Alpha thalassemia, but not ßS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort.

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

Circulating Exosomal miRNAs as Biomarkers for the Diagnosis and Prognosis of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract. It is a multifactorial disease that involves environmental factors, genetic factors, and lifestyle factors. Due to the absence of specific and sensitive biomarkers, CRC patients are usually diagnosed at an advanced stage and consequently suffer from a low 5-year overall survival rate. Despite improvements in surgical resection and adjuvant chemotherapy, the prognosis of patients with CRC remains unfavorable due to local and distant metastases. Several studies have shown that small noncoding RNAs, such as microRNAs packed in exosomes, are potential biomarkers in various types of cancers, including CRC, and that they can be detected in a stable form in both serum and plasma. In this review, we report the potential of circulating exosomal miRNAs to act as biomarkers for the diagnosis and prognosis of CRC.

Global gene expression reveals an increase of HMGB1 and APEX1 proteins and their involvement in oxidative stress, apoptosis and inflammation pathways among beta-thalassaemia intermedia and major phenotypes.

Beta-thalassaemia (BT) is classified according to blood transfusion requirement as minor (BTMi), intermedia (BTI) and major (BTM). BTM is the most severe form, requiring regular transfusions while transfusion need is only occasional in BTI. Differential gene expression between patients has not been assessed so far. Here, we evaluated the global gene expression profiles during differentiation of human erythroid cells of two patients carrying the same mutation [CD39, (C → T)], though displaying different phenotypes (BTI and BTM). Considering the role of reactive oxygen species (ROS) in the pathophysiology of thalassaemia, we focused on differentially expressed genes involved in metabolic pathways triggered by ROS, such as inflammation and apoptosis, and, from these, we selected the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) and High Mobility Group Box1 (HMGB1) genes, whose role in BT is not well established. An in-depth expression analysis of transcriptional and protein levels in patients carrying a range of mutations associated with BT phenotypes indicated that APEX1 was increased in both BTI and BTM. Furthermore, higher amounts of HMGB1 was found in the plasma of BTI patients. Our findings suggest that these proteins have important roles in BT and could represent new targets for further studies aiming to improve the management of the disease.

Association between the genetic polymorphisms of glutathione S-transferase (GSTM1 and GSTT1) and the clinical manifestations in sickle cell anemia.

The hereditary deficiency of antioxidant enzymes when associated with sickle cell anemia (SCA) further contributes to the oxidation of hemoglobin S, which increases the formation of degradation products of this hemoglobin. The glutathione S transferases play an important role in the conjugation of glutathione to endogenous products of peroxidation of lipids and protect cells from the deleterious effects of oxidative stress. We analyzed genomic DNA from 278 patients with sickle cell anemia to correlate the genotypes GSTT1 and/or GSTM1 null (determined by multiplex PCR technique) and the clinical manifestations of the disease. 27% of patients showed absence of the GSTM1 gene and 15% had absence of GSTT1. The GSTM1 and GSTT1 null genotypes were found in 11% of the population. The risk of individuals with the GSTT1 null genotype developing acute chest syndrome and aseptic necrosis of the femoral head were, respectively, 10 and 6.3 times higher when compared with those individuals who had of this gene. Patients with GSTM1 null showed a risk 3.9 times higher to develop stroke and high risk for malleolar ulcers and acute chest syndrome (OR=6.9 and 4.2, respectively). The individuals with the GSTM1 and GSTT1 null genotypes showed a higher chance of developing acute chest syndrome, malleolar ulcer and aseptic necrosis of the femoral head. The absence of GSTT1 and/or GSTM1 was an important risk factor for increasing the morbidity of SCA, especially in regard to acute chest syndrome.