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Cellular Reprogramming Jun 2024Our group generated two induced pluripotent stem cell (iPSC) lines for red blood cell (RBC) production from blood donors with extensively known erythrocyte antigen...
Our group generated two induced pluripotent stem cell (iPSC) lines for red blood cell (RBC) production from blood donors with extensively known erythrocyte antigen profiles. One line was intended to give rise to RBCs for transfusions in patients with sickle cell disease (SCD), while the other was developed to create RBC panel reagents. Two blood donors were selected based on their RBC phenotypes, further complemented by high-throughput DNA array analysis to obtain a more comprehensive erythrocyte antigen profile. Enriched erythroblast populations from the donors' peripheral blood mononuclear cells were reprogrammed into iPSCs using nonintegrative plasmid vectors. The iPSC lines were characterized and subsequently subjected to hematopoietic differentiation. iPSC PB02 and iPSC PB12 demonstrated and iPSC features and retained the genotype of each blood donor's RBC antigen profile. Colony-forming cell assays confirmed that iPSC PB02 and iPSC PB12 generated hematopoietic progenitors. These two iPSC lines were generated with defined erythrocyte antigen profiles, self-renewal capacity, and hematopoietic differentiation potential. With improvements in hematopoietic differentiation, these cells could potentially be more efficiently differentiated into RBCs in the future. They could serve as a complementary approach for obtaining donor-independent RBCs and addressing specific demands for blood transfusions.
Topics: Induced Pluripotent Stem Cells; Humans; Erythrocytes; Cell Differentiation; Blood Donors; Cell Line; Animals; Blood Group Antigens; Mice; Anemia, Sickle Cell
PubMed: 38917437
DOI: 10.1089/cell.2024.0018 -
PloS One 2024Sickle cell disease (SCD) is an inherited blood disorder that affects approximately 100,000 Americans, primarily from underrepresented racial minority populations, and...
Study protocol for ADHERE (Applying Directly observed therapy to HydroxyurEa to Realize Effectiveness): Using small business partnerships to deliver a scalable and novel hydroxyurea adherence solution to youth with sickle cell disease.
Sickle cell disease (SCD) is an inherited blood disorder that affects approximately 100,000 Americans, primarily from underrepresented racial minority populations, and results in costly, multi-organ complications. Hydroxyurea, the primary disease-modifying therapy for SCD, is effective at reducing most complications; however, adherence to hydroxyurea remains suboptimal and is the primary barrier to clinical effectiveness. Video directly observed therapy (VDOT) has shown promise as an adherence-promoting intervention for hydroxyurea, yet previous VDOT trials were limited by high attrition from gaps in technology access, use of unvalidated adherence measures, and healthcare system limitations of delivering VDOT to patients. As such, we fostered a small business partnership to compare VDOT for hydroxyurea to attention control to address previous shortcomings, promote equitable trial participation, and maximize scalability. VDOT will be administered by Scene Health (formerly emocha Health) and adherence monitoring will be performed using a novel electronic adherence monitor developed to meet the unique needs of the target population. Adolescent and young adult patients as well as caregivers of younger patients (<11 years of age) will be recruited. In addition to visit incentives, all participants will be offered a smartphone with a data plan to ensure all participants have equal opportunity to complete study activities. The primary objectives of this pilot, multi-center, randomized controlled trial (RCT) are to assess retention and sustained engagement and to explore needs and preferences for longer-term adherence monitoring and interventions. This RCT is registered with the National Institutes of Health (NCT06264700). Findings will inform a future efficacy RCT applying VDOT to hydroxyurea to address adherence gaps and improve outcomes within this vulnerable population.
Topics: Humans; Anemia, Sickle Cell; Hydroxyurea; Adolescent; Child; Medication Adherence; Young Adult; Antisickling Agents; Male; Female; Adult
PubMed: 38917111
DOI: 10.1371/journal.pone.0304644 -
Health Science Reports Jun 2024Despite advancements in the management of patients with sickle cell disease (SCD), the involvement of the cardiovascular system in these patients remains a significant...
BACKGROUND
Despite advancements in the management of patients with sickle cell disease (SCD), the involvement of the cardiovascular system in these patients remains a significant concern. Cardiovascular manifestations of SCD are well-documented, with electrocardiography (ECG) serving as a valuable diagnostic tool. Studies have reported a high rate of critical ECG findings in patients with SCD that warrants consideration when managing these patients, indicating the need for proactive cardiac screening and management strategies in this patient population. This study aims to systematically review the literature to identify sociodemographic, clinical, and paraclinical factors associated with ECG abnormalities in patients with SCD.
