Early and late-onset preeclampsia: effects of DDAH2 polymorphisms on ADMA levels and association with DDAH2 haplotypes.

Objective: To examine whether the DDAH2 promoter polymorphisms -1415G/A (rs2272592), -1151A/C (rs805304) and -449G/C (rs805305), and their haplotypes, are associated with PE compared with normotensive pregnant women, and whether they affect ADMA levels in these groups. Methods: A total of 208 pregnant women were included in the study and classified as early-onset (N=57) or late-onset PE (N =49), and as normotensive pregnant women (N = 102). Results: Pregnant with early-onset PE carrying the GC and GG genotypes for the DDAH2 -449G/C polymorphism had increased ADMA levels (P=0.01). No association of DDAH2 polymorphisms with PE in single-locus analysis was found. However, the G-C-G haplotype was associated with the risk for late-onset PE. Conclusion: It is suggested that DDAH2 polymorphisms could affect ADMA levels in PE, and that DDAH2 haplotypes may affect the risk for PE.

Early and late-onset preeclampsia: effects of DDAH2 polymorphisms on ADMA levels and association with DDAH2 haplotypes

Abstract Objective: To examine whether the DDAH2 promoter polymorphisms -1415G/A (rs2272592), -1151A/C (rs805304) and -449G/C (rs805305), and their haplotypes, are associated with PE compared with normotensive pregnant women, and whether they affect ADMA levels in these groups. Methods: A total of 208 pregnant women were included in the study and classified as early-onset (N=57) or late-onset PE (N =49), and as normotensive pregnant women (N = 102). Results: Pregnant with early-onset PE carrying the GC and GG genotypes for the DDAH2 -449G/C polymorphism had increased ADMA levels (P=0.01). No association of DDAH2 polymorphisms with PE in single-locus analysis was found. However, the G-C-G haplotype was associated with the risk for late-onset PE. Conclusion: It is suggested that DDAH2 polymorphisms could affect ADMA levels in PE, and that DDAH2 haplotypes may affect the risk for PE.

Evaluation of miR-15a, miR-16-1, ZAP-70, Ang-2, and Bcl-2 as potential prognostic biomarkers in chronic lymphocytic leukemia

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

Canine umbilical cord perivascular tissue: A source of stem cells for therapy and research.

There are numerous sources of multipotent mesenchymal stromal cells (MSC) with therapeutic potential, and bone marrow is the main one. However, pain, lack of donors and comorbidities associated with harvesting stimulate the search for new sources of MSCs. The aim of this work is to obtain cells from umbilical cord (UC) perivascular tissue of dogs and characterize them as MSCs. For this, the UC was obtained from therapeutic cesarean sections and submitted to enzymatic digestion. The obtained cells were subjected to growth and proliferation tests, as well as the analysis of surface markers, differentiation test in three mesenchymal lineages and analysis of differentiation markers expression. From all the UC used in this study an adherent with fibroblastoid shape cell was obtained, with an initial number of 4.8 × 105 of cells. The growth curves showed a lag phase from 0 to 24 h, followed by a phase of growth of 24 to 168 h, and then phase of cell decay. The doubling time was kept around 15 h until the sixth passage, from which there were signs of cellular senescence. The differentiation assays demonstrated the ability of cells to differentiate into osteoblasts, adipocytes and chondrocytes when subjected to the induction mediums. The study of surface markers was positive for adhesion markers and negative for hematopoietic markers. Thus, cells obtained from canine UC perivascular tissue by enzymatic digestion are multipotent MSC and the protocol developed ensures the perivascular origin of these cells.

Advances in chronic lymphocytic leukemia pharmacotherapy.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that affects B lymphocytes in most cases. Leukemic lymphocytes have prolonged longevity, defined by resistance to apoptosis. These cells can accumulate in peripheral blood, bone marrow, and solid lymphoid organs. CLL may be indolent or aggressive and has a range of prognostic factors such as expression of CD38 and ZAP-70, immunophenotypic and cytogenetic changes, imbalanced apoptosis proteins, and others. Although CLL has a low mortality rate, this disease is generally not considered curable until today. CLL treatment involves alkylating agents and glucocorticoids, purine analogs, monoclonal antibody therapies, and bone marrow transplantation. In recent decades, new drugs have appeared focusing on new targets and specific molecules, such as the BCR receptor, Bruton's tyrosine kinase, phosphatidylinositol 3-kinase, spleen tyrosine kinase, apoptosis proteins and microRNAs. The most appropriate treatment for CLL is one that involves in its protocol a combination of drugs according to the prognostic factors presented by each patient. In this sense, treatment individualization is essential. This article examines standard treatments for CLL and explores new treatments and potential new targets, as well as schematic protocols to understand where we are, how the treatment has evolved, and the advantages and disadvantages of new targets for CLL therapy.

