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Extracellular vesicles (EVs) are heterogeneous, phospholipid membrane enclosed particles that are secreted by healthy and cancerous cells. EVs are present in diverse biological fluids and have been associated with the severity of diseases, which indicates their potential as biomarkers for diagnosis, prognosis and as therapeutic targets. This study investigated the phenotypic characteristics of EVs derived from peripheral blood (PB) and bone marrow (BM) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) during different treatment stages. PB and BM plasma were collected from 20 B-ALL patients at three time points during induction therapy, referred to as: diagnosis baseline (D0), day 15 of induction therapy (D15) and the end of the induction therapy (D35). In addition, PB samples were collected from 10 healthy children at a single time point. The EVs were measured using CytoFLEX S flow cytometer. Calibration beads were employed to ensure accurate size analysis. The following, fluorescent-labeled specific cellular markers were used to label the EVs: Annexin V (phosphatidylserine), CD235a (erythrocyte), CD41a (platelet), CD51 (endothelial cell), CD45 (leukocyte), CD66b (neutrophil), CD14 (monocyte), CD3 (T lymphocyte), CD19, CD34 and CD10 (B lymphoblast/leukemic blast). Our results demonstrate that B-ALL patients had a marked production of EV-CD51/61 + , EV-CD10 + , EV-CD19 + and EV-CD10 + CD19 + (double-positive) with a decrease in EV-CD41a + on D0. However, the kinetics and signature of production during induction therapy revealed a clear decline in EV-CD10 + and EV-CD19 + , with an increase of EV-CD41a + on D35. Furthermore, B-ALL patients showed a complex biological network, exhibiting distinct profiles on D0 and D35. Interestingly, fold change and ROC curve analysis demonstrated that EV-CD10 + CD19 + were associated with B-ALL patients, exhibited excellent clinical performance and standing out as a potential diagnostic biomarker. In conclusion, our data indicate that EVs represent a promising field of investigation in B-ALL, offering the possibility of identifying potential biomarkers and therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Magalhães-Gama, Malheiros Araújo Silvestrini, Neves, Araújo, Alves-Hanna, Kerr, Carvalho, Tarragô, Soares Pontes, Martins-Filho, Malheiro, Teixeira-Carvalho and Costa.)

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD (-) and MRD (+) ). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD (-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD (+) subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kerr, Magalhães-Gama, Ibiapina, Hanna, Xabregas, Alves, Pimentel, Carvalho, Tarragô, Teixeira-Carvalho, Martins-Filho, da Costa and Malheiro.)

In the hematopoietic microenvironment, leukemic cells secrete factors that imbalanced chemokine and cytokine production. However, the network of soluble immunological molecules in the bone marrow microenvironment of acute lymphoblastic leukemia (ALL) remains underexplored. Herein, we evaluated the levels of the immunological molecules (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-6, TNF, IFN- γ , IL-17A, IL-4, IL-10, and IL-2) in the bone marrow plasma of 47 recently diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients during induction therapy using cytometric beads arrays. The results demonstrated that B-ALL patients showed high levels of CXCL9, CXCL10, IL-6, and IL-10 at the time of diagnosis, while at the end of induction therapy, a decrease in the levels of these immunological molecules and an increase in CCL5, IFN- γ , and IL-17A levels were observed. These findings indicate that B-ALL patients have an imbalance in chemokines and cytokines in the bone marrow microenvironment that contributes to suppressing the immune response. This immune imbalance may be associated with the presence of leukemic cells since, at the end of the induction therapy, with the elimination and reduction to residual cells, the proinflammatory profile is reestablished, characterized by an increase in the cytokines of the Th1 and Th17 profiles., Competing Interests: FM-G, MWAK, FSAH, LAX, and JCFN have fellowship from FAPEAM and CAPES (Master's student). AT-C is level 2 research fellow from CNPq and research fellow from FAPEAM (PVN-II, PECTI-AM/SAÚDE Program #004/2020). OAM-F is level 1 research fellow from CNPq and a research fellow from FAPEAM (PVN-II, Pŕo-Estado Program-#002/2008, #007/2018 and #005/2019). AM is level 2 research fellow from CNPq. The authors declare no conflicts of interest., (Copyright © 2021 Fábio Magalhães-Gama et al.)

