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Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells in T. crassiceps cysticerci after HU treatment (25 mM and 40 mM of HU for 6 days) through in vitro assays. Viability and morphological changes were evaluated. The recovery of cysticerci's mobility and morphology was evaluated at 3 and 6 days, after 6 days of treatment. The number of proliferative cells was evaluated using EdU. Our results show morphological changes in the size, shape, and number of evaginated cysticerci at the 40 mM dose. The mobility of cysticerci was lower after 6 days of HU treatment at both concentrations. On days 3 and 6 of recovery after 25 mM of HU treatment, a partial recovery of the proliferative cells was observed. Proteomic and Gene Ontology analyses identified modifications in protein groups related to DNA binding, DNA damage, glycolytic enzymes, cytoskeleton, skeletal muscle, and RNA binding.

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Objectives: Our study evaluated the association of the polymorphism rs724016 in the ZBTB38 gene, previously associated with height in other populations, with predictors of height, clinical outcomes, and laboratory parameters in sickle cell anemia (SCA). Methods: Cross-sectional study with individuals with SCA and aged between 3 and 20 years. Clinical, laboratory, molecular, and bone age (BA) data were evaluated. Levels of IGF-1 and IGFBP-3 were adjusted for BA, target height (TH) was calculated as the mean parental height standard deviation score (SDS), and predicted adult height (PAH) SDS was calculated using BA. Results: We evaluated 80 individuals with SCA. The homozygous genotype of the G allele of rs724016 was associated with a lower height SDS (p < 0.001) and, in a additive genetic model, was negatively associated with HbF levels (p = 0.016). Lower adjusted IGF-1 levels were associated with co-inheritance of alpha-thalassemia and with the absence of HU therapy. Elevated HbF levels were associated with a lower deficit in adjusted growth potential (TH minus PAH). Conclusion: Our analysis shows that SNP rs724016 in the ZBTB38 is associated with shorter height and lower HbF levels, an important modifier of SCA.

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Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the ß-globin gene (c20A > T, pGlu6Val) and is characterized by the presence of abnormal hemoglobin, hemoglobin S, hemolysis, and vaso-occlusion. This mutation, either in a homozygous configuration or in compound states with other ß-globin mutations, leads to polymerization of hemoglobin S in deoxygenated conditions, causing modifications in red blood cell shape, particularly sickling. Vaso-occlusive crisis (VOC) is the hallmark of the disease, but other severe complications may arise from repeated bouts of VOCs. SCD is considered a global health problem, and its incidence has increased in some areas of the world, particularly the Americas and Africa. Management of the disease varies according to the region of the world, mainly due to local resources and socioeconomic status. This review aimed to describe more recent data on SCD regarding available treatment options, especially in Brazil. New treatment options are expected to be available to all patients, particularly crizanlizumab, which is already approved in the country.

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OBJECTIVE: This study aims to evaluate the markers of tubular phosphate handling in adults with sickle cell anemia (SCA) and the influence of hydroxyurea (HU), the degree of anemia and Hb F concentration on these markers. METHODS: Eighty-eight steady state SCA patients in outpatient follow-up in Fortaleza, Ceara, Brazil and 31 healthy individuals were included in this study. Vitamin D (25OHD) was measured by enzyme-bound fluorescence assay, intact parathyroid hormone (iPTH) by electrochemiluminescence, and serum and urinary phosphate and creatinine by colorimetric methods. Details of Hb F and HU use were obtained from clinical records. Tubular reabsorption of phosphate (TRP) and maximum tubular reabsorption of phosphate (MTRP) were calculated. SCA patients were stratified according to the use of HU, degree of anemia and percentage of Hb F. The significance level was set for p-values <0.05. RESULTS: Compared to controls the 25OHD level (25 ± 11 vs. 30 ± 9 pg/mL) was lower in SCA, while serum phosphate and MTRP were higher (3.86 ± 0.94 vs. 3.46 ± 0.72 and 3.6 ± 1.21 vs. 3.21 ± 0.53, respectively). There was no significant difference in iPTH, TRP and phosphaturia. Serum phosphate showed correlation with TRP (r = 0.32; p-value = 0.008) and MTRP (r = 0.9; p-value <0.001) in SCA. Patients taking HU, especially those with Hb F >10 % presented reduced serum phosphate levels, and TRP and MTRP rates. Those with mild anemia presented reduced serum phosphate levels and MTRP rates. CONCLUSION: Serum phosphate levels and renal phosphate reabsorption rate were increased in SCA. HU use, high Hb F concentration and total Hb were associated with better control of tubular phosphate handling markers.

