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Blood Advances Jun 2024
Comparative Study
Bala NS, Stanek JR, Vesely SK, et al. Comparison of thromboembolism outcomes in patients with sickle cell disease prescribed hormonal contraception. Blood Adv. 2023;7(20):6140-6150.
Topics: Humans; Anemia, Sickle Cell; Female; Hormonal Contraception; Thromboembolism
PubMed: 38865149
DOI: 10.1182/bloodadvances.2024013554 -
Hematology (Amsterdam, Netherlands) Dec 2024This study aimed to establish a droplet digital polymerase chain reaction (ddPCR) assay for South-East Asian (SEA) deletion based on a fully integrated digital PCR...
OBJECTIVES
This study aimed to establish a droplet digital polymerase chain reaction (ddPCR) assay for South-East Asian (SEA) deletion based on a fully integrated digital PCR system DropXpert S6.
METHODS
A total of 151 whole blood samples, 10 chorionic villus samples, and 17 amniotic fluid samples were collected, including 106 SEA heterozygotes, 43 normal individuals, 10 Hb Bart's hydrops details, and 19 SEA deletions combined with other genotypes.Genotypes of these samples were determined by the Gap-PCR method. We perform a series of optimizations of the ddPCR system to ensure the performance of the entire ddPCR reaction, such as droplet stability, fluorescence clustering, sensitivity, and accuracy.
RESULTS
Our assay exhibited 99.4% (177/178) accuracy compared with the Gap-PCR method, and the minimum detection limit of DNA was 0.1 ng/μL.Both targets have reliable linearity, R= 0.9999 for the α-thalassemia SEA deletion allele and R= 1 for the wild-type allele. The coefficient of variation for α-thalassemia SEA deletion allele detection at 2 and 10 ng/μL concentrations was 5.42% and 1.91%, respectively. In contrast, the coefficient of variation for wild-type allele detection was 4.06% and 1.83%, demonstrating its high quantitative accuracy. In addition, the DropXpert S6 PCR system showed some advantages over other ddPCR instruments, such as reducing testing costs, simplifying and automating the workflow.
CONCLUSIONS
The DropXpert S6 PCR system provided a highly accurate diagnosis for α-thalassemia SEA deletion and can be used to detect α-thalassemia as an alternative method.
Topics: alpha-Thalassemia; Humans; Polymerase Chain Reaction; Female; Asia, Southeastern; Sequence Deletion; Asian People; East Asian People
PubMed: 38864494
DOI: 10.1080/16078454.2024.2365596 -
Nature Communications Jun 2024Sickle cell disease is a devastating blood disorder that originates from a single point mutation in the HBB gene coding for hemoglobin. Here, we develop a GMP-compatible...
Sickle cell disease is a devastating blood disorder that originates from a single point mutation in the HBB gene coding for hemoglobin. Here, we develop a GMP-compatible TALEN-mediated gene editing process enabling efficient HBB correction via a DNA repair template while minimizing risks associated with HBB inactivation. Comparing viral versus non-viral DNA repair template delivery in hematopoietic stem and progenitor cells in vitro, both strategies achieve comparable HBB correction and result in over 50% expression of normal adult hemoglobin in red blood cells without inducing β-thalassemic phenotype. In an immunodeficient female mouse model, transplanted cells edited with the non-viral strategy exhibit higher engraftment and gene correction levels compared to those edited with the viral strategy. Transcriptomic analysis reveals that non-viral DNA repair template delivery mitigates P53-mediated toxicity and preserves high levels of long-term hematopoietic stem cells. This work paves the way for TALEN-based autologous gene therapy for sickle cell disease.
