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Frontiers in Bioscience (Landmark... Jun 2024Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the... (Review)
Review
Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the forkhead box (FOX) proteins, characterized by a conserved DNA-binding domain, play vital roles in various cellular processes, including cancer. The FOXA subfamily, encompassing FOXA1, FOXA2, and FOXA3, stands out for its pivotal role in mammalian development. FOXA1, initially identified in the liver, exhibits diverse expression across multiple organ tissues and plays a critical role in cell proliferation, differentiation, and tumor development. Its structural composition includes transactivation domains and a DNA-binding domain, facilitating its function as a pioneer factor, which is crucial for chromatin interaction and the recruitment of other transcriptional regulators. The involvement of FOXA1 in sex hormone-related tumors underscores its significance in cancer biology. This review provides an overview of multifaceted roles of FOXA1 in normal development and its implications in the pathogenesis of hormone-related cancers, particularly breast cancer and prostate cancer.
Topics: Humans; Hepatocyte Nuclear Factor 3-alpha; Male; Female; Breast Neoplasms; Prostatic Neoplasms; Gonadal Steroid Hormones; Neoplasms; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38940052
DOI: 10.31083/j.fbl2906225 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for... (Review)
Review
Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for thalassemia. Thalassemia are classified into transfusion-dependent thalassemia and non-transfusion-dependent thalassemia based on the need for blood transfusion. Traditional treatment modalities include blood transfusion, splenectomy, hydroxyurea therapy, and iron chelation therapy, which are now widely used for clinical treatment and constitute the main methods recommended in the β-thalassemia treatment guidelines. However, there are multiple barriers and limitations to the application of these approaches, and there is an urgent need to explore new therapeutic approaches. With the in-depth study of the pathophysiological process of β-thalassemia, a deeper understanding of the pathogenesis of the disease has been gained. It has been demonstrated that the pathogenesis of thalassemia is closely related to ineffective erythropoiesis (IE), imbalance in the ratio of α/β-globin protein chains and iron overload. New therapeutic approaches are emerging for different pathogenic mechanisms. Among them, new drugs for the treatment of IE mainly include activin receptor II trap ligands, Janus kinase 2 inhibitors, pyruvate kinase activators, and glycine transporter protein 1 inhibitors. Correcting the imbalance in the hemoglobin chain is mainly due to emerging technologies such as bone marrow transplantation and gene editing. Measures in reducing iron overload are associated with inhibiting the activity of transferrin and hepcidin. These new approaches provide new ideas and options for the treatment and management of β-thalassemia.
Topics: beta-Thalassemia; Humans; Genetic Therapy; Blood Transfusion; Janus Kinase 2; Activin Receptors, Type II; Splenectomy; Gene Editing; Iron Chelating Agents; Bone Marrow Transplantation; Iron Overload; Erythropoiesis; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins
PubMed: 38939943
DOI: No ID Found -
International Journal of Molecular... Jun 2024The blood counts of α thalassemia carriers (α-thal) are similar to those of β thalassemia carriers, except for Hemoglobin A (Hb A), which is not elevated. The...
The blood counts of α thalassemia carriers (α-thal) are similar to those of β thalassemia carriers, except for Hemoglobin A (Hb A), which is not elevated. The objective of this study was to determine whether mathematical formulas are effective for detecting suspected α-thal. The data were obtained from the database of the prevention program for detecting couples at risk for having a child with hemoglobinopathy. Red Blood Cells (RBC) indices were analyzed using mathematical formulas, and the sensitivity and negative predictive value (NPV) were calculated. Among 1334 blood counts suspected of α-thal analyzed, only the Shine and Lal and the Support Vector Machine formulas revealed high sensitivity and NPV. Sensitivity was 85.54 and 99.33%, and NPV was 98.93 and 99.93%, respectively. Molecular defects were found in 291, and 81 had normal α genes. Molecular analysis was not performed in 962 of the samples. Based on these results, mathematical formulas incorporating one of these reliable formulas for detecting suspected α or β thalassemia carriers in the program of the automatic analyzers can flag these results, increase the awareness of the primary physicians about the carrier risk, and send an alert with a recommendation for further testing.
Topics: Humans; Support Vector Machine; alpha-Thalassemia; Heterozygote; Female; Male; Erythrocyte Indices; beta-Thalassemia; Genetic Carrier Screening
PubMed: 38928152
DOI: 10.3390/ijms25126446 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To perform molecular diagnosis and pedigree analysis for one case with α-thalassemia who does not conform to the genetic laws, and explore the effects of a newly...
OBJECTIVE
To perform molecular diagnosis and pedigree analysis for one case with α-thalassemia who does not conform to the genetic laws, and explore the effects of a newly discovered rare mutation () on clinical phenotypes.
METHODS
Blood samples of the proband and her family members were collected for blood routine analysis, and the hemoglobin components were analyzed by capillary electrophoresis. The common α- and β-globin gene loci in Chinese population were detected by conventional techniques (Gap-PCR, RDB-PCR). The α-globin gene sequences () were analyzed by Sanger sequencing.
RESULTS
By analyzing the test results of proband and her family members, the genotype of the proband was -α/, her father was heterozygous mutation carrier.
CONCLUSION
This study identifies a rare α-globin gene mutation () that has not been reported before. It is found that heterozygous mutation carriers present with static α-thalassemia.
Topics: Female; Humans; Male; alpha-Globins; alpha-Thalassemia; Genotype; Hemoglobin A2; Heterozygote; Mutation; Pedigree; Phenotype; East Asian People
PubMed: 38926992
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.044 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the gene mutation types and frequence of thalassemia patients in Jingzhou area.