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Abstract To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

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To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

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INTRODUCTION: Sickle cell disease (SCD) is a common hemoglobinopathy worldwide that causes painful crises and hospitalization of patients. These attacks decrease survival and cause chronic end-organ damage in these patients. HYPOTHESIS: For this reason, finding new treatment approaches could be helpful. METHOD: In this study, Imatinib was applied as a mast cell inhibitor to reduce pain crises in these patients. Seven patients resistant to hydroxyurea and folic acid treatment and who had at least four painful crises per year with hospitalization were enrolled in this study with treatment with Imatinib (100 mg, twice daily). Subsequently, the number and duration of hospitalizations, analgesic requirement, the severity of chronic pain, and changes in the hematological parameters of these patients were evaluated before and after the treatment. RESULTS: The data showed that the total number of hospitalizations and the entire duration of hospitalizations were reduced 16 times after treatment with Imatinib, without apparent changes in hematological parameters. Also, the demand for pethidine, tramadol, and nonsteroidal anti-inflammatory drugs (NSAIDs) was reduced in all patients. The average reduction in chronic pain was over 70%. CONCLUSION: This study demonstrates that treatment with Imatinib in patients with SCD or sickle cell anemia (SCA) may be a suitable therapeutic option for reducing painful crises.

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Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are observed in most SCA patients. To overcome this limitation, several studies have performed HU dose adjustments in SCA patients based on individualized pharmacokinetic profiles. The present systematic mini-review aims to select and analyze published data to present an overview of HU pharmacokinetics studies performed in SCA patients, as well as evaluate the effectiveness of the dose adjustment strategy. A systematic search was performed in the Embase, Pubmed, Scopus, Web of Science, Scielo, Google Scholar, and the Virtual Library of Health databases from December 2020 to August 2022, with a total of five studies included. Inclusion criteria consisted of studies in which the dose adjustment was performed in SCA patients based on pharmacokinetic parameters. Quality analyzes were performed using QAT, while data synthesis was performed according to the Cochrane Manual of Systematic Reviews of Interventions. Analysis of the selected studies revealed improved HU treatment effectiveness using personalized dosages in SCA patients. Moreover, several laboratory parameters were utilized as biomarkers of the HU response, and methods designed to simplify the adoption of this practice were presented. Despite the scarcity of studies on this topic, HU-personalized treatment based on individualized pharmacokinetic profiles represents a viable alternative for SCA patients who are candidates for HU therapy, especially for pediatric patients. Registration number: PROSPERO CRD42022344512.

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Sickle cell disease is the most common hemoglobinopathy among humans. As the condition promotes susceptibility to infections, chronic inflammation, and hypercoagulability disorders, several international agencies have included individuals with this disease in the COVID-19 risk group for severe outcomes. However, available information about the subject is not properly systematized yet. This review aimed to understand and summarize the scientific knowledge about the impact of SARS-CoV-2 infection in patients with sickle cell disease. Searches were performed in the Medline, PubMed, and Virtual Health Library databases based on descriptors chosen according to the Medical Subject Headings. We analyzed studies published between 2020 and October 2022, developed with qualitative, quantitative, or mixed methodology, and written in English, Spanish, or Portuguese. The search resulted in 90 articles organized into six categories. There is disagreement in the literature about how different aspects related to sickle cell disease, such as chronic inflammation status, hypercoagulability, hemolytic anemia, use of hydroxyurea, and access to medical care interference with the clinical course of COVID-19. These topics deserve further investigation. It is evident, however, that the infection may manifest in an atypical way and act as a trigger for the development of sickle cell-specific complications, such as acute chest syndrome and vaso-occlusive crises, conditions that are associated with great morbidity and mortality. Therefore, healthcare professionals must be aware of the different forms of presentation of COVID-19 among these individuals. Specific guidelines and therapeutic protocols, as well as public policies for sickle cell individuals, must be considered. Systematic review registration: This review (https://doi.org/10.17605/OSF.IO/NH4AS) and the review protocol (https://osf.io/3y649/) are registered in the Open Science Framework platform.