Evaluation of MiR-15a and MiR-16-1 as prognostic biomarkers in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a B lineage neoplasm, characterized by the accumulation of B lymphocytes of great longevity, and usually develops as a result of the inhibition of apoptosis. Clinical evolution is extremely variable amongst affected individuals with survival ranging from a few months in aggressive cases, to a few decades in cases of indolent CLL. The identification of new prognostic factors, apart from clinical staging, has been an important research topic aiming at a better understanding of CLL. There are approximately one thousand miRNAs in the human genome. They are expressed in specific tissues and changes in this expression are associated with different pathologies. In recent years, several studies have focused on the role of regulatory miRNAs in the pathogenesis of various diseases, including CLL. It has become evident that the profiles of miRNAs have great potential for application in the evaluation of CLL prognosis, since changes in miRNA expression profiles contribute to cell survival, proliferation and development of the disease. The deletion 13q14, the most prevalent alteration in CLL, leads to the deletion of the human tumor suppressor genes miR-15a and miR-16-1, which act on cell proliferation and in the process of apoptosis. Therefore, in patients with 13q deletion, loss of miR-15a and miR-16-1 displaces the expression balance for higher levels of Bcl-2 anti-apoptotic and pro-apoptotic p53 proteins. Regarding these microRNAs, the correlation of miR-15a and miR-16-1 with low-risk CLL is of particular interest. In this context, this mini review summarizes the current evidences on the role of regulatory miRNAs in the pathogenesis of CLL, particularly miR-15a and miR-16-1, involved on cell proliferation and apoptosis. In addition, it is our intention to highlight the potential role of micro RNAs as a marker of prognosis in this disease and to arouse interest in future studies addressing this interesting issue. Several current and future studies may shed light on the role of microRNAs in the pathogenesis of CLL, possibly leading to the development of new laboratory biomarkers.

Prognosis biomarkers evaluation in chronic lymphocytic leukemia.

OBJECTIVE/BACKGROUND: From clinical and biological points of view, chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by a progressive accumulation of lymphocytes in the peripheral blood, bone marrow, and lymphoid organs. New prognostic markers in CLL may be useful to clinicians for predicting outcome and in clinical decision-making. The aim of this study was to evaluate the potential prognostic value of the apoptotic/survival-controlling proteins and protein tyrosine kinase ZAP-70 gene expression in CLL patients and control individuals, correlating such findings with patients' clinical data. METHODS: Fifty-three patients diagnosed with CLL attending the hematology service of a clinical hospital, and 24 healthy individuals with no history of leukemia (Control group) were enrolled in this study. Analyses of apoptotic/survival-controlling proteins were performed by western blot and ZAP-70 gene expression was evaluated by real-time polymerase chain reaction. RESULTS: Significant differences were observed for the p-p38, Mcl-1 long, and Mcl-1 short proteins when patients were compared with CLL and controls. A positive correlation between the results for Mcl-1 short and Mcl-1 long and lymphocyte count was observed, corroborating the hypothesis of an imbalance between proteins of cell survival pathways/apoptosis in CLL. CONCLUSION: ZAP-70 gene expression was not detected as a discriminant biomarker in these CLL patients. An imbalance between apoptosis-related proteins was observed in the present study, corroborating the hypothesis of increased survival of lymphocytes in CLL patients.

Influence of ACE I/D Polymorphism on Circulating Levels of Plasminogen Activator Inhibitor 1, D-Dimer, Ultrasensitive C-Reactive Protein and Transforming Growth Factor ß1 in Patients Undergoing Hemodialysis.

BACKGROUND: There is substantial evidence that chronic renal and cardiovascular diseases are associated with coagulation disorders, endothelial dysfunction, inflammation and fibrosis. Angiotensin-Converting Enzyme Insertion/Deletion polymorphism (ACE I/D polymorphism) has also be linked to cardiovascular diseases. Therefore, this study aimed to compare plasma levels of ultrassensible C-reactive protein (usCRP), PAI-1, D-dimer and TGF-ß1 in patients undergoing HD with different ACE I/D polymorphisms. METHODS: The study was performed in 138 patients at ESRD under hemodialysis therapy for more than six months. The patients were divided into three groups according to the genotype. Genomic DNA was extracted from blood cells (leukocytes). ACE I/D polymorphism was investigated by single polymerase chain reaction (PCR). Plasma levels of D-dimer, PAI-1 and TGF-ß1 were measured by enzyme-linked immunosorbent assay (ELISA), and the determination of plasma levels of usCRP was performed by immunonephelometry. Data were analyzed by the software SigmaStat 2.03. RESULTS: Clinical characteristics were similar in patients with these three ACE I/D polymorphisms, except for interdialytic weight gain. I allele could be associated with higher interdialytic weight gain (P = 0.017). Patients genotyped as DD and as ID had significantly higher levels of PAI-1 than those with II genotype. Other laboratory parameters did not significantly differ among the three subgroups (P = 0.033). Despite not reaching statistical significance, plasma levels of usCRP were higher in patients carrying the D allele. CONCLUSION: ACE I/D polymorphisms could be associated with changes in the regulation of sodium, fibrinolytic system, and possibly, inflammation. Our data showed that high levels of PAI-1 are detected when D allele is present, whereas greater interdialytic gain is associated with the presence of I allele. However, further studies with different experimental designs are necessary to elucidate the mechanisms involved in these associations.