OBJECTIVE
To analyze the gene mutation types and frequence of thalassemia patients in Jingzhou area.
METHODS
A total of 721 suspected thalassemia patients who were visited in Jingzhou Central Hospital from June 2019 to June 2022 were selected as the research objects. There were 204 males and 517 females. PCR-reverse dot hybridization method was used to analyze the types and frequencies of 23 common α or β thalassemia gene mutations.
RESULTS
Among the 721 patients with suspected thalassemia, 228 cases were positive for α or β thalassemia gene, with a total positive rate of 31.62%, including 87 cases of α-thalassemia, accounting for 38.16%, and 140 cases of β-thalassemia, accounting for 61.40%. There was 1 case of α β complex thalassemia, accounting for 0.44%. A total of 4 types of α-thalassemia gene mutations were detected, all of which were deletion types, including αα/-- (64/87, 73.56%), αα/-α (14/87, 16.09%), -- /-α (7/87, 8.05%), αα/-α (2/87, 2.30%). Among 140 patients with β-thalassemia, 138 were pure heterozygotes, and the genotypes of (63/140, 45.00%), (34/140, 24.29%), (18/140, 12.86%) and (10/140, 7.14%) accounted for 89.29% of all mutations (125/140), 2 cases of double heterozygosity (2/140, 1.43%) were found, no homozygous β-thalassemia were detected; 1 case of αβ complex thalassemia with genotype -α/ was found. The incidence of difference types of thalassemia was statistically significant (χ=194.250, < 0.001). The percentage of positive thalassemia genes was not significantly difference between male and female suspected patients (χ=0.199, =0.655).
CONCLUSION
The α-thalassemia gene mutation in Jingzhou area is dominated by αα/--, and the mutation is more common in β-thalassemia, and α β complex thalassemia is relatively rare, which can provide a reference for the formulation of prevention and treatment measures for thalassemia in Jingzhou area.
Topics: Humans; Male; Female; Mutation; alpha-Thalassemia; beta-Thalassemia; China; Heterozygote; alpha-Globins
PubMed: 38926976
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.028 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze thalassemia genotypes and distribution of children in Wuzhou Guangxi, and evaluate the diagnostic value of HbA2 in children's thalassemia screening, so as to...
OBJECTIVE
To analyze thalassemia genotypes and distribution of children in Wuzhou Guangxi, and evaluate the diagnostic value of HbA2 in children's thalassemia screening, so as to provide scientific evidence for the prevention and control strategies of thalassemia.
METHODS
Four hundred and fifty-eight children suspected with thalassemia in Wuzhou were enrolled from March 2017 to June 2022. The level of HbA2 was detected using Bio-Rad VARIANT II Hb analysis system. The deletion of α-thalassemia was measured with gap-PCR assay, and the point mutation of α- and β-thalassemia was tested with DNA reverse dot blot hybridization assay. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of HbA2 for children's thalassemia.
RESULTS
A total of 304 thalassemia carriers were detected in 458 children, accounting for 66.38%. One hundred and seventy-five cases were defined to be α-thalassemia, with the main type of --/αα (54.86%). Thirty-six cases were defined to be intermediate α-thalassemia, with the main type of -α/-- (9.72%). In 108 cases with β-thalassemia, / was the main type, accounting for 49.07%, followed by / (14.81%). Seven cases were moderate/severe β-thalassemia (predominantly / and //). Twenty-one genotypes of α- and β-thalassemia were found in the children. There was significant difference of HbA2 level between the children with different types of thalassemia and healthy controls (all < 0.001). ROC curve analysis showed that the sensitivities of HbA2 for α-thalassemia, β-thalassemia and αβ-thalassemia were 74.3%, 82.4% and 85.7%, with the optimal cut-off values of 2.60%, 3.60% and 3.70%, respectively, the specificities were 64.3%, 96.1% and 96.8%, and the area under the curve were 0.690, 0.887 and 0.916, respectively.
CONCLUSION
The thalassemia genotypes of children in Wuzhou are diverse. It is necessary to further strengthen the prevention and control measure of thalassemia to reduce birth defects and improve birth quality.
Topics: Humans; Genotype; China; Child; alpha-Thalassemia; beta-Thalassemia; Hemoglobin A2; Point Mutation; Male
PubMed: 38926975
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.027 -
Clinica Chimica Acta; International... Jun 2024To update the molecular characteristics of α-thalassemia in northeast Thailand, the molecular basis and genetic interactions of Hb H disease were examined in a large...
BACKGROUND AND AIMS
To update the molecular characteristics of α-thalassemia in northeast Thailand, the molecular basis and genetic interactions of Hb H disease were examined in a large cohort of patients.
MATERIALS AND METHODS
A study was done on 1,170 subjects with Hb H disease and various genetic interactions encountered during 2009-2023. Hb and DNA analyses were carried out.
RESULTS
As many as 40 genotypes with several known, previously undescribed, and novel mutations were observed. These included 698 subjects (59.8 %) of Hb H disease, 357 (30.6 %) with EABart's disease, 63 (5.4 %) with EEBart's disease, 18 (1.7 %) with abnormal Hbs, 17 (1.5 %) with β-thalassemia, and 4 (0.4 %) with EFBart's or EFABart's disease. The molecular basis of 13 subjects (1.1 %) remains unknown. The α-thalassemia included -- (n = 1,139, 97.4 %) and -- (n = 21, 1.8 %). Two rare mutations were identified in 3 subjects (0.3 %) with -- and -- deletions. For α-thalassemia, -α (n = 