METHODS
A comprehensive search strategy will be employed across multiple online databases, including PubMed, Embase, Scopus, Web of Science, and Google Scholar, for published and gray literature. Eligible studies will include original articles reporting associations between sociodemographic, clinical, and paraclinical variables and a spectrum of ECG findings in patients with SCD. Independent reviewers will conduct the screening, quality assessment, and data extraction. Quantitative analyses will be performed under a random-effect model using Comprehensive Meta-Analysis software, with subgroup analyses based on SCD status, sickle hemoglobinopathy form, and age group.
PubMed: 38915361
DOI: 10.1002/hsr2.2212 -
Biomedicine & Pharmacotherapy =... Jun 2024The induction of immunological tolerance is a promising strategy for managing autoimmune diseases, allergies, and transplant rejection. Tregitopes, a class of peptides,... (Review)
Review
The induction of immunological tolerance is a promising strategy for managing autoimmune diseases, allergies, and transplant rejection. Tregitopes, a class of peptides, have emerged as potential agents for this purpose. They activate regulatory T cells, which are pivotal in reducing inflammation and promoting tolerance, by binding to MHC II molecules and facilitating their processing and presentation to Treg cells, thereby encouraging their proliferation. Moreover, Tregitopes influence the phenotype of antigen-presenting cells by attenuating the expression of CD80, CD86, and MHC class II while enhancing ILT3, resulting in the inhibition of NF-kappa B signaling pathways. Various techniques, including in vitro and in silico methods, are applied to identify Tregitope candidates. Currently, Tregitopes play a vital role in balancing immune activation and tolerance in clinical applications such as Pompe disease, diabetes-related antigens, and the prevention of spontaneous abortions in autoimmune diseases. Similarly, Tregitopes can induce antigen-specific regulatory T cells. Their anti-inflammatory effects are significant in conditions such as autoimmune encephalomyelitis, inflammatory bowel disease, and Guillain-Barré syndrome. Additionally, Tregitopes have been leveraged to enhance vaccine design and efficacy. Recent advancements in understanding the potential benefits and drawbacks of IVIG and the discovery of the function and mechanism of Tregitopes have introduced Tregitopes as a popular option for immune system modulation. It is expected that they will bring about a significant revolution in the management and treatment of autoimmune and immunological diseases. This article is a comprehensive review of Tregitopes, concluding with the potential of these epitopes as a therapeutic avenue for immunological disorders.
PubMed: 38908205
DOI: 10.1016/j.biopha.2024.116983 -
Clinical Chemistry Jun 2024Hemoglobinopathies, the most common inherited blood disorder, are frequently underdiagnosed. Early identification of carriers is important for genetic counseling of...
BACKGROUND
Hemoglobinopathies, the most common inherited blood disorder, are frequently underdiagnosed. Early identification of carriers is important for genetic counseling of couples at risk. The aim of this study was to develop and validate a novel machine learning model on a multicenter data set, covering a wide spectrum of hemoglobinopathies based on routine complete blood count (CBC) testing.
METHODS
Hemoglobinopathy test results from 10 322 adults were extracted retrospectively from 8 Dutch laboratories. eXtreme Gradient Boosting (XGB) and logistic regression models were developed to differentiate negative from positive hemoglobinopathy cases, using 7 routine CBC parameters. External validation was conducted on a data set from an independent Dutch laboratory, with an additional external validation on a Spanish data set (n = 2629) specifically for differentiating thalassemia from iron deficiency anemia (IDA).
RESULTS
The XGB and logistic regression models achieved an area under the receiver operating characteristic (AUROC) of 0.88 and 0.84, respectively, in distinguishing negative from positive hemoglobinopathy cases in the independent external validation set. Subclass analysis showed that the XGB model reached an AUROC of 0.97 for β-thalassemia, 0.98 for α0-thalassemia, 0.95 for homozygous α+-thalassemia, 0.78 for heterozygous α+-thalassemia, and 0.94 for the structural hemoglobin variants Hemoglobin C, Hemoglobin D, Hemoglobin E. Both models attained AUROCs of 0.95 in differentiating IDA from thalassemia.
CONCLUSIONS
Both the XGB and logistic regression model demonstrate high accuracy in predicting a broad range of hemoglobinopathies and are effective in differentiating hemoglobinopathies from IDA. Integration of these models into the laboratory information system facilitates automated hemoglobinopathy detection using routine CBC parameters.
PubMed: 38906831
DOI: 10.1093/clinchem/hvae081 -
Annals of Hematology Jun 2024
PubMed: 38902376
DOI: 10.1007/s00277-024-05838-1 -
Blood Jun 2024
Topics: Humans; Anemia, Sickle Cell
PubMed: 38900474
DOI: 10.1182/blood.2024024273 -
AAPS PharmSciTech Jun 2024Chemotherapeutic agents often lack specificity, intratumoral accumulation, and face drug resistance. Targeted drug delivery systems based on nanoparticles (NPs) mitigate...