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In the present work, the impact of Sickle Cell Disease (SCD) degrees of severity, as well hydroxyurea treatment on the systemic immunological signatures of patients was evaluated. Based on a high-throughput chemokine, cytokine and growth factor multiplex analysis, it was possible to obtain the systemic immunological profile of patients with SCD (n = 40), treated or not with hydroxyurea, as compared to healthy controls (n = 40). Overall, SCD patients with severe disease displayed increased levels of almost all biomarkers analyzed. Our data demonstrated that CXCL8, CCL3 and CXCL10 were pointed out as universal biomarkers of SCD. The results also indicated that HU-untreated patients with indication of HU-therapy display a more prominent increase on plasma immune mediators in a similar way as those with severe SCD disease. Together, these findings provided a comprehensive landscape of evidence that may have implications for further therapeutic strategies and SCD clinical management.

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ABSTRACT Background: Stroke is a serious complication of sickle cell anemia (SCA). The transcranial Doppler (TCD) is the risk-screening tool for ischemic strokes. The objective of the study was to describe the clinical progression of children with SCA who presented with high risk for stroke by TCD or relevant changes by magnetic resonance angiography (MRA) and underwent the regular transfusion program (RTP) and/or hydroxyurea (HU) treatment between 2007 and 2018. Method: This was a neonatal retrospective/prospective cohort study with children born between 1999 and 2014 with the homozygotic form (HbSS) or Sβ0-thalassemia who underwent TCD at least once. Results: Of the 718 children screened during this period, 675 had HbSS and 43 Sβ0-thalassemia. In 54 children (7.5%), all with HbSS, a high-risk TCD (n = 45) or, when the TCD was inconclusive, an MRA with cerebral vasculopathy (n = 9) was used for detection. Of these, 51 started the RTP and the families of three refused treatment. Of the 43 children with a highrisk TCD who initiated the RTP, 29 (67.4%) reverted to low risk. In 18 of them (62%), HU was started at the maximum tolerated dose (MTD) before transfusion discontinuation. None of these 29 patients had a stroke. Eight children (18.6%) maintained a high-risk TCD, even using the RTP/HU and two had a stroke. Conclusions: The TCD was confirmed as a viable tool for tracking patients with a risk for stroke. The RTP was effective in preventing the primary event. New strategies are necessary to prevent stroke using HU and new drugs, in addition to bone marrow transplantation.

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OBJECTIVES: Given the complex pathology of sickle cell anemia (SCA) and low adherence to hydroxyurea (HU) treatment, there is a need to seek parameters that identify recent changes in patient status. The advanced clinical parameters (ACPs) allow an early analysis of hematopoiesis. We aimed to draw the demographic profile of non-adherent SCA patients and to verify the use of ACPs as a measure of HU treatment adherence. METHOD: In a cross-sectional study, we divided 83 SCA subjects treated with HU into Children (<12 years old) and adolescents/adults (≥12 years old). Their hemogram with the ACPs, electronic medical charts and pharmacy claim data were analyzed. RESULTS: Non-adherent ≥12 years old patients had significantly increased WBC, absolute neutrophil, lymphocyte, monocyte, and basophil counts, RBC, RET, RDW, and PLT, and significantly decreased MCV and MCH. Subjects in the adolescent/adult group with IG† ≥0.035 cells/mm3 had the RR for non-adherence increased by 4.6 times (p = .014), and the systemic immune inflammation index (SII) of non-adherent patients was also significantly higher (p = .042). CONCLUSION: IG† presents clinical utility in early identification of non-adherence to HU, especially when combined with other parameters, suggesting the evaluation of ACPs in laboratory routine, as they can be easily implemented.

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Leishmania spp. comprises a group of protozoan parasites that affect millions of people around the world. Understanding the main cell cycle-dependent events could provide an important route for developing specific therapies since some factors involved in cell cycle control may have low similarity relative to their homologs in mammals. Furthermore, accurate cell cycle-dependent analyses often require many cells, which can be achieved through cell cycle synchronization. Here, we described a useful method to synchronize procyclic promastigote forms of Leishmania amazonensis using hydroxyurea (HU) and the analysis of its DNA content profile. This approach can be extended to other trypanosomatids, such as Trypanosoma cruzi or Trypanosoma brucei, and provides an effective method for arresting more than 80% of cells at the G1/S phase transition.

