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. DCV (DCV CXCL16 CXCL 16 CXCL-1 ligante CXC C X 16, 16) FABP proteína 3, 3 3) 4, 4 4) membro 14/TNFS14, 14TNFS14 TNFS 14/TNFS14 14 TNFS14 14/TNFS14) GDF 15 GDF-1 crescimentodiferenciação crescimento diferenciação sCD forma CD14 CD matriz Glaproteína Gla carboxilada . (DOXO) casocontrole caso oncológica 5 5% p<0,001, p0001 p p<0,001 0 001 (p<0,001) p=0,038, p0038 p=0,038 038 (p=0,038) p=0003, p0003 p=0003 0003 (p=0003) sCD1 (p<0,00 ambos. ambos ambos) GDF1 cenário adiposidade vascular tudo CXCL1 1 CXCL- 14TNFS1 14/TNFS1 TNFS1 GDF- CD1 (DOXO p000 p<0,00 00 p003 p=0,03 03 (p=0,038 p=000 000 (p=0003 (p<0,0 14TNFS 14/TNFS p00 p<0,0 p=0,0 (p=0,03 p=00 (p=000 (p<0, p0 p<0, p=0, (p=0,0 p=0 (p=00 (p<0 p<0 (p=0, p= (p=0 (p< p< (p= (p

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. CVDs (CVDs CXCL16 CXCL 16 CXCL-1 CXC C X 16, , 16) FABP fatty 3, 3 3) 4, 4 4) tumor 14/TNFS14, 14TNFS14 TNFS 14/TNFS14 14 TNFS14 14/TNFS14) GDF 15 GDF-1 Growth/differentiation Growthdifferentiation Growth differentiation 15, 15) sCD soluble CD14, CD14 CD CD14) uncarboxylated GlaProtein Gla Protein Gla-Protein . (DOXO) casecontrol case CVD 5 5% p<0.001, p0001 p p<0.001 0 001 (p<0.001) p=0.038, p0038 p=0.038 038 (p=0.038) p=0003, p0003 p=0003 0003 (p=0003) (p<0.00 both. both both) GDF1 scenario adiposity biology sCD1 calcification CXCL1 1 CXCL- 14TNFS1 14/TNFS1 TNFS1 GDF- CD1 (DOXO p000 p<0.00 00 p003 p=0.03 03 (p=0.038 p=000 000 (p=0003 (p<0.0 14TNFS 14/TNFS p00 p<0.0 p=0.0 (p=0.03 p=00 (p=000 (p<0. p0 p<0. p=0. (p=0.0 p=0 (p=00 (p<0 p<0 (p=0. p= (p=0 (p< p< (p= (p

Abstract Chronic lymphocytic leukemia (CLL) is a blood cancer characterized by the accumulation of clonal B-lymphocytes. This study evaluated the mRNA gene expression of miR-15a, miR-16- 1, ZAP-70, and Ang-2 by qPCR, as well as the plasma levels of Bcl-2 by Elisa immunoassay, in CLL patients and healthy controls. Significant differences were observed when comparing patients and controls regarding miR-15a (p < 0.001), miR-16-1 (p < 0.001) mRNA, Ang-2 gene expression, and Bcl-2 plasma levels (p < 0.001). When stratified by risk, differences were maintained with a significantly reduced expression in high-risk patients. A positive correlation was observed between miR-15a and platelets (R2 = 0.340; p = 0.009) as well as between Bcl-2 and leukocytes (R2 = 0.310; p = 0.019). Conversely, negative correlations were observed between ZAP-70 and platelets (R2 = - 0.334; p = 0.011), between miR-15a and lymphocytes (R2 = - 0.376; p = 0.004), as well as between miR-16-and lymphocytes (R2 = - 0.515; p = 0.00004). The data suggest that a reduction in miR-15a and miR-16-1 expressions, in addition to an overexpression of Bcl-2, are associated with the reduction in apoptosis and, consequently, to a longer survival of lymphocytes, thus contributing to lymphocyte accumulation and aggravation of the disease. By contrast, Ang-2 expression was significantly higher in A than in B + C Binet groups. This context leads to the speculation that this biomarker should be investigated in more robust studies within populations with a still relevantly indolent form of the disease in an attempt to identify those patients with a greater potential for an aggravation of the disease.

