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Blood Advances Apr 2024Iron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are...
Iron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in β-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in β-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the β-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of β-thalassemia.
Topics: Mice; Humans; Animals; Hepcidins; beta-Thalassemia; Splenomegaly; Iron Overload; Iron; Membrane Proteins; Serine Endopeptidases
PubMed: 38241484
DOI: 10.1182/bloodadvances.2023012010 -
Quantitative Imaging in Medicine and... Jan 2024The mutational status of alpha-thalassemia X-linked intellectual disability () is an important indicator for the treatment and prognosis of high-grade gliomas, but...
A fusion model integrating magnetic resonance imaging radiomics and deep learning features for predicting alpha-thalassemia X-linked intellectual disability mutation status in isocitrate dehydrogenase-mutant high-grade astrocytoma: a multicenter study.
BACKGROUND
The mutational status of alpha-thalassemia X-linked intellectual disability () is an important indicator for the treatment and prognosis of high-grade gliomas, but reliable testing currently requires invasive procedures. The objective of this study was to develop a clinical trait-imaging fusion model that combines preoperative magnetic resonance imaging (MRI) radiomics and deep learning (DL) features with clinical variables to predict status in isocitrate dehydrogenase ()-mutant high-grade astrocytoma.
METHODS
A total of 234 patients with -mutant high-grade astrocytoma (120 mutant type, 114 wild type) from 3 centers were retrospectively analyzed. Radiomics and DL features from different regions (edema, tumor, and the overall lesion) were extracted to construct multiple imaging models by combining different features in different regions for predicting status. An optimal imaging model was then selected, and its features and linear coefficients were used to calculate an imaging score. Finally, a fusion model was developed by combining the imaging score and clinical variables. The performance and application value of the fusion model were evaluated through the comparison of receiver operating characteristic curves, the construction of a nomogram, calibration curves, decision curves, and clinical application curves.
RESULTS
The overall hybrid model constructed with radiomics and DL features from the overall lesion was identified as the optimal imaging model. The fusion model showed the best prediction performance with an area under curve of 0.969 in the training set, 0.956 in the validation set, and 0.949 in the test set as compared to the optimal imaging model (0.966, 0.916, and 0.936, respectively) and clinical model (0.677, 0.641, 0.772, respectively).
CONCLUSIONS
The clinical trait-imaging fusion model based on preoperative MRI could effectively predict the mutation status of individuals with -mutant high-grade astrocytoma and has the potential to help patients through the development of a more effective treatment strategy before treatment.
PubMed: 38223098
DOI: 10.21037/qims-23-807 -
Molecules (Basel, Switzerland) Dec 2023Induction of fetal hemoglobin (HbF) is highly beneficial for patients carrying β-thalassemia, and novel HbF inducers are highly needed. Here, we describe a new class of...
Induction of fetal hemoglobin (HbF) is highly beneficial for patients carrying β-thalassemia, and novel HbF inducers are highly needed. Here, we describe a new class of promising HbF inducers characterized by an isoxazole chemical skeleton and obtained through modification of two natural molecules, geldanamycin and radicicol. After preliminary biological assays based on benzidine staining and RT-qPCR conducted on human erythroleukemic K562 cells, we employed erythroid precursors cells (ErPCs) isolated from β-thalassemic patients. ErPCs weretreated with appropriate concentrations of isoxazole derivatives. The accumulation of globin mRNAs was studied by RT-qPCR, and hemoglobin production by HPLC. We demonstrated the high efficacy of isozaxoles in inducing HbF. Most of these derivatives displayed an activity similar to that observed using known HbF inducers, such as hydroxyurea (HU) or rapamycin; some of the analyzed compounds were able to induce HbF with more efficiency than HU. All the compounds were active in reducing the excess of free α-globin in treated ErPCs. All the compounds displayed a lack of genotoxicity. These novel isoxazoles deserve further pre-clinical study aimed at verifying whether they are suitable for the development of therapeutic protocols for β-thalassemia.
