bims-conane 2025-08-17 papers

Oxid Med Cell Longev. 2025 ;2025 7041213

Molecular Mechanisms of Drug-Induced Hemolysis in G6PD Deficiency: Mechanistic Insights.

Sulaiman Paika, Matthew Machini, Mayur S Parmar.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a prevalent enzymopathy, predisposes individuals to hemolytic anemia upon exposure to various medications. This literature review explores the molecular underpinnings of drug-induced hemolytic anemia (DIHA) in G6PD-deficient patients, focusing on dapsone, amoxicillin, and primaquine. These drugs are essential for treating infections such as leprosy and malaria. However, they can damage red blood cell (RBC) membranes through complex mechanisms distinct from traditional immune-mediated pathways. Evidence suggests that drug metabolites, such as dapsone hydroxylamine and 5-hydroxyprimaquine, induce oxidative stress and disrupt RBC membrane integrity. The band 3 protein, a critical component of the RBC cytoskeleton, emerges as a key player in this process, undergoing tyrosine phosphorylation and aggregation, leading to membrane remodeling and instability. This review underscores the need for further research to elucidate the precise molecular interactions involved in drug-induced hemolysis in G6PD deficiency. Understanding these mechanisms may pave the way for developing targeted therapies, including adjuvant treatments and novel drug formulations, to mitigate the risk of hemolytic anemia in this vulnerable population.

DOI: https://doi.org/10.1155/omcl/7041213

Nat Biomed Eng. 2025 Aug 12.

In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery.

Saijuan Xu, Dan Liang, Qiudao Wang, Yan Cheng, Da Xie, Yang Gui, Haokun Zhang, Changrui Feng, Feiyan Zhao, Wendan Ren, Gongrui Sun, Yang Yang, Lin Li, Yongrong Lai, Bin Fu, Yuming Lu, Zi Jun Wang, Yuxuan Wu.

Ex vivo autologous haematopoietic stem cell (HSC) gene therapy provides a promising treatment option for haematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and major side effects. Here we develop antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the γ-globin gene (HBG1/2) promoter target in human HSCs to reactivate fetal haemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG1/2 in transfusion-dependent β-thalassaemia (TDT) patient-derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicates that using LNPs for genome editor delivery achieves efficient editing of endogenous genes of human HSCs. This non-viral delivery system eliminates the need for collecting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders such as sickle cell disease and TDT.

DOI: https://doi.org/10.1038/s41551-025-01480-y

BMC Surg. 2025 Aug 09. 25(1): 359

Pediatric splenectomy for hematologic disorders: two-decade experience and prophylactic cholecystectomy outcomes.

Oguzhan Uzaslan, Ali Ekber Hakalmaz, Suheyla Ocak, Osman Faruk Senyuz, Senol Emre.

BACKGROUND: While splenectomy remains a cornerstone treatment for certain hematologic diseases, controversy persists regarding the optimal timing and indications for prophylactic cholecystectomy. This study evaluates long-term outcomes from a large single-center series.
METHODS: We retrospectively analyzed 87 patients (48 male, 39 female) with hematologic disorders who underwent splenectomy between 2003 and 2023. Primary outcomes included improvement in hematologic parameters, resolution of bilirubinemia, prevalence of cholelithiasis, and complication rates. Subgroup analyses examined disease-specific outcomes and age-stratified results.
RESULTS: Hereditary spherocytosis was the predominant diagnosis (70.1%), followed by thalassemia (11.5%) and immune thrombocytopenia (ITP) (10.3%). The mean age at splenectomy was 9.6 years (range 3-17), with a mean interval from diagnosis to surgery of 4.3 years. Spleen size significantly differed across diseases, being largest in rare hematologic disorders (178 mm) and smallest in ITP (97.56 mm). Cholelithiasis was present in 65.6% of hereditary spherocytosis cases and 50% of thalassemia cases but was absent in ITP. Simultaneous cholecystectomy was performed in 55 patients (63.2%), including 10 prophylactic procedures. Postoperatively, hemoglobin levels increased by factors of 1.24, 1.13, and 1.25 in hereditary spherocytosis, thalassemia, and ITP, respectively. Platelet counts increased by factors of 2.24, 2.8, and 6.5, respectively. Bilirubin levels decreased significantly in all groups. Notably, preoperative total bilirubin was significantly higher (p = 0.016) in patients selected for prophylactic cholecystectomy (mean 4.17 mg/dL) compared to those without cholecystectomy (mean 1.92 mg/dL).
CONCLUSIONS: Splenectomy offers durable improvements in hematologic parameters across various hematologic diseases, with minimal complications. Prophylactic cholecystectomy appears justified in patients with marked hyperbilirubinemia, even without cholelithiasis, particularly in hereditary spherocytosis. The absence of post-splenectomy sepsis in this series supports the continued role of total splenectomy when appropriate vaccination protocols and antibiotic prophylaxis are implemented.

Keywords: Cholecystectomy; Hematologic disorders; Hereditary spherocytosis; Hyperbilirubinemia; Prophylactic cholecystectomy; Splenectomy

DOI: https://doi.org/10.1186/s12893-025-03107-0

Nat Commun. 2025 Aug 15. 16(1): 7619

BMI1 regulates human erythroid self-renewal through both gene repression and gene activation.