Abstract Chronic Lymphocytic Leukemia (CLL) has shown great biological heterogeneity, with a variable prognosis, and a short survival in some patients. In this light, the present study focused on the prognostic utility of circulating microparticles (MPs) and a Thrombin Generation (TG) Profile for thrombotic risk and disease progression in CLL patients. Circulating microparticles and TG were evaluated in 35 patients with CLL and 35 healthy individuals. For circulating microparticles, significant differences were observed among the following groups: MPs derived from endothelial cells (p = 0.002), B lymphocytes (p < 0.001), platelets (p = 0.003), and Tissue Factor MPs in monocytes (p < 0.001). In all cases, MP values were higher for the CLL group. When compared to the controls, CLL patients presented a decrease in TG, characterized by a reduced endogen thrombin potential (ETP) (p = 0.031). When the results were analyzed according to the Binet stage, as compared to the controls, the Binet B+C group also presented lower ETP values (p = 0.009). No significant differences were observed between the control and the Binet A groups or between the Binet A and the Binet B + C groups. Although hemostatic alterations may occur in patients with CLL, these parameters do not seem to be useful to indicate disease progression.

Abstract The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.

Salacia crassifolia traditionally known as “Bacupari-do-Cerrado” is used to treat kidney problems, and as a healing agent for coughs and malaria. The phytochemical study of the S. crassifolia roots led to the isolation of thirteen compounds: abruslactone-A (1), urs-12-ene-3β,25,30-triol (2), carioprystimerin (3), β-sitosterol (4), pristimerin (5), dispermoquinone (6), netzahualcoyonol (7), 20-hydroxy-20-epi-tingenone (8), 6-oxo-pristimerol (9), 9β,10β-epoxi-3β-hydroxy-1βH,4βH,5βH,7βH,11αH-guaian-12,8β-olide (10), 3-O-b-D-glucosyl-b-sitosterol (11), 4`-O-methylepigalocatechin (12) and cerebroside (13). The chemical structures of 1-13 were determined by IR, 1D/2D NMR together with X-ray diffractometry. Compounds 2 and 10 are herein described for the first time. Extracts of S. crassifolia and compounds 3, 5, 8 and 9 were evaluated on acetylcholinesterase inhibition, in vitro cytotoxic activity and in vivo toxicity tests using Caenorhabditis elegans model. All tested compounds inhibited acetylcholinesterase, and compounds 3, 8 and 9 demonstrated a greater potential when compared to the standard eserine. The tested compounds showed low cytotoxicity against the THP-1, K562 and MDA-MB-231 cancer cell lines. None of the tested compounds and extracts were toxic against C. elegans since the larvae survival rate in L1 stage was higher than 90%.

RESUMO Introdução: A trombose arterial é considerada uma doença multifatorial, resultante da interação de fatores de risco genéticos e adquiridos. Objetivos: O objetivo deste estudo foi investigar a presença dos polimorfismos nos genes do inibidor da ativação do plasminogênio tipo 1 (PAI-1) e da apolipoproteína E (ApoE), bem como suas interações com níveis de PAI-1 e lipídios e perfis de apolipoproteína, respectivamente, além das frequências desses polimorfismos e sua associação com trombose. Métodos: Noventa e sete pacientes [48 com acidente vascular cerebral isquêmico arterial (AVC) e 49 com doença arterial periférica (DAP)], tratados no serviço médico de hematologia, foram incluídos neste estudo. Os polimorfismos também foram investigados em 201 indivíduos-controle. Os polimorfismos foram investigados por reação em cadeia da polimerase-fragmento de restrição polimorfismo (PCR-RFLP). Resultados: Para o polimorfismo PAI-1, havia 54,2% genótipos heterozigotos (HT) e 12,5% genótipos de homozigoto (HM) no grupo dos pacientes, e 52,7% genótipos HT e 21,3% genótipos HM nos grupos-controle. Para o polimorfismo da ApoE, havia 56,3% (ε3ε3), 6,3% (ε4ε4), 8,3% (ε2ε3), 4,2% (ε2ε4) e 24,9% (ε3ε4) nos pacientes, e 61,2% (ε3ε3), 4,5% (ε4ε4), 8% (ε2ε3), 4,5% (ε2ε4) e 21,8% (ε3ε4) nos controles. Conclusão: Nenhuma diferença significativa foi observada comparando pacientes e controles. Neste estudo, não foi encontrada associação entre a presença dos polimorfismos avaliados e a ocorrência de eventos trombóticos.

