Sickle cell anemia is one of the most prevalent genetic diseases worldwide, showing great clinical heterogeneity. This study compared the gene expression patterns between sickle cell anemia pediatric patients in steady state and in crisis state, as compared to age‐paired, healthy individuals. RNA sequencing was performed from these groups of patients/controls using Illumina HiSeq 2500 equipment. The resulting differentially expressed genes were loaded into QIAGEN's ingenuity pathway analysis. The results showed that EIF2 pathway and NRF2‐mediated oxidative stress‐response pathways were more highly activated both in steady state and in crisis patients, as compared to healthy individuals. In addition, we found increased activation of eIF4 and p70S6K signaling pathways in crisis state compared to healthy individuals. The transcription factor GATA‐1 was found exclusively in steady state while SPI was found exclusively in crisis state. IL6 and VEGFA were found only in crisis state, while IL‐1B was found exclusively in steady state. The regulator effects analysis revealed IgG1 as an upstream regulator in steady state compared to healthy individuals, resulting in invasion of prostate cancer cell lines as the disease/function outcome. For crisis‐state patients versus healthy individuals, two networks of regulator effects revealed STAT1, CD40LG, TGM2, IRF7, IRF4, and IRF1 acting as upstream regulators, resulting in disease/function outcomes, including engulfment of cells and aggregation of blood cells and inflammation of joints. Our results indicated genes and pathways that can provide clues on the molecular events involved in the severity of sickle cell disease.
Introduction The vascular alterations play an important role in the SCA chronic inflammatory state with the participation of different cell types, including macrophages and dendritic cells (DCs). Aim Here, we evaluated the mRNA expression of TLRs in DCs cells pre and post LPS stimulus and also measured IL-1β, TNF-α and IL-10 cytokines in plasma and supernatant of DCs pre and post LPS challenge, in order to indentify a possible role of this cell and receptor in the inflammatory state described in sickle cell anemia. Methods In vitro generation of immature DCs (imDC) monocyte-derived was obtained of monocytes from peripheral blood mononuclear cells (PBMC) of seven hospitalized HbSS patients. Relative mRNA abundance of each transcript was investigated by quantitative real time PCR and cytokines levels were measured by ELISA. Results We found that different HbSS patients showed specific DCs TLR expression and a differential levels of IL-1β among HbSS patients with and without pneumonia history (p=0.0253) and with hemoglobin concentration (p=0.0288) (Fig. 1). There was difference of TLR4 mRNA expression between HbSS patients groups without and with leg ulcers history (0.320+0.302 and 1.60+0.014) respectively (p=0.0016); with platelets count between HbSS patients groups with TLR2 expression < 50th (569.7+3.512) and > 50th (304.5+111.7) (p=0.0102) and reticulocytes count between HbSS patients groups with TLR2 expression < 50th (15.97+2.450) and > 50th (2.025+2.417) (p=0.0007) and of TNF-alpha concentration in DCs supernatant culture among HbSS patients with TLR5 expression < 50th (30.57+11.92) and > 50th (7.053+6.918) (p=0.0496) and of IL-10 concentration in DCs supernatant culture among HbSS patients with TLR5 expression < 50th (3.525+0.921) and > 50th (5.790+1.226) (p=0.0374) (Fig.2). It was also found statistic difference of IL-1 beta concentration in DCs supernatant culture post LPS stimulus between HbSS patients without and with pneumonia history (P=0.0253); analysis of TLR4 mRNA expression between HbSS patients without and with leg ulcer history (P=0.0016); analysis of hemoglobin concentration between HbSS patients with different plasma IL-1 beta concentration (P=0.0288) Conclusion Ours results show that these molecules and cell type possibly have an important role in maintain the inflammatory state described in this disease. Disclosures: No relevant conflicts of interest to declare.
BackgroundStroke is one of the highest complications of sickle-cell anemia (SCA). The Transcranial Doppler (TCD) has been adopted worldwide as a gold standard method for detecting alterations in the blood velocity in cerebral arteries. In this study, we investigated the association between laboratory parameters and increased cerebral blood flow velocity in Brazilian SCA pediatric patients.MethodsThe study included 159 pediatric patients with SCA, submitted to TCD velocity screening, and the time-averaged maximum mean velocity (TAMMV) was determined in the middle cerebral artery (MCA), anterior cerebral artery (ACA), and distal intracranial internal carotid artery (ICA). We compared cerebral blood flow in patients stratified by the following: TCD1—defined as normal, with TAMMV inferior to 170 cm/s; TCD2—conditional, with TAMMV above 170 cm/s, but less than 199 cm/s; TCD3—altered, with TAMMV greater than or equal to 200 cm/s.ResultsTAMMV was negatively correlated with age and weight (p < 0.05). Moreover, TAMMV was associated or correlated with reductions in HbF, RBC, hemoglobin, hematocrit, HDL, and haptoglobin and, increases in MCV, MCH, RDW, reticulocytes, WBC, lymphocytes, monocytes, eosinophils, total and indirect bilirubin, LDH, AST, ALT, glucose, ferritin, and AAT (p < 0.05).ConclusionThe current study highlights the importance of the investigation of hemolytic and inflammatory biomarkers for monitoring the clinical outcome of SCA pediatric patients, to avoid acute or chronic stroke. Moreover, glucose and HDL-C appear useful for predicting higher TAMMV.
Introduction:Ticagrelor is an antiplatelet agent approved for the treatment of patients with an acute coronary syndrome or a history of myocardial infarction. Considering the evidence demonstrating that ticagrelor-mediated inhibition of platelet activation and aggregation have beneficial effects in the treatment of thrombotic conditions, clinical studies have been conducted to evaluate the use of this drug for the treatment of sickle cell disease (SCD), demonstrating satisfactory tolerability and safety. Areas covered: Clinical investigation has characterized the pharmacokinetic and pharmacodynamical profile, as well as the efficacy and safety of ticagrelor to prevent painful vaso-occlusive crisis (painful episodes and acute chest syndrome) in SCD patients. Expert opinion: While phase 1 and 2 clinical trials demonstrated satisfactory tolerability and safety, the conclusion of phase 3 clinical trials is crucial to prove the efficacy of ticagrelor as a therapeutic option for the treatment of SCD. Thus, it is expected that ticagrelor, especially in combination with other drugs, will improve the clinical profile and quality of life of patients with SCD.
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