Topics: Anemia, Sickle Cell; Gene Editing; Animals; Hematopoietic Stem Cells; Humans; Female; Mice; Genetic Therapy; Transcription Activator-Like Effector Nucleases; Hematopoietic Stem Cell Transplantation; beta-Globins; Tumor Suppressor Protein p53; DNA Repair; Mutation; beta-Thalassemia; Disease Models, Animal; Gene Transfer Techniques
PubMed: 38862518
DOI: 10.1038/s41467-024-49353-3 -
Blood Reviews Jun 2024Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by excessive reticuloendothelial platelet destruction and inadequate compensatory platelet... (Review)
Review
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by excessive reticuloendothelial platelet destruction and inadequate compensatory platelet production. However, the pathogenesis of ITP is relatively complex, and its exact mechanisms and etiology have not been definitively established. The gut microbiome, namely a diverse community of symbiotic microorganisms residing in the gastrointestinal system, affects health through involvement in human metabolism, immune modulation, and maintaining physiological balance. Emerging evidence reveals that the gut microbiome composition differs in patients with ITP compared to healthy individuals, which is related with platelet count, disease duration, and response to treatment. These findings suggest that the microbiome and metabolome profiles of individuals could unveil a new pathway for aiding diagnosis, predicting prognosis, assessing treatment response, and formulating personalized therapeutic approaches for ITP. However, due to controversial reports, definitive conclusions cannot be drawn, and further investigations are needed.
PubMed: 38862311
DOI: 10.1016/j.blre.2024.101219 -
Experimental Hematology Jun 2024Genetic downregulation of the BCL11A transcription factor (TF) reverses the switch from fetal to adult hemoglobin and is effective in treating β-hemoglobinopathies.... (Review)
Review
Genetic downregulation of the BCL11A transcription factor (TF) reverses the switch from fetal to adult hemoglobin and is effective in treating β-hemoglobinopathies. Genetic ablation results in a gradual reduction in protein abundance and does not lend itself to the analysis of the immediate consequences of protein loss or the determination of the direct interactors/targets of the protein of interest. We achieved acute degradation of the largely disordered and 'undruggable' BCL11A protein by fusing it with a conditional degradation (degron) tag, FKBP12, called degradable tags (dTAG). Small molecules then depleted the BCL11A-dTAG through endogenous proteolytic pathways. By integrating acute depletion with nascent transcriptomics and cell cycle separation techniques, we demonstrate the necessity of BCL11A occupancy at the target chromatin for sustained transcriptional repression in erythroid cells. We advocate for expanding the exploration of TF function to include acute depletion, which holds the potential to unveil unprecedented kinetic insights into TF mechanisms of action.
PubMed: 38862078
DOI: 10.1016/j.exphem.2024.104250 -
Expert Opinion on Therapeutic Targets May 2024HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate... (Review)
Review
INTRODUCTION
HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate balance required for its modulation. HIF-1α stands as a cornerstone in medical research, its role extending to therapeutic strategies. This review explores the intricate interplay surrounding HIF-1α, highlighting its critical involvement and the necessity for cautious modulation.
AREAS COVERED
In sickle cell disease (SCD), HIF-1α's potential to augment fetal hemoglobin (HbF) production and mitigate symptoms is underscored. Furthermore, its role in cancer is examined, particularly its influence on survival in hypoxic tumor microenvironments, angiogenesis, and metastasis. The discussion extends to the intricate relationship between HIF-1α modulation and cancer risks in SCD patients, emphasizing the importance of balancing therapeutic benefits and potential hazards.
EXPERT OPINION
Managing HIF-1α modulation in SCD patients requires a nuanced approach, considering therapeutic potential alongside associated risks, especially in exacerbating cancer risks. An evolutionary perspective adds depth, highlighting adaptations in populations adapted to low-oxygen environments and aligning cancer cell metabolism with primitive cells. The role of HIF-1α as a therapeutic target is discussed within the context of complex cancer biology and metabolism, acknowledging varied responses across diverse cancers influenced by intricate evolutionary adaptations.
Topics: Humans; Anemia, Sickle Cell; Neoplasms; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Tumor Microenvironment; Molecular Targeted Therapy; Fetal Hemoglobin; Neovascularization, Pathologic
PubMed: 38861226
DOI: 10.1080/14728222.2024.2367640 -
Journal of Pediatric Hematology/oncology Jul 2024Sickle cell disease (SCD) is a common hereditary hemoglobin disorder worldwide. One of the main treatments for patients with SCD is the requirement for blood...