ABSTRACT Introduction: Arterial thrombosis is considered a multifactorial disease, resulting from the interaction of genetic and acquired risk factors. Objectives: The aim of this study was to investigate the presence of the polymorphism in inhibitor of plasminogen activator type 1 (PAI-1) and apolipoprotein E (ApoE) genes and its interactions with PAI-1 levels and lipids and apolipoprotein profiles, respectively, as well as the frequencies of these polymorphisms and their association with thrombosis. Methods: Ninety-seven patients [48 with arterial ischemic stroke (IS) and 49 with peripheral arterial disease (PAD)], treated at the hematology medical service were included in this study. Polymorphisms were also investigated in 201 control subjects. Polymorphisms were investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: For the PAI-1 polymorphism, there were 54.2% heterozygous (HT) genotypes and 12.5% homozygous (HM) genotypes in the patients' group, and 52.7% HT genotypes and 21.3% HM genotypes in the controls. For the ApoE polymorphism, there were 56.3% (ε3ε3), 6.3% (ε4ε4), 8.3% (ε2ε3), 4.2% (ε2ε4) and 24.9% (ε3ε4) in the patients, and 61.2% (ε3ε3), 4.5% (ε4ε4), 8% (ε2ε3), 4.5% (ε2ε4) and 21.8% (ε3ε4) in the controls. Conclusion: No significant difference was observed by comparing patients and controls. In this study, no association was found between the presence of the evaluated polymorphisms and the occurrence of thrombotic events.

Resumo A prevalência da doença renal crônica (DRC) tem aumentado nos últimos anos e vários fatores estão associados à instalação e progressão da DRC, tais como obesidade, hipertensão arterial e diabetes mellitus. Uma das complicações da DRC é a anemia causada principalmente pela deficiência de ferro e de eritropoetina (EPO). Um dos tratamentos para este tipo de anemia é uso de eritropoetina exógena. O paciente com DRC submetido à diálise apresenta um estado inflamatório crônico, provocando uma situação de má resposta à ação medular da EPO, causando anemia, desnutrição, agravamento da aterosclerose e aumento da mortalidade. O objetivo deste artigo foi revisar as evidências científicas referentes à associação da má resposta clínica ao uso de EPO e a presença de inflamação na DRC.

Abstract The prevalence of kidney chronic disease (CKD) has increased in recent years and several risk factors have been associated with the onset and progression of CDK, such as obesity, hypertension and diabetes mellitus. In addition, anemia is one of the complications of CRD, mainly by iron and erythropoietin (EPO) deficiency and the management of this situation is with exogenous erythropoietin, but patients undergoing dialysis present chronic inflammatory process followed by EPO resistance and anemia, malnutrition, worse of atherosclerosis and increased mortality ratio. The aim of this study was to review the association of erythropoietin resistance and chronic inflammatory process in patients with chronic renal disease.

A locução sombras de Gumprecht refere-se, historicamente, aos linfócitos lisados comumente observados em portadores de leucemia linfocítica crônica (LLC). Uma revisão da literatura revelou que esse termo restringe-se aos casos de LLC e não deve ser utilizado em outras situações que cursam com linfocitose. A utilização inapropriada dessa terminologia pode gerar ansiedade no indivíduo que recebe tal observação no hemograma, bem como em seus familiares. Em um site de busca da internet muito utilizado para sanar dúvidas relativas a termos clínicos, há inúmeras páginas com relatos nos quais essa expressão associa-se à LLC.

