin, an anthracycline, is an important drug due to its efficacy in treating solid cancers, especially breast cancer. However, this drug is often responsible for cardiotoxicity that may affect more than 25% of patients. This study aimed to evaluate the red cell distribution width (RDW) in women with breast cancer to monitor adverse events associated with the use of doxorubicin. A prospective study of 80 women with breast malignancy undergoing neoadjuvant doxorubicin-based chemotherapy was conducted. The patients were evaluated at baseline (T0), just after the last cycle of chemotherapy with doxorubicin (T1), and 1 year after the treatment (T2). There was a significant increase over the time points for the RDW (p < 0.001). There was a negative correlation between the RDW and C-reactive protein (CRP) levels at T1. The RDW did not show a significant difference between the groups classified according to cardiotoxicity. Based on these results, the RDW is a cost-effective test that shows a relationship with the doxorubicin response, but not with cardiotoxicity. It is a potential biomarker to evaluate patients with breast cancer after they receive chemotherapy with doxorubicin.

New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy. / Novos Biomarcadores Cardiovasculares em Pacientes com Câncer de Mama Submetidas a Quimioterapia à Base de Doxorrubicina.

BACKGROUND: Central Illustration : New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy. Cardiovascular diseases (CVDs) are relevant to the management of breast cancer treatment since a substantial number of patients develop these complications after chemotherapy. OBJECTIVE: This study aims to evaluate new cardiovascular biomarkers, namely CXCL-16 (C-X-C motif ligand 16), FABP3 (fatty acid binding protein 3), FABP4 (fatty acid binding protein 4), LIGHT (tumor necrosis factor superfamily member 14/TNFS14), GDF-15 (Growth/differentiation factor 15), sCD4 (soluble form of CD14), and ucMGP (uncarboxylated Matrix Gla-Protein) in breast cancer patients treated with doxorubicin (DOXO). METHODS: This case-control study was conducted in an oncology clinic that included 34 women diagnosed with breast cancer and chemotherapy with DOXO and 34 control women without cancer and CVD. The markers were determined immediately after the last cycle of chemotherapy. The statistical significance level adopted was 5%. RESULTS: The breast cancer group presented higher levels of GDF-15 (p<0.001), while control subjects had higher levels of FABP3 (p=0.038), FABP4 (p=0003), sCD14, and ucMGP (p<0.001 for both). Positive correlations were observed between FABPs and BMI in the cancer group. CONCLUSION: GDF15 is an emerging biomarker with potential clinical applicability in this scenario. FABPs are proteins related to adiposity, which are potentially involved in breast cancer biology. sCD14 and ucMGP engage in inflammatory and vascular calcification. The evaluation of these novel cardiovascular biomarkers could be useful in the management of breast cancer chemotherapy with DOXO.

FUNDAMENTO: Figura Central: Novos Biomarcadores Cardiovasculares em Pacientes com Câncer de Mama Submetidas a Quimioterapia à Base de Doxorrubicina. As doenças cardiovasculares (DCV) são relevantes para o manejo do tratamento do câncer de mama, uma vez que um número significativo de pacientes desenvolve essas complicações após a quimioterapia. OBJETIVO: Este estudo teve como objetivo avaliar novos biomarcadores cardiovasculares, sendo eles CXCL-16 (ligante de motivo C-X-C 16), FABP3 (proteína de ligação a ácidos graxos 3), FABP4 (proteína de ligação a ácidos graxos 4), LIGHT (membro da superfamília do fator de necrose tumoral 14/TNFS14), GDF-15 (fator de crescimento/diferenciação 15) , sCD4 (forma solúvel de CD14) e ucMGP (matriz Gla-proteína não carboxilada) em pacientes com câncer de mama tratadas com doxorrubicina (DOXO). MÉTODOS: Este estudo de caso-controle foi realizado em uma clínica oncológica, incluindo 34 mulheres com diagnóstico de câncer de mama tratadas com quimioterapia com DOXO e 34 mulheres controle, sem câncer ou DCV. Os marcadores foram determinados imediatamente após o último ciclo de quimioterapia. O nível de significância estatística adotado foi de 5%. RESULTADOS: O grupo com câncer de mama apresentou níveis mais elevados de GDF-15 (p<0,001), enquanto os indivíduos controle apresentaram níveis mais elevados de FABP3 (p=0,038), FABP4 (p=0003), sCD14 e ucMGP (p<0,001 para ambos). Correlações positivas foram observadas entre FABPs e IMC no grupo com câncer. CONCLUSÃO: GDF15 é um biomarcador emergente com potencial aplicabilidade clínica neste cenário. FABPs são proteínas relacionadas à adiposidade, potencialmente envolvidas na biologia do câncer de mama. sCD14 e ucMGP estão envolvidos na calcificação inflamatória e vascular. Acima de tudo, a avaliação destes novos biomarcadores cardiovasculares pode ser útil no tratamento da quimioterapia do câncer de mama com DOXO.