Kathleen E McGrath, Jayme L Olsen, Anne D Koniski, Kristin E Murphy, Michael Getman, Hyun Hyung An, Vincent P Schulz, Ah Ram Kim, Bin Zhang, Taylor L Carlson, Julien Papoin, Lionel Blanc, Paul D Kingsley, Connie M Westhoff, Patrick G Gallagher, Stella T Chou, Laurie A Steiner, James Palis.

The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient in vitro-derived red blood cells for clinical purposes. While BMI1, a Polycomb Repressive Complex 1 member, is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts, its mechanism of action remains poorly understood. Here we report that BMI1 overexpression leads to 10 billion-fold increase in self-renewal of human erythroblasts, which can terminally mature and agglutinate with typing reagent monoclonal antibodies. BMI1 and RING1B occupancy, along with repressive histone marks, are present at known BMI1 target genes, including the INK-ARF locus, consistent with altered cell cycle kinetics following BMI1 inhibition. Upregulation of BMI1 target genes with low repressive histone modifications, including key regulators of cholesterol homeostasis, along with functional studies, suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. We conclude that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand immature erythroid precursors for eventual clinical uses.

DOI: https://doi.org/10.1038/s41467-025-62993-3

Echocardiography. 2025 Aug;42(8): e70262

Echocardiographic Left Atrial Stiffness Index Predicts Myocardial Iron Overload in Pediatric β-Thalassemia.

Yiqun Guan, Yan Deng, Xiao Li, Shaolin Luo, Guizi Liang, Jie Hu, Yongshou Pan.

OBJECTIVES: Myocardial iron overload (MIO) is the leading cause of mortality among individuals with thalassemia major. This study aimed to evaluate the predictive value of the left atrial stiffness index (LASI) for MIO among β-thalassemia pediatric patients.
METHODS: A total of 105 children with thalassemia and 30 healthy controls were included in the study. The patients were categorized into three groups on the basis of LASI tertiles. MIO was assessed via cardiac magnetic resonance (CMR) T2* imaging.
RESULTS: The LASI differed significantly between patients and controls (p < 0.001). The LASI and E/e' ratio were negatively correlated with the CMR T2* value (LASI: r = -0.76, p < 0.001; E/e': r = -0.48, p < 0.001), whereas left atrial reservoir strain (LASr), global longitudinal strain (GLS), and left atrial strain conduit strain (LAScd) were positively correlated with the CMR T2* value (LASr: r = 0.64, p = 0.002; GLS: r = 0.70, p < 0.001; LAScd: r = 0.57, p = 0.009). Restricted cubic spline (RCS) analysis revealed nonlinear associations between the LASI, GLS, and CMR T2* values (nonlinearity p < 0.001). In pediatric thalassemia patients, the LASI, GLS, and LASr independently predicted MIO. The LASI demonstrated the highest diagnostic accuracy (AUC = 0.90; optimal cutoff: 22.68%), outperforming GLS (AUC = 0.76; cutoff: 18.70%) and LASr (AUC = 0.80; cutoff: 37.05%) (DeLong test: p = 0.048 vs. GLS; p = 0.022 vs. LASr).
CONCLUSIONS: The LASI is strongly correlated with the CMR T2* value and is a promising tool for predicting MIO in pediatric patients with thalassemia.

Keywords: echocardiographic; myocardial iron overload; pediatric; thalassemia

DOI: https://doi.org/10.1111/echo.70262

Ann Hematol. 2025 Aug 16.

Beyond transfusions and transplants: genomic innovations rewriting the narrative of thalassemia.

Liangbin Shi, Xili Yan, Yanwei Xia, Yingdi Zhao, Xiuling Zhu, Qiang Li, Zhiliang Xu.

Thalassemia is a globally prevalent inherited blood disorder that usually leads to severe complications and even premature death due to impaired hemoglobin synthesis. The conventional treatment approach encompasses a range of interventions, including red blood cell transfusions, iron chelation therapy, splenectomy, and allogeneic hematopoietic stem cell transplantation. However, transfusion-induced iron overload and the limitation of graft matching have emerged as significant clinical impediments. In recent years, with the advent of precision medicine and translational research, the treatment of thalassemia has undergone a paradigm shift toward stem cell gene therapy, gene editing combined with nanodelivery, and pharmacogenomics-guided, personalized treatment regimens. In preclinical and early-phase clinical trials, these approaches have demonstrated efficacy in modulating hemoglobin gene expression and reversing ineffective hematopoiesis. Consequently, this review explores the constraints imposed by conventional therapeutic approaches and the advancements in the field of gene therapy for thalassaemia. It elucidates the mechanisms of gene editing and the potential of stem cell therapies. Furthermore, the discourse encompasses the advancement of primary prevention strategies, including genetic testing and prenatal screening, in the context of reducing morbidity. It is our hope that this review will provide the latest clues and insights in gene therapy for the effective management of thalassemia.

Keywords: Diagnosis; Gene editing; Molecular mechanisms; Thalassemia

DOI: https://doi.org/10.1007/s00277-025-06548-y

Am J Hematol. 2025 Aug 13.

Double Bite Cells in Oxidative Hemolytic Anemia.

Jacob R Anderson, Marie A Hollenhorst.

Double bite cells on a peripheral blood smear help to establish the diagnosis of oxidant hemolysis due to recreational alkyl nitrite use in a man with normal G6PD.

Keywords: anemias; hemoglobin; hemolytic anemia; oxidation; red blood cell morphology

DOI: https://doi.org/10.1002/ajh.70035