The immune system plays an important role in the control of cancer development. To investigate the possible association of inflammasome genes to childhood leukemia we performed a case-control study with 158 patients with acute lymphoblastic leukemia and 192 healthy individuals. The IL1B and IL18 genetic polymorphisms were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and NLRP1, NLRP3 and P2RX7 were genotyped using Real Time quantitative PCR (qPCR). The IL1B C/T rs19644 genotype was associated with the risk of developing ALL (C/C vs. C/T + T/T OR: 2.48 [95% CI: 1.26-4.88, p = 0.006]; C/C vs C/T OR: 2.74 [95% CI: 1.37-5.51, p = 0.003]) and the NLRP1 A/T rs12150220 (OR: 0.37 [95% CI: 0.16-0.87, p = 0.023]) was associated with protection against infectious comorbidities. It was not found association between NLRP3 and P2RX7 polymorphisms and acute lymphoblastic leukemia in our study. Our results suggest that the inflammasome single-variant polymorphisms (SNVs) may play a role in the development and prognostic of childhood leukemia. However, this finds requires further study within a larger population in order to prove it.

Introduction: Leukemia is the most common cancer in children and has the highest rates of incidence in industrialized countries, followed by developing countries. This epidemiologic profile can mainly be attributed to the availability of diagnostic resources. In Brazil, leukemia diagnosis is a challenge due to financial viability, lack of hemovigilance services in isolated regions and the vast size of the territory. Its incidence in the state of Amazonas has been increasing since 2010. Therefore, this study aims to describe the epidemiological pattern and spatial distribution of patients with acute lymphoid leukemia and acute myeloid leukemia in Amazonas and identify the predictors of comorbidity and death., Materials and Methods: A retrospective cross-sectional study was carried out based on patients' data which was obtained from the database of a referral center for the period of 2005 to 2015. Variables included age, gender, ethnicity, civil status, schooling, income, location of residence, subtype of leukemia, comorbidities, and date of death. The spatial distribution was performed using QGIS v.2.18. Stata software was used for univariable and multivariable logistic regression to evaluate the association between both comorbidities and death for all characteristic groups of ALL and AML., Results: The group that was studied was composed of 577 ALL and 266 AML patients. For both, most patients were male, with a schooling period of 1-4 years, received<1 minimum wage, and lived mostly in Manaus, followed by the municipality of Tefé. There was no association between the development of comorbidities and analyzed variables in patients with ALL. AML patients that were >60 years old and with family history of the disease had the highest risk of developing comorbidities (OR = 5.06, p = 0.038; OR = 2.44, p = 0.041, respectively). Furthermore, patients with ALL and in the 41-50-year age group had a higher risk of death (OR = 31.12; p = 0.001). No association between death and explanatory variables were found in patients with AML. In addition, significant difference was observed in time to death (chi2 = 4,098.32, p = 0.000), with 50% of patients with AML dying within two years after diagnosis, whereas in ALL, this percentual of death only is reached in approximately 5 years., Conclusion: Our study describes the data of patients with acute leukemia in Amazonas, a remote region in the north of Brazil. In addition, it highlights the importance of hemovigilance in an Amazon region state, while focusing on peripheral areas which don't have prevention, diagnosis and treatment tools for this disease., Competing Interests: The authors have declared that no competing interests exist.

Snakebites are a serious public health problem and, in the Amazon, the Bothrops atrox snake is the most frequent cause of envenomation. B. atrox venom (BaV) causes pathophysiological changes with intense, local inflammatory processes, such as severe tissue complication (STC). However, mechanisms associated with the inflammatory process in humans are still poorly understood. Thus, in this study, we sought to describe the profile of local and systemic immunological soluble molecules in Bothrops envenomation patients treated at a specialist tertiary healthcare unit in the Brazilian Amazon. An analytical and prospective study was performed with patients who had snakebites with different clinical outcomes (STC and Mild Tissue Complication-MTC) using venous blood and blister exudate in order to measure immunological soluble molecules present in the response process. Twenty STC patients and 20 MTC patients were eligible for the study. In addition, 20 healthy donors (HD) who had never been bitten by a snake were used as controls. The biomarkers CXCL-8, CCL-5, CXCL-9, CCL-2 and CXCL-10; C3a, C4a, and C5a; IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IFN-γ and IL-17A were quantified using flow cytometry and ELISA. The circulating response profile differs between the studied groups, with MTC patients presenting a mixed profile and STC patients presenting a more polarized profile for Th1 response. In addition, individuals who develop STC have a more intense local immune response, because the tissue response differs from the circulating immunological soluble molecules and presents Th1/Th2/Th17 response polarization. Furthermore, these results suggest that CCL-2 and CXCL-10 are biomarkers for STC and the response profile they assume against Bothrops snakebite should reflect in the clinical practice for the patient.