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BACKGROUND: Sickle cell anemia is a disease that develops episodes of acute pain and multiple organ dysfunction that can affect the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The severity of sickle cell anemia is influenced by modifying factors, such as levels of fetal hemoglobin (HbF), the co-inheritance of alphathalassemia, or treatment with hydroxyurea. METHODS: This cross-sectional study in children with sickle cell anemia evaluated bone age (BA), adult height prediction (AHP) using BA, a target height (TH) calculated as the mean SDS of the parents, and laboratory parameters. Children were grouped according to serum levels of HbF, co-inheritance of alpha-thalassemia, and hydroxyurea therapy.. RESULTS: The mean age of the 39 children was 8.2 ± 2.2 years old. The average height was -0.75 ± 0.30 SDS, and 10.3% (4/39) had short stature. Adjusted levels of IGF-1 or IGFBP- 3 were significantly higher in children with sickle cell anemia on hydroxyurea treatment, in children with HbF levels >10%, and in those without alpha-thalassemia. Using SDS, the growth potential of children with sickle cell anemia in relation to their parents calculated by the difference between AHP and TH as well as the difference between children's height and their TH, were lower in children with co-inheritance of alphathalassemia. CONCLUSION: The study showed an association between modifying factors and the GH/IGF-1 axis in children with sickle cell anemia. Additionally, the co-inheritance of alpha-thalassemia was associated with decreased height in these children when adjusted for their parents' height.

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Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK) 2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. Although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

La mielofibrosis (MF) es una neoplasia mieloproliferativa negativa para BCR-ABL1 caracterizada por mieloproliferación clonal, señalización de cinasa desregulada y liberación de citocinas anormales. En los últimos años se han realizado importantes avances en el conocimiento de la biología molecular y la valoración pronóstica de la MF. El tratamiento convencional tiene un impacto limitado en la supervivencia de los pacientes; incluye un enfoque de espera para pacientes asintomáticos, agentes estimulantes de la eritropoyesis, andrógenos o agentes inmunomoduladores para la anemia, fármacos citorreductores como la hidroxiurea para la esplenomegalia y los síntomas constitucionales, y esplenectomía o radioterapia en pacientes seleccionados. El descubrimiento de la mutación Janus cinasa (JAK) 2 desencadenó el desarrollo de la terapia dirigida molecular de la MF. Los inhibidores de JAK son efectivos tanto en MF con JAK2 positivo como con JAK2 negativo; uno de ellos, el ruxolitinib, es la mejor terapia disponible actualmente para la esplenomegalia y los síntomas constitucionales de la MF. Sin embargo, aunque el ruxolitinib ha cambiado el escenario terapéutico de la MF, no hay indicios claros de un efecto modificador de la enfermedad. El alotrasplante de células madre sigue siendo la única terapia curativa de la MF, pero debido a su morbilidad y mortalidad asociadas, generalmente se restringe a pacientes elegibles con MF de riesgo alto e intermedio 2. Para mejorar los resultados terapéuticos actuales, actualmente se está probando la combinación de inhibidores de JAK con otros agentes y se están investigando fármacos más nuevos.

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BACKGROUND: Stroke is a serious complication of sickle cell anemia (SCA). The transcranial Doppler (TCD) is the risk-screening tool for ischemic strokes. The objective of the study was to describe the clinical progression of children with SCA who presented with high risk for stroke by TCD or relevant changes by magnetic resonance angiography (MRA) and underwent the regular transfusion program (RTP) and/or hydroxyurea (HU) treatment between 2007 and 2018. METHOD: This was a neonatal retrospective/prospective cohort study with children born between 1999 and 2014 with the homozygotic form (HbSS) or Sß0-thalassemia who underwent TCD at least once. RESULTS: Of the 718 children screened during this period, 675 had HbSS and 43 Sß0-thalassemia. In 54 children (7.5%), all with HbSS, a high-risk TCD (n = 45) or, when the TCD was inconclusive, an MRA with cerebral vasculopathy (n = 9) was used for detection. Of these, 51 started the RTP and the families of three refused treatment. Of the 43 children with a high-risk TCD who initiated the RTP, 29 (67.4%) reverted to low risk. In 18 of them (62%), HU was started at the maximum tolerated dose (MTD) before transfusion discontinuation. None of these 29 patients had a stroke. Eight children (18.6%) maintained a high-risk TCD, even using the RTP/HU and two had a stroke. CONCLUSIONS: The TCD was confirmed as a viable tool for tracking patients with a risk for stroke. The RTP was effective in preventing the primary event. New strategies are necessary to prevent stroke using HU and new drugs, in addition to bone marrow transplantation.