Frequency of germline genetic variants in women with a personal or family history of breast cancer from Brazil.

BACKGROUND: About 5-10% of breast cancer cases are related to genetic and hereditary factors. The application of Next Generation Sequencing (NGS) in oncology has allowed the identification of genetic variants present in several genes related to the increased risk of breast cancer. This study aimed to determine the frequency of germline genetic variants in patients with a family and/or personal history of breast cancer. METHODS: An analysis of positive reports from NGS panels was carried out in female individuals with a personal and/or family history of breast cancer, present in the database of a private laboratory in Brazil. RESULTS: From about 2000 reports, 183 individuals presented 219 different germline genetic variants. The genes with the highest number of variants were BRCA2 (16.0%), ATM (15.0%) and BRCA1 (12.8%). Among the variants found, 78 were either pathogenic or probably pathogenic, accounting for 35% of all variants discovered. The gene with the highest proportion of pathogenic/probably pathogenic variants was TP53 (80%) and the most frequent pathogenic variant was also reported in this gene (c.1010G > A p.(Arg337His)). Furthermore, the study obtained a high proportion of variants of uncertain significance (VUS) (65%) and approximately 32% of the variants found were in genes of moderate penetrance. CONCLUSIONS: Our results could improve the risk estimation and clinical follow-up of Brazilian patients with a history of breast cancer.

microRNA miR-133a as a Biomarker for Doxorubicin-Induced Cardiotoxicity in Women with Breast Cancer: A Signaling Pathway Investigation.

Cardiovascular toxicity is the main adverse effect of Doxorubicin (DOX) in cancer patients. microRNAs (miRNAs) are promising biomarkers to identify cardiac injury induced by DOX in breast cancer patients during the subclinical phase. Using RT-qPCR, we compared the expression of circulating miR-208a5p, miR-133a, miR-499a5p, miR-15a, miR-133b, and miR-49a3p in serum samples from DOX-induced cardiotoxicity (case) compared to the non-cardiotoxicity group (control). To further explore the potential roles of these circulating miRNA in cardiotoxicity, we searched the miRTarBase for experimentally validated miRNA-target interactions and performed a functional enrichment analysis based on those interactions. miR-133a was significantly upregulated in case compared to control group. The most relevant pathway regulated by miR-133a was ErbB2 signaling, whose main genes involved are EGFR, ERBB2, and RHOA, which are possibly downregulated by miR133a. The other miRNAs did not show significant differential expression when compared on both groups. The data suggest that miR-133a is associated with DOX-based cardiotoxicity during chemotherapy in breast cancer patients through ErbB2 signaling pathway. Moreover, miR-133a may be a future marker of DOX-induced cardiotoxicity in women with breast cancer.