OBJECTIVE
Sickle cell disease (SCD) is a common hereditary hemoglobin disorder worldwide. One of the main treatments for patients with SCD is the requirement for blood transfusions. Posttransfusion alloimmunization with red blood cell (RBC) antigens continues to be a major risk factor for SCD. The objective of this study was to determine the rate, nature, and risk factors of red cell alloimmunization among pediatric patients with SCD in our center and compare our results with published reports from Saudia Arabia SA, regional countries, and some international countries.
MATERIALS AND METHODS
A retrospective chart review of patients with SCD at King Abdulaziz Medical City-Jeddah, between 2008 and 2019 was performed. Demographic characteristics and transfusion histories were recorded. Blood samples were analyzed for alloimmunization using immunohematologic techniques.
RESULTS
In total, 121 patients were analyzed. Alloantibodies were detected in 21 patients (17.4%) and were mostly single in 15 patients (71.4%), anti-K (23.7%), anti-E (19.0%), and anti-S (9.5%). The other 6 patients (28.6%) had multiple alloantibodies, especially the combination of anti-C and anti-K (9.5%) and the combination of anti-C and anti-E (9.5%). Alloantibody levels were significantly higher in patients with frequent hospital admissions (>5 times annually), those who had an exchange blood transfusion, those younger than 3 years old, and those who received a larger number of blood units ( P ≤0.05).
CONCLUSION
The rate of RBC alloimmunization is determined and considered relatively low compared with that in other nations. Matching for extended RBC antigens to include ABO, RH (D, C, c, E, e), K, Fy a , Fy b , Jk a , and Jk b antigens in the screening panel for donors and recipients is highly recommended to ensure better transfusion practices and avoid transfusion-related complications.
Topics: Humans; Anemia, Sickle Cell; Saudi Arabia; Child; Male; Retrospective Studies; Female; Isoantibodies; Child, Preschool; Adolescent; Prevalence; Erythrocytes; Infant; Blood Group Incompatibility; Blood Group Antigens; Risk Factors; Blood Transfusion
PubMed: 38857199
DOI: 10.1097/MPH.0000000000002889 -
Lipids in Health and Disease Jun 2024Obesity is a metabolic syndrome where allelic and environmental variations together determine the susceptibility of an individual to the disease. Caloric restriction...
BACKGROUND
Obesity is a metabolic syndrome where allelic and environmental variations together determine the susceptibility of an individual to the disease. Caloric restriction (CR) is a nutritional dietary strategy recognized to be beneficial as a weight loss regime in obese individuals. Preconceptional parental CR is proven to have detrimental effects on the health and development of their offspring. As yet studies on maternal CR effect on their offspring are well established but paternal CR studies are not progressing. In current study, the impact of different paternal CR regimes in diet-induced obese male Wistar rats (WNIN), on their offspring concerning metabolic syndrome are addressed.
METHODS
High-fat diet-induced obese male Wistar rats were subjected to caloric restriction of 50% (HFCR-I) and 40% (HFCR-II) and then they were mated with normal females. The male parent's reproductive function was assessed by sperm parameters and their DNMT's mRNA expression levels were also examined. The offspring's metabolic function was assessed by physiological, biochemical and molecular parameters.
RESULTS
The HFCR-I male parents have shown reduced body weights, compromised male fertility and reduced DNA methylation activity. Further, the HFCR-I offspring showed attenuation of the AMPK/SIRT1 pathway, which is associated with the progression of proinflammatory status and oxidative stress. In line, the HFCR-I offspring also developed altered glucose and lipid homeostasis by exhibiting impaired glucose tolerance & insulin sensitivity, dyslipidemia and steatosis. However, these effects were largely mitigated in HFCR-II offspring. Regarding the obesogenic effects, female offspring exhibited greater susceptibility than male offspring, suggesting that females are more prone to the influences of the paternal diet.