Topics: Humans; Fetal Hemoglobin; Erythroid Precursor Cells; beta-Thalassemia; Biological Assay; Hydroxyurea; Isoxazoles
PubMed: 38202591
DOI: 10.3390/molecules29010008 -
BMC Neurology Jan 2024Patients with severe thalassemia may experience adverse effects from transfusion such as fever, rash, and iron overload after long-term transfusion therapy. Severe... (Review)
Review
BACKGROUND
Patients with severe thalassemia may experience adverse effects from transfusion such as fever, rash, and iron overload after long-term transfusion therapy. Severe headaches as a side effect of blood transfusion in patients with thalassemia are not commonly observed, especially when combined with superficial siderosis of the central nervous system, which is easily misdiagnosed and requires excessive examination and treatment.
CASE PRESENTATION
A 31-year-old woman was admitted with severe headache and vomiting over 3 days following blood transfusion. She was diagnosed with intermediate α-thalassemia at 2 years of age and had a history of irregular blood transfusions. Physical examination revealed horizontal nystagmus with no other abnormal neurological signs. Magnetic resonance (MR) imaging, MR venography, MR arteriography, and cerebrospinal fluid analysis were normal. However, susceptibility-weighted imaging showed abnormal signals in the bilateral and fourth ventricles. Initial antibiotics, antivirals, decompression of intracranial pressure, iron chelation, and symptomatic treatments were administered; subsequently, small intermittent blood transfusions were cautiously administered for severe anemia. The patient's headache was gradually relieved, and she was discharged on day 9. At the 5-month follow-up, the patient's headache recurred following another transfusion.
CONCLUSIONS
Severe post-transfusion headache in patients with thalassemia has not been fully recognized and is easily misdiagnosed, leading to excessive examination and treatment. Understanding the clinical features of transfusion-related headaches can help identify this complication, but the exact pathophysiological mechanism requires further research.
Topics: Female; Humans; Adult; Siderosis; Central Nervous System; Thalassemia; Headache; Nystagmus, Pathologic
PubMed: 38184518
DOI: 10.1186/s12883-024-03526-1 -
Blood Reviews Mar 2024α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying... (Review)
Review
α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.
Topics: Humans; beta-Thalassemia; alpha-Thalassemia; Erythropoiesis; Hematologic Diseases; Erythrocyte Transfusion; Iron Overload
PubMed: 38182489
DOI: 10.1016/j.blre.2023.101165 -
Hematology, Transfusion and Cell Therapy 2024Hemoglobinopathy Sβ-thalassemia (HbSβ-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSβ-thal and...
INTRODUCTION
Hemoglobinopathy Sβ-thalassemia (HbSβ-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSβ-thal and its modulating factors. We described the molecular, hematological, and clinical characteristics of a cohort of children with HbSβ-thal and estimated its incidence in Minas Gerais, Brazil.
METHODS
Laboratory and clinical data were retrieved from medical records. Molecular analysis was performed by HBB gene sequencing, PCR-RFLP, gap-PCR, and MLPA.
RESULTS
Eighty-nine children were included in the study. Fourteen alleles of β-thal mutations were identified. The incidence of HbSβ-thal in the state was 1 per 22,250 newborns. The most common β-haplotypes were CAR and Benin. The most frequent β-haplotypes were V, II, and I. Coexistence of 3.7 kb HBA1/HBA2 deletion was present in 21.3 % of children. β-thalassemia mutations were associated with several clinical and laboratory features. In general, the incidence of clinical events per 100 patient-years was similar for children with HbSβ-thal, IVS-I-5 G>A, and IVS-I-110 G>A. Children with HbSβ-intermediate phenotypes had a more severe laboratory and clinical profile when compared with those with HbSβ-mild ones. β-haplotypes and α-thalassemia did not meaningfully influence the phenotype of children with HbSβ-thal.