Effects of Resveratrol Supplementation on the Cognitive Function of Patients with Alzheimer's Disease: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Alzheimer's disease (AD) comprises 60-70% of diagnosed dementia cases, and is characterized by the deposition of ß-amyloid peptide and the formation of neurofibrillary tangles of tau protein. Resveratrol is a neuroprotective agent acting in the prevention of redox impairment in addition to exerting anti-apoptotic actions on brain cells. An ability to reduce neuronal damage in patients with AD has been suggested by preclinical studies. OBJECTIVES: The aim of this systematic review was to investigate the evidence in the published literature from studies that evaluated the effects of supplementation with resveratrol, alone or in a solution with glucose and malate (RGM), on the functional and cognitive performance of patients with AD, as assessed by validated instruments. METHODS: A systematic literature search was performed in MEDLINE, CENTRAL, Embase, CINAHL, Web of Science, and Scopus databases including articles published up to August 2021. Randomized, placebo-controlled, clinical trials that reported cognitive and functional performance, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Cooperative Study of Alzheimer's Disease-Activities of Daily Living (ADCS-ADL), or the Mini Mental State Examination (MMSE), in AD patients treated with resveratrol, alone or as RGM, were included. RESULTS: After 1855 studies were identified, 24 RCTs underwent full-text review, with 20 studies excluded because they did not meet the inclusion criteria. Thus, four RCTs were included in the qualitative analyses. The findings demonstrate that there are still few studies in humans, but they showed that this polyphenol acts in the delay of cognitive impairment in patients with AD, when administered alone or in combination with glucose and malate. CONCLUSIONS: Supplementation with resveratrol seems to influence the progressive cognitive and functional decline in AD patients, when compared with a placebo group. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021229234.

Interleukin-10 Levels are Associated with Doxorubicin-Related Cardiotoxicity in Breast Cancer Patients in a One-Year Follow-Up Study.

BACKGROUND: Myocardial toxicity is a common side effect of doxorubicin (DOXO) therapy in breast cancer patients. We hypothesized that DOXO-induced cardiotoxicity may be related to the release of inflammatory cytokines in response to the treatment. This study aimed to assess changes in plasma levels of interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor (TNF) after chemotherapy and to correlate these levels with cardiac biomarkers and clinical data. METHODS: Sixty-four patients with breast cancer treated with DOXO were included. Twenty-two subjects (cases) developed cardiotoxicity until one year after the end of DOXO treatment. Cytokines and cardiac markers were evaluated before starting chemotherapy (T0), up to 7 days after the last infusion (T1) and 12 months after the last infusion (T2). RESULTS: Higher IL-10 levels were observed in the case group compared to controls at T1 (p = .006) and T2 (p = .046). The IL-1ß, IL-6 and TNF levels did not change during treatment in each group (p > .05), nor between the case and control groups. The IL-10 levels were higher at T1 than at T0 and T2 (p < .05 for both) in the cardiotoxicity group. A correlation between IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at T0 and T2 in the cardiotoxicity group was observed (p = .048 and p = .004, respectively). CONCLUSION: Our study demonstrated that DOXO induced an increase in plasma IL-10 levels in patients who presented cardiotoxicity after treatment, which correlated with NT-proBNP levels.

Identification of Clinical and Laboratory Variables Associated with Cardiotoxicity Events Due to Doxorubicin in Breast Cancer Patients: A 1-Year Follow-Up Study.

Cardiovascular adverse events in patients with breast cancer undergoing chemotherapy (CT) are frequent due to the high cardiotoxic potential of treatments, especially doxorubicin (DOXO). This study aimed to evaluate the association of plasma levels of various biomarkers with cardiotoxicity in women with breast cancer on DOXO-based chemotherapy. In this single center prospective cohort, 80 breast cancer patients who used DOXO as a first-line treatment for cancer were evaluated. Patients were assessed at three time points: before CT (T0), 1 week after (T1) and 12 months after DOXO treatment (T2). The predominant histological classification was ductal carcinoma, n = 72 (90.0%); the most frequent molecular classification was Human epidermal growth factor receptor-type 2 positive (HER2+), n = 34 (43.0%). In patients submitted to complementary treatment with trastuzumab (n = 23), there was no association with cardio-specific biomarkers. Evaluating the clinical variables and the laboratory parameters in T1 and T2 in relation to T0, the reduction any time of N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP), triglycerides and hematocrit levels showed an association with higher cardiotoxicity risk. In addition, increased levels of troponin I (cTnI) and glycated hemoglobin (HbA1c) showed an independent association with the occurrence of cardiotoxicity. These results suggest that the evaluation of these laboratory tests should be included routinely to identify breast cancer patients under DOXO treatment at cardiotoxicity risk.

Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by high levels of low-density lipoprotein-cholesterol (LDLc), associated to premature cardiovascular disease. The detection of the variants related to FH is important to improve the early diagnosis in probands / index-cases (ICs) and their relatives. We included ICs with FH and their relatives, living in a small region of Minas Gerais state-Brazil, which were classified according to Dutch Lipid Clinic Network Criteria (DLCNC) and submitted to sequencing of genes related to FH (LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, APOE, ABCG5 e ABCG8). In a total of 143 subjects (32 ICs and 111 relatives), eight variants were identified in 91 individuals. From these variants, five were in LDLR [p.(Asp224Asn), p.(Ser854Gly), p.(Cys34Arg), p.(Asp601His), deletion of exon15 in LDLR)], one in APOB [p.(Met499Val)], one in PCSK9 [p.(Arg237Trp)] and one in APOE [p.(Pro28Leu)] genes. The variants were detected in 100% of those subjects classified as definitive, 87% as probable and 69% as possible FH cases based on DLCNC. The LDLc level was higher in individuals with corneal arch and xanthomas or xanthelasmas, as well as in pathogenic or probably pathogenic variants carriers. This study showed higher frequency of LDLR gene variants compared to other genes related to LDL metabolism in individuals with FH in Minas Gerais - Brazil and the presence of FH in relatives without previous diagnosis. Our data reinforce the importance of molecular and clinical evaluation of FH relatives in order to early diagnosis the FH, as well as cardiovascular diseases prevention.

microRNAs associated to anthracycline-induced cardiotoxicity in women with breast cancer: A systematic review and pathway analysis.

BACKGROUND: Cardiotoxicity is a common and serious adverse effect of anthracycline therapy in breast cancer patients. The current criteria for cardiotoxicity are based on imaging and cardiac biomarkers. However, there is a need for new biomarkers to help with early diagnosis. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression. Several miRNAs have been associated with cardiovascular diseases and are biomarkers under investigation for cancer treatment-related cardiotoxicity. METHODS: We performed a systematic literature search of Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Web of Science and Embase, until April 2020. Cohort studies that reported miRNA biomarkers in breast cancer patients with anthracycline-induced cardiotoxicity and non-cardiotoxicity patients were included. Moreover, we searched the miRTarBase for experimentally validated miRNA-target interactions. RESULTS: Among the 209 studies retrieved, five fulfilled the inclusion criteria. Let-7f, miR-1, miR-20a, miR-126 and miR-210 were validated in two population-based cohorts. The pro-angiogenic miRNAs let-7f, miR-20a, miR-126 and miR-210 were significantly down-regulated in epirubicin-cardiotoxicity when compared to the non-cardiotoxicity group. miR-1 has been shown to provide diagnostic and prognostic information in the setting of myocardial infarction, but changes in its levels are controversial in doxorubicin-treated breast cancer patients with cardiotoxicity. Reactome pathways relevant to cardiotoxicity were found from the target genes for let-7f, miR-1, miR-20a, miR-126 and miR-210 at miRTarBase. CONCLUSION: The data suggest that let-7f, miR-1, miR-20a, miR-126 and miR-210 are associated with anthracycline-based cardiotoxicity during chemotherapy in breast cancer patients.

TNF, IL-6, and IL-10 cytokines levels and their polymorphisms in renal function and time after transplantation.

Cytokine polymorphisms can influence their plasma levels and thus affect the immune response in renal transplantation. A total of 146 renal transplant recipients (RTR) were classified into groups according to the estimated glomerular filtration rate (R1: < 60 and R2: ≥ 60 mL/min/1.73 m2) and time after transplantation (T1: 1 to 24, T2: 25 to 60, T3: 61 to 120, and T4: > 120 months after transplantation). The polymorphisms were genotyped by single specific primer-polymerase chain reaction. IL-10 was measured by ELISA and IL-6, and TNF levels were determined using Miliplex®. A higher frequency of the - 308G allele and the - 308G/G genotype, low-producer, was observed in the R1 group compared with R2. In addition, a higher frequency of the - 308A carriers, high-producer, was found in the R2 group. However, no significant difference was observed in cytokine levels when both groups were compared. Higher levels of IL-6 were observed in T1 compared with T2 and T4 groups. Lower IL-6 levels were found in T2 compared with T3 group. Lower levels of IL-10 were also found in T1 group in relation to T2, while higher levels of this cytokine were observed in T2 group compared with T3. The results suggest that the - 308G > A polymorphism in the TNF gene is associated with filtration function after renal transplantation, and IL-6 and IL-10 levels change according to the time after transplantation. Thus, the joint evaluation of - 308G > A polymorphism in TNF gene and IL-6 and IL-10 levels would provide a broader and effective view on the clinical monitoring of RTR.