Chemotherapeutic agents often lack specificity, intratumoral accumulation, and face drug resistance. Targeted drug delivery systems based on nanoparticles (NPs) mitigate these issues. Poly (lactic-co-glycolic acid) (PLGA) is a well-studied polymer, commonly modified with aptamers (Apts) for cancer diagnosis and therapy. In this study, silybin (SBN), a natural agent with established anticancer properties, was encapsulated into PLGA NPs to control delivery and improve its poor solubility. The field-emission scanning electron microscopy (FE-SEM) showed spherical and uniform morphology of optimum SBN-PLGA NPs with 138.57±1.30nm diameter, 0.202±0.004 polydispersity index (PDI), -16.93±0.45mV zeta potential (ZP), and 70.19±1.63% entrapment efficiency (EE). The results of attenuated total reflectance-Fourier transform infrared (ATR-FTIR) showed no chemical interaction between formulation components, and differential scanning calorimetry (DSC) thermograms confirmed efficient SBN entrapment in the carrier. Then, the optimum formulation was functionalized with 5TR1 Apt for active targeted delivery of SBN to colorectal cancer (CRC) cells in vitro. The SBN-PLGA-5TR1 nanocomplex released SBN at a sustained and constant rate (zero-order kinetic), favoring passive delivery to acidic CRC environments. The MTT assay demonstrated the highest cytotoxicity of the SBN-PLGA-5TR1 nanocomplex in C26 and HT29 cells and no significant cytotoxicity in normal cells. Apoptosis analysis supported these results, showing early apoptosis induction with SBN-PLGA-5TR1 nanocomplex which indicated this agent could cause programmed death more than necrosis. This study presents the first targeted delivery of SBN to cancer cells using Apts. The SBN-PLGA-5TR1 nanocomplex effectively targeted and suppressed CRC cell proliferation, providing valuable insights into CRC treatment without harmful effects on healthy tissues.
Topics: Humans; Polylactic Acid-Polyglycolic Acid Copolymer; Silybin; Colorectal Neoplasms; Nanoparticles; Lactic Acid; Drug Delivery Systems; Silymarin; Drug Carriers; Cell Line, Tumor; Polyglycolic Acid; Particle Size; Aptamers, Nucleotide; Cell Survival; Antineoplastic Agents; Solubility; HT29 Cells; Drug Liberation; Calorimetry, Differential Scanning
PubMed: 38898204
DOI: 10.1208/s12249-024-02858-y -
EJHaem Jun 2024A universal newborn screening program for sickle cell disease (uNS-SCD) was implemented in the province of Québec (Qc) in November 2013, close in time to the...
A universal newborn screening program for sickle cell disease (uNS-SCD) was implemented in the province of Québec (Qc) in November 2013, close in time to the recommendation of early initiation of hydroxyurea (HU) therapy for children. This retrospective cohort study evaluated the impact of such a program on children first seen between January 2000 and December 2019. Cohorts pre-SCD-uNS in Qc (pre-QcNS) ( = 253) and post-QcNS ( = 157) for patients seen prior to or after Nov 2013 were compared. Kaplan-Meier curves, Poisson regression, and logistic regressions were used for statistical analysis, using Software R version 4.2.1. Median age at first visit decreased significantly from 14.4 [interquartile range: 2.4-72.0] to 1.2 months [1.2-57.6] ( < 0.001). The percentage of children born in Qc undiagnosed at birth and referred after a first SCD-related complication dropped from 42.6% to 0.0% ( < 0.0001). The median age of HU introduction for patients with SS/Sβ°-thalassemia decreased from 56.4 [31.2-96.0] to 9.0 months post-QcNS [8.0-12.1] ( < 0.001). Event-free survival improved significantly for any type of hospitalization as well as for vaso-occlusive crisis (VOC) (140-257 days ( < 0.001) and 1320 vs. 573 days ( < 0.002), respectively), resulting in a reduction from 2 [interquartile range: 1.0-3.0] to 1.0 hospitalizations/patient-year [0.6-1.4] ( < 0.001). Children with SS/Sβ°-thalassemia referred post-QcNS also had fewer emergency department visits for VOC (RR: 0.69, 95% confidence interval: 0.54-0.88). The Universal NS program allows early detection and referral of children with SCD to comprehensive care centers. Earlier access ensures that children benefit from essential preventive interventions, reducing disease burden. This cohort study highlights that uNS-SCD is an essential public health measure.
PubMed: 38895082
DOI: 10.1002/jha2.926 -
EJHaem Jun 2024
PubMed: 38895073
DOI: 10.1002/jha2.916