CONCLUSION
The findings highlight that HFCR-I resulted in paternal undernutrition, impacting the health of offspring, whereas HFCR-II largely restored the effects of a high-fat diet on their offspring. As a result, moderate caloric restriction has emerged as an effective weight loss strategy with minimal implications on future generations. This underscores the shared responsibility of fathers in contributing to sperm-specific epigenetic imprints that influence the health of adult offspring.
Topics: Animals; Sirtuin 1; Diet, High-Fat; Obesity; Male; Rats, Wistar; Female; Caloric Restriction; Rats; DNA Methylation; AMP-Activated Protein Kinases; Signal Transduction; Pregnancy
PubMed: 38851752
DOI: 10.1186/s12944-024-02161-6 -
Transfusion Clinique Et Biologique :... Jun 2024Systematic transfusions coupled with iron chelation therapy have substantially improved the life expectancy of thalassemia patients in developed nations. As the human... (Review)
Review
Systematic transfusions coupled with iron chelation therapy have substantially improved the life expectancy of thalassemia patients in developed nations. As the human organism does not have a protective mechanism to remove excess iron, iron overload is a significant concern in thalassemia, leading to organ damage, especially in the heart and liver. Thus, iron chelation therapy is crucial to prevent or reverse organ iron overload. There are three widely used iron chelators, either as monotherapy or in combination. The choice of iron chelator depends on several factors, including local guidelines, drug availability, and the individual clinical scenario. Despite treatment advancements, challenges persist, especially in resource-limited settings, highlighting the need for improved global healthcare access. This review discusses clinical management, current treatments, and future directions for thalassemia, focusing on iron overload and its complications. Furthermore, it underscores the progress in transforming thalassemia into a manageable chronic condition and the potential of novel therapies to further enhance patient outcomes.
PubMed: 38849068
DOI: 10.1016/j.tracli.2024.06.001 -
PloS One 2024Evidence supports the benefits of hydroxyurea (HU) in adults with sickle cell disease (SCD), but reservations remain due to long-term concerns of fertility.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence supports the benefits of hydroxyurea (HU) in adults with sickle cell disease (SCD), but reservations remain due to long-term concerns of fertility. Retrospective analysis of clinical records of SCD patients (haemoglobin SS genotype) have identified gender-related differences in disease progression. This could inform risk stratification during SCD at diagnosis with the possibility to guide therapeutic decisions.
METHODS
This systemic review and meta-analysis evaluated fertility parameters in both children (aged ≥ 6 years) and adults with SCD receiving HU therapy. Studies were sourced from PubMed and EMBASE from inception to July 2023. A total of 160 potentially relevant articles were identified.
RESULTS
Four studies were included that evaluated the effects of HU on sperm parameters in males. A further 4 studies assessed anti-mullerian hormone (AMH) levels and ovarian reserves in females. Differences from baseline values were used to identify compromised fertility. Amongst males, HU treatment negatively impacted the concentration of spermatozoa (MD = -15.48 million/mL; 95% CI: [-20.69, -10.26]; p< 0.001), which continued following treatment cessation (MD = -20.09 million/mL; 95% CI: [-38.78, -1.40]; P = 0.04). HU treatment also led to lower total sperm counts (MD = -105.87 million; 95% CI: [-140.61, -71.13]; P< 0.001) which persisted after treatment (MD = -53.05 million; 95% CI: [-104.96, -1.14]; P = 0.05). Sperm volume, initial forward motility and morphology were unaffected by HU treatment. In females, HU treatment decreased the mean AMH levels 1.83 (95% CI [1.42, 2.56]. A total of 18.2.% patients treated with HU showed reduced ovarian reserves.
INTERPRETATION & CONCLUSIONS
This systemic review and meta-analysis suggest that the use of HU for SCD impacts seminal fluid parameters in males and can diminish AMH levels and ovarian reserves in females.
Topics: Adult; Child; Female; Humans; Male; Anemia, Sickle Cell; Anti-Mullerian Hormone; Antisickling Agents; Fertility; Hydroxyurea; Ovarian Reserve; Sperm Count; Spermatozoa
PubMed: 38848387
DOI: 10.1371/journal.pone.0304241