Frontotemporal dementia: Plasma metabolomic signature using gas chromatography-mass spectrometry.

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive impairment in behavior, executive function, and language. The behavioral variant (bvFTD) is the most clinical common form and requires differential diagnosis with atypical Alzheimer's disease (AD) cases. This study aimed to investigate the plasma metabolite profile of patients with bvFTD compared to AD patients and cognitively healthy individuals using gas chromatography coupled to mass spectrometry (GCMS). This study included nine patients with bvFTD, 17 with AD and 15 cognitively healthy controls (training set), whose data were validated on a testing set (eight bvFTD, 14 AD and ten controls). The metabolites were detected by GCMS. A tendency towards a reduction in the levels of palmitoleic, oleic and lauric acids was found in the bvFTD group compared to the AD group; however, no significance after multiple comparison correction was observed. However, bvFTD group showed reduced levels of creatinine, glycine, tryptophan, uric acid, hypoxanthine, serine, valine, threonine, isoleucine, homoserine, methionine, glutamic acid, capric acid, tartronic acid, fumaric acid, and myo-inositol, metabolites related to glycine/serine/threonine, alanine/aspartate/glutamate pathways and aminoacyl-tRNA biosynthesis, when compared to controls. The data suggest that bvFTD patients may present an impairment of amino acid metabolism and the translation process. This pioneering study on bvFTD and its plasma metabolomic signature can be useful to provide new ideas about pathophysiological mechanisms, as well as guide more robust studies in search of possible biomarkers for the diagnosis of this important dementia.

Association among ACE, ESR1 polymorphisms and preeclampsia in Brazilian pregnant women.

BACKGROUND: Genetic, immune and environmental factors are involved in preeclampsia (PE) etiopathogenesis. Considering that hypertension and poor placental perfusion are important features in PE, polymorphisms in the angiotensin-converting enzyme (ACE) and estrogen nuclear receptor 1 (ESR1) genes could be involved in the predisposition and/or development of the disease. The aim of this study was to evaluate if polymorphisms in ACE and ESR1 genes were associated with PE occurrence. MATERIAL AND METHODS: This case-control study included 209 Brazilian pregnant women (107 with severe PE and 102 normotensive controls). The polymorphisms were investigated by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis. RESULTS: No significant difference between PE versus normotensive pregnant women, as well as early versus late PE, was observed when compared the allelic and genotypic frequencies of insertion/deletion polymorphism in intron 16 of the ACE gene and the single nucleotide polymorphisms (SNPs - rs2234693 and rs9340799) of the ESR1 gene. CONCLUSION: This pioneer study involving Brazilian women showed no association among the studied polymorphisms and PE, which suggests that ins/del ACE and SNPs ESR1 do not contribute to this disease occurrence in Brazil.

The dual effect of C-peptide on cellular activation and atherosclerosis: Protective or not?

C-peptide is a cleavage product of proinsulin that acts on different type of cells, such as blood and endothelial cells. C-peptide biological effects may be different in type 1 and type 2 diabetes. Besides, there are further evidence for a functional interaction between C-peptide and insulin. In this way, C-peptide has ambiguous effects, acting as an antithrombotic or thrombotic molecule, depending on the physiological environment and disease conditions. Moreover, C-peptide regulates interaction of leucocytes, erythrocytes, and platelets with the endothelium. The beneficial effects include stimulation of nitric oxide production with its subsequent release by platelets and endothelium, the interaction with erythrocytes leading to the generation of adenosine triphosphate, and inhibition of atherogenic cytokine release. The undesirable action of C-peptide includes the chemotaxis of monocytes, lymphocytes, and smooth muscle cells. Also, C-peptide was related with increased lipid deposits and elevated smooth muscle cells proliferation in the vessel wall, contributing to atherosclerosis. Purpose of this review is to explore these dual roles of C-peptide on the blood, contributing at one side to haemostasis and the other to atherosclerotic process.