The expression Gumprecht shadows historically refers to lymphocyte lysates commonly observed in patients with chronic lymphocytic leukemia (CLL). A literature review revealed that this term is restricted to CLL cases, and should not be applied to lymphocytosis-related conditions. Inappropriate use of this term can cause great anxiety in individuals receiving their blood count results, as well as in their families. In a web search engine commonly used to clear doubts on medical terms, there are countless pages where Gumprecht shadows are associated with CLL.

Obesidad sin síndrome metabólico y expansión del tejido lipidio basado exclusivamente en factores de riesgo e marcador inflamatorio de la enfermedad coronaria em mujeres en la pré-menopausia. El objetivo de esta investigación fue analizar si las mujeres obesas que no tienen el síndrome metabólico (MetS), tienen riesgo cardiometabólico aumentado comparado con mujeres no obesas y observar las correlaciones entre factores de riesgo de la adiposidad y la enfermedad coronaria del corazón (CHD) en mujeres metabólicamente saludables. Fueron estudiadas mujeres de 20-40 años de edad no-obesas (n=41), obesas sin MetS (n=30) y obesas con MetS (n=28). Se analizaron también factores tradicionales de riesgo y marcadores inflamatorios. Un sub conjunto de mujeres obesas (13) y no obesas (33) sin componentes mayores de MetS fueron comparados adicionalmente. Mujeres obesas sin MetS y mujeres no obesas evidenciaron un perfil metabólico semejante, estadísticamente diferente de lo visto en mujeres obesas con MetS. El número de mujeres obesas sin MetS y no obesas que presentaban dos ó más factores de riesgo (23.3 y 19.5%, respectivamente) ó presentaban riesgo alto con Framingham (6.7 y 2.4%, respectivamente) también fueron semejantes. Estos datos sugieren que la obesidad sin MetS induce un riesgo de CHD comparable al riesgo observado en mujeres no obesas. Sin embargo, cuando las mujeres sin componentes importantes del MetS únicamente fueron llevadas en cuenta, la adiposidad fue correlacionada a la presión sanguínea y a la hs-CRP. Aunque el riesgo de la CHD de mujeres obesas sin MetS sea más próximo al de mujeres no obesas, la expansión del tejido adiposo fue positivamente correlacionado a la presión sanguínea y a la hs-CRP, ambos importantes factores de riesgo para la CHD.

The objective of this study was to analyze whether obese women with no metabolic syndrome (MetS) have increased cardiometabolic risk compared to non-obese women and to observe the correlations between adiposity and coronary heart disease (CHD) risk factors in metabolically healthy women. 20-40 year old non-obese (n=41), obese with no MetS (n=30) and obese with MetS (n=28) women were studied. Lipid profile, blood pressure, CHD family history, physical inactivity, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, interleukin-1β and tumor necrosis factor-alpha were analyzed. A subset of obese (13) and non-obese (33) women with no major components of MetS (except waist circumference) were further compared. Obese women with no MetS and non-obese women presented a similar metabolic profile that was statistically different from those seen in obese women with MetS. The number of obese women with no MetS and non-obese women presenting two or more risk factors (23.3 and 19.5%, respectively) or presenting high Framingham Risk Score (6.7 and 2.4%, respectively) were also similar. The only pro inflammatory protein correlated to waist circumference was hs-CRP. These data suggest that obesity with no MetS induce a CHD risk comparable to the risk seen in non-obese women. However, when women with no major components of MetS alone were considered, adiposity was positively correlated to blood pressure and hs-CRP. Although CHD risk of obese women with no MetS is closer to non-obese women, adipose tissue expansion was positively correlated to blood pressure and hs-CRP that are important risk factors for CHD.