CONCLUSION
The early identification of β-thalassemia alleles may help the clinical management of these children.
PubMed: 38182466
DOI: 10.1016/j.htct.2023.11.002 -
Frontiers in Cellular and Infection... 2023parasites have a complex life cycle, but the most clinically relevant stage of the disease is the invasion of erythrocytes and the proliferation of the parasite in the...
parasites have a complex life cycle, but the most clinically relevant stage of the disease is the invasion of erythrocytes and the proliferation of the parasite in the blood. The influence of human genetic traits on malaria has been known for a long time, however understanding the role of the proteins involved is hampered by the anuclear nature of erythrocytes that makes them inaccessible to genetic tools. Here we overcome this limitation using stem cells to generate erythroid cells with an differentiation protocol and assess parasite invasion with an adaptation of flow cytometry to detect parasite hemozoin. We combine this strategy with reprogramming of patient cells to Induced Pluripotent Stem Cells and genome editing to understand the role of key genes and human traits in malaria infection. We show that deletion of basigin ablates invasion while deletion of ATP2B4 has a minor effect and that erythroid cells from reprogrammed patient-derived HbBart α-thalassemia samples poorly support infection. The possibility to obtain patient-secific and genetically modifed erythoid cells offers an unparalleled opportunity to study the role of human genes and polymorphisms in malaria allowing preservation of the genomic background to demonstrate their function and understand their mechanisms.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Malaria; Erythrocytes; Stem Cells
PubMed: 38173794
DOI: 10.3389/fcimb.2023.1287355 -
Journal of Advanced Research Dec 2023The population of Taiwan has a long history of ethno-cultural evolution. The Taiwanese population was isolated from other large populations such as the European, Han...
INTRODUCTION
The population of Taiwan has a long history of ethno-cultural evolution. The Taiwanese population was isolated from other large populations such as the European, Han Chinese, and Japanese population. The Taiwan Biobank (TWB) project has built a nationwide database, particularly for personal whole-genome sequence (WGS) to facilitate basic and clinical collaboration nationally and internationally, making it one of the most valuable public datasets of the East Asian population.
OBJECTIVES
This study provides comprehensive medical genomic findings from TWB WGS data, for better characterization of disease susceptibility and the choice of ideal treatment regimens in Taiwanese population.
METHODS
We reanalyzed 1496 WGS using a PrecisionFDA Truth challenge winner method Sentieon DNAscope. Single nucleotide variants (SNV) and small insertions/deletions (INDEL) were benchmarked. We also analyzed pharmacogenomic (PGx) drug-associated alleles, and copy number variants (CNV). Multiple practicing clinicians reviewed and curated the clinically significant variants. Variant annotations can be browsed at TaiwanGenomes (https://genomes.tw).
RESULTS
We found that each participant had an average of 6,870.7 globally novel variants and 75.3% (831/1103) of the participants harbored at least one PharmGKB-selected high evidence level human leukocyte antigen (HLA) risk allele. 54 PharmGKB-reported high-level instances of evidence of Cytochrome P450 variant-drug pairs, with a population frequency of over 13.2%. We also identified 23 variants in the ACMG secondary finding V3 gene list from 25 participants, suggesting that 1.67% (25/1496) of the population is harboring at least one medical actionable variant. Our carrier status analyses suggest that one in 25 couples (3.94%) would risk having offspring with at least one pathogenic variant, which is in line with rates found in Japan and Singapore. For pathogenic CNV, we detected 6.88% and 2.02% carrier rates for alpha thalassemia and spinal muscular atrophy, respectively.
CONCLUSION
Our study highlights the overall medical insights of a complete Taiwanese genomic profile.
PubMed: 38159844
DOI: 10.1016/j.jare.2023.12.018 -
Asian Journal of Neurosurgery Sep 2023The 2021 WHO Classification of Central Nervous System Tumors taxonomy laid further stress on molecular classification and prognostication of glial tumors in...