Polymorphisms in vitamin D receptor gene, but not vitamin D levels, are associated with polycystic ovary syndrome in Brazilian women.

This study aimed to investigate the association between vitamin D (VitD) levels, polymorphisms in VDR gene (ApaI, BsmI, FokI, and TaqI) and the polycystic ovary syndrome (PCOS) in a group of Brazilian women. A total of 100 patients with PCOS and 100 control women were included. The quantification of 25-hydroxyvitamin D (25(OH)D) was performed in high-performance liquid chromatography (HPLC). Polymorphisms on VDR gene were performed by PCR-RFLP. The BsmI AG genotype was more frequent in PCOS group, while the GG genotype was more frequent in the control group (p = .007). The frequency of the Taql CC genotype was higher in PCOS group, while the CT genotype was the most frequent in the control group (p = .021). Mean serum VitD levels were similar between the groups. However, there was a negative correlation between VitD levels and Ferriman-Gallwey score (p = .031, r = -.260) in the PCOS group. The TaqI and BsmI polymorphisms were associated with PCOS. Moreover, VitD levels are associated with the clinical hyperandrogenism. The data suggest the role of VitD in PCOS development and its complications.

Troponin as a cardiotoxicity marker in breast cancer patients receiving anthracycline-based chemotherapy: A narrative review.

The approach to breast cancer has changed in recent decades due to significant advances in screening, early diagnosis, and treatment; however, the risk of cardiovascular injury induced by chemotherapy has remained similar. Anthracyclines are the most common agents used in breast cancer treatment and may lead to cardiotoxicity, which appears to have a direct relationship with accumulated dose and duration of treatment. Therefore, the use of cardiac biomarkers derived from those used in cardiac disease diagnosis has been applied to the early identification, evaluation, and cardiotoxicity monitoring during chemotherapy. Cardiac troponins (cTn) have high specificities and high sensitivity in myocardial injury and are used in the diagnosis and risk stratification of acute coronary syndromes. cTn have been validated by clinical studies in the cardiotoxicity diagnosis and prognosis in patients treated with high doses of anthracyclines alone or in combination, mainly with trastuzumab. Thus, the identification of cardiotoxicity through cTn in the preclinical phase would be crucial for the application of preventive strategies. Here, we analyzed 23 cross-sectional, prospective and retrospective studies using cTn as the biomarker of cardiotoxicity in patients with breast cancer receiving treatment with anthracyclines. Studies showed that the association of cTn with different biomarkers can contribute to the early diagnosis of cardiotoxicity; however the main evidence is that low cTn levels is related to a better outcome with a good negative predictive value (NPV). In conclusion, different studies are still necessary for the adoption of cTn as a routine clinical biomarker in patients with breast cancer receiving anthracycline treatment.

Association of different biomarkers of renal function with D-dimer levels in patients with type 1 diabetes mellitus (renal biomarkers and D-dimer in diabetes).

Objective This study aimed to evaluate the association between different renal biomarkers with D-Dimer levels in diabetes mellitus (DM1) patients group classified as: low D-Dimer levels (< 318 ng/mL), which included first and second D-Dimer tertiles, and high D-Dimer levels (≥ 318 ng/mL), which included third D-Dimer tertile. Materials and methods D-Dimer and cystatin C were measured by ELISA. Creatinine and urea were determined by enzymatic method. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Albuminuria was assessed by immunoturbidimetry. Presence of renal disease was evaluated using each renal biomarker: creatinine, urea, cystatin C, eGFR and albuminuria. Bivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels and odds ratio was calculated. After, multivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels (after adjusting for sex and age) and odds ratio was calculated. Results Cystatin C presented a better association [OR of 9.8 (3.8-25.5)] with high D-Dimer levels than albuminuria, creatinine, eGFR and urea [OR of 5.3 (2.2-12.9), 8.4 (2.5-25.4), 9.1 (2.6-31.4) and 3.5 (1.4-8.4), respectively] after adjusting for sex and age. All biomarkers showed a good association with D-Dimer levels, and consequently, with hypercoagulability status, and cystatin C showed the best association among them. Conclusion Therefore, cystatin C might be useful to detect patients with incipient diabetic kidney disease that present an increased risk of cardiovascular disease, contributing to an early adoption of reno and cardioprotective therapies.