OBJETIVO: Determinar os níveis plasmáticos de homocisteína e a incidência do polimorfismo C677T no gene da enzima metilenotetrahidrofolato redutase (MTHFR) em um grupo de indivíduos submetidos a angiografia coronariana, buscando estabelecer a possível correlação entre esses parâmetros e a gravidade da doença arterial coronariana (DAC), bem como investigar a correlação entre hiper-homocisteinemia e a presença do polimorfismo. MÉTODOS: Vinte indivíduos com ausência de ateromatose nas coronárias (controles), quatorze indivíduos apresentando ateromatose leve/moderada e vinte e nove indivíduos apresentando ateromatose grave foram avaliados. RESULTADOS: Para o parâmetro homocisteína foram observadas diferenças significativas entre as médias dos grupos controle e ateromatose grave (p < 0,001). Entre os demais grupos não foram observadas diferenças significativas. O grupo ateromatose grave apresentou uma freqüência de 62,0% e 6,9% para o polimorfismo C677T no gene da enzima MTHFR, em heterozigose e homozigose, respectivamente. Entretanto, não foi observada correlação entre a presença da mutação e hiper-homocisteinemia. Foi observada uma correlação positiva da ordem de 41,91% (p < 0,001) entre hiper-homocisteinemia e a presença de DAC. CONCLUSÃO: O achado mais importante deste estudo foi a associação entre hiper-homocisteinemia e a presença de estenose coronariana superior a 70%; entretanto, permanece a dúvida se o aumento da concentração plasmática de homocisteína constitui um fator determinante para o agravamento da lesão aterosclerótica nas coronárias ou se o mesmo é uma conseqüência desta lesão.

OBJECTIVE: To determine plasma homocysteine levels and the incidence of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD), as well as investigate the correlation between hyperhomocysteinemia and the presence of polymorphism. METHODS: Twenty subjects with no coronary atheromatosis (controls), fourteen subjects with mild/moderate atheromatosis, and twenty-nine subjects with severe atheromatosis were evaluated. RESULTS: Significant differences were observed in mean homocysteine levels between the control and the severe atheromatosis groups (p < 0.001). No significant differences were observed among the other groups. The severe atheromatosis group showed rates of 62.0% and 6.9% for the C677T MTHFR gene polymorphism, in heterozygous and homozygous subjects, respectively. However, there was no correlation between the presence of mutation and hyperhomocysteinemia. A positive correlation of 41.91% (p < 0.001) was found between hyperhomocysteinemia and CAD. CONCLUSION: The most important finding of this study was the association between hyperhomocysteinemia and coronary stenosis > 70%; yet, whether elevated plasma homocysteine worsens atherosclerosis or is a consequence remains to be established.

Em estudo prévio, os níveis plasmáticos do fragmento 1+2 da protrombina não foram associados com a presença ou com a gravidade da doença arterial coronariana (DAC), não trazendo benefício adicional pelo menos em indivíduos com diagnóstico de DAC estabelecido por angiografia. Desta forma, neste estudo outro marcador de hipercoagulabilidade foi avaliado nos mesmos pacientes. O presente estudo teve como objetivo determinar os níveis plasmáticos do dímero D de um grupo de indivíduos submetidos à angiografia coronariana, buscando estabelecer a possível correlação entre este parâmetro e a gravidade da DAC. Os níveis plasmáticos do dímero D foram determinados em amostras de sangue de 17 indivíduos com ausência de ateromatose nas coronárias (controles), 12 indivíduos apresentando ateromatose leve/moderada e 28 indivíduos apresentando ateromatose grave. Não foram encontradas diferenças estatisticamente significativas entre as médias dos três grupos para o parâmetro avaliado. Uma análise dos dados permite inferir sobre uma tendência ao aumento da atividade fibrinolítica nos pacientes com ateromatose, refletida pela elevação da concentração de dímero D no grupo ateromatose grave em indivíduos com diagnóstico de DAC estabelecido por angiografia coronariana.

We have previously reported that prothrombin fragment 1+2 levels were not associated to the presence or severity of coronary artery disease (CAD) and do not provide further information on subjects with CAD diagnosed by angiography. Thus, in the present study another marker of hypercoagulability was evaluated in the same subjects. This study aimed at determining D-Dimer plasma levels in a group of subjects undergoing coronary angiography to establish a likely relation between this parameter and the severity of CAD. D-Dimer plasma levels were determined in 17 subjects with no coronary atheromatosis (controls), 12 subjects with mild/moderate atheromatosis and 28 subjects with severe atheromatosis. No significant differences were observed among the three groups. Data analysis enables an inference on a tendency towards an increase in fibrinolytic activity in patients with atheromatosis, reflected by the increase in D-Dimer concentrations in the severe atheromatosis group in subjects with CAD diagnosed by coronary angiography.