The 2021 WHO Classification of Central Nervous System Tumors taxonomy laid further stress on molecular classification and prognostication of glial tumors in comparison to histopathological grading. Research shows that low-grade gliomas (LGGs) can go through malignant differentiation and lead to severe disability and death. Data from various populations will be necessary to ascertain the exact interplay between genotypic predictors of LGG and outcomes. To assess the molecular pathology for glial tumors in the Pakistani population, the Shaukat Khanum Memorial Cancer Hospital carried out a retrospective chart review of electronic health records from 2008 to 2018, with immunohistochemistry analysis findings from 2010 to 2018. Patients with a pathological diagnosis of a glioma were included. Analysis was performed using IBM SPSS Statistics Version 23 and STATA Version 16. A -value of less than 0.05 was considered statistically significant with 95% confidence intervals reported. In all, 281 operable tumors were recorded. The most common procedure was a subtotal resection, and astrocytomas (64.77%) were the most common tumors. Radiation therapy and PCV (procarbazine, CCNU, and vincristine) was received by 85 patients, while radiation therapy and temozolomide were administered to 15 patients. Isocitrate dehydrogenase (IDH) wild-type LGG had a lower survival time, while improved survival times were seen for alpha-thalassemia X-linked intellectual disability syndrome (ATRX) retained and 1p19q co-deleted LGGs. Further studies are required to gain a better understanding of lower-grade glial tumor treatment and survival in Pakistan.
PubMed: 38152532
DOI: 10.1055/s-0043-1771369 -
Frontiers in Endocrinology 2023The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and...
BACKGROUND
The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and prognostic significance of NE marker expression in TNBC, determine its association with other clinicopathological parameters, and further explore the pathological features and potential treatment options for TNBC patients expressing NE markers.
METHODS
Clinicopathological data were collected from 396 TNBC patients undergoing radical breast cancer surgery at Peking Union Medical College Hospital from January 2002 to December 2014, with a final follow-up in July 2019. Immunohistochemistry (IHC) staining was performed for NE markers including chromogranin A (CgA) and synaptophysin (Syn). For TNBC patients with positive NE marker expression, IHC staining was then performed for alpha-thalassemia/mental retardation X-linked (ATRX), O(6)-methylguanine-methyltransferase (MGMT), somatostatin receptor 2 (SSTR2), and programmed death receptor-ligand 1 (PD-L1). The chi-square or Fisher exact test was used to evaluate the correlations between NE marker expression and other parameters. Survival curves were plotted using the Kaplan-Meier (K-M) method to assess the prognostic significance of NE markers in TNBC.
RESULTS
NE marker-positive staining was observed in 7.6% (30/396) of all TNBC cases. Only 0.5% (2/396) cases had ≥ 90% neoplastic cells expressing NE markers. Positive NE marker expression was associated with negative basal-like marker expression. K-M survival analysis showed that the NE marker-positive TNBC patients had higher disease-free survival (DFS) rates than the NE marker-negative patients at the same stage. Among the 30 NE marker-positive TNBC cases, 13.3% and 26.7% showed negative IHC staining for ATRX and MGMT, respectively, while 13.3% had a 3+ score for SSTR2 IHC staining. For PD-L1 IHC staining, 13.3% of the 30 TNBC cases were higher than 10 scores in Combined Positive Score (CPS), and 10.0% were higher than 10% in Tumor Cell Proportion Score (TPS).
CONCLUSION
There was a small proportion of TNBC patients expressing NE markers. TNBC patients with positive NE marker expression had a better prognosis than the negative group at the same stage. TNBC cases with positive NE marker expression may potentially benefit from immunotherapy or somatostatin analogue treatment.
Topics: Humans; Triple Negative Breast Neoplasms; B7-H1 Antigen; Prognosis; Disease-Free Survival; Mastectomy
PubMed: 38125789
DOI: 10.3389/fendo.2023.1205631