OxLDL plasma levels in patients with Alzheimer's disease / Níveis plasmáticos de LDL-ox em pacientes com doença de Alzheimer

ABSTRACT Objective: The objective of this study was to characterize the conventional lipid profile, oxLDL levels and ApoE polymorphism in patients with Alzheimer's disease (AD) and in elderly individuals without cognitive impairment. Methods: Eighty elderly individuals were selected and the levels of oxLDL were determined using the ELISA kit, and ApoE gene polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism. Results: Significantly reduced levels of oxLDL were observed in patients with AD compared to the control group. A higher frequency of the ApoE ε4 allele was observed in patients with AD compared to controls. No difference was observed for total cholesterol, HDL-C, and LDL-C levels between the two groups, while triglyceride levels were higher in controls compared with patients with AD. Conclusion: The data analyzed together did not reveal significant differences in lipid profiles, including oxLDL levels. However, the importance of lipid changes in the genesis of the disease cannot be ruled out. Nevertheless, the ApoE ε4 allele was significantly more frequent in patients with Alzheimer's dementia in agreement with previous findings in the literature, but this genetic component did not change the levels of oxLDL.

RESUMO Objetivo: O objetivo deste estudo foi caracterizar o perfil lipídico convencional, os níveis de LDL-ox e o polimorfismo da ApoE em pacientes com doença de Alzheimer (DA) e em indivíduos idosos sem comprometimento cognitivo. Métodos: Foram selecionados oitenta indivíduos idosos. Os níveis de LDL-ox foram determinados usando o kit ELISA e a investigação do polimorfismo do gene da ApoE por PCR-RFLP. Resultados: Níveis significativamente reduzidos de LDL-ox foram observados em pacientes com DA comparado ao grupo controle. Uma maior frequência do alelo ε4 da ApoE foi observada nos pacientes com DA em relação aos controles. Nenhuma diferença foi observada para os níveis de colesterol total, HDL-C e LDL-C entre os dois grupos, enquanto níveis de triglicérides foram mais altos em controles comparados aos pacientes com DA. Conclusão: Os dados analisados em conjunto não revelaram diferenças significativas no perfil lipídico, incluindo os níveis de LDL-ox. No entanto, não se pode excluir a importância de alterações lipídicas na gênese da doença. Não obstante, o alelo ε4 da ApoE foi signicativamente mais frequente nos pacientes com demência de Alzheimer em concordância com achados prévios da literatura, mas esse componente genético não interferiu nos níveis de LDL-ox.

Association of different biomarkers of renal function with D-dimer levels in patients with type 1 diabetes mellitus (renal biomarkers and D-dimer in diabetes)

ABSTRACT Objective This study aimed to evaluate the association between different renal biomarkers with D-Dimer levels in diabetes mellitus (DM1) patients group classified as: low D-Dimer levels (< 318 ng/mL), which included first and second D-Dimer tertiles, and high D-Dimer levels (≥ 318 ng/mL), which included third D-Dimer tertile. Materials and methods D-Dimer and cystatin C were measured by ELISA. Creatinine and urea were determined by enzymatic method. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Albuminuria was assessed by immunoturbidimetry. Presence of renal disease was evaluated using each renal biomarker: creatinine, urea, cystatin C, eGFR and albuminuria. Bivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels and odds ratio was calculated. After, multivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels (after adjusting for sex and age) and odds ratio was calculated. Results Cystatin C presented a better association [OR of 9.8 (3.8-25.5)] with high D-Dimer levels than albuminuria, creatinine, eGFR and urea [OR of 5.3 (2.2-12.9), 8.4 (2.5-25.4), 9.1 (2.6-31.4) and 3.5 (1.4-8.4), respectively] after adjusting for sex and age. All biomarkers showed a good association with D-Dimer levels, and consequently, with hypercoagulability status, and cystatin C showed the best association among them. Conclusion Therefore, cystatin C might be useful to detect patients with incipient diabetic kidney disease that present an increased risk of cardiovascular disease, contributing to an early adoption of reno and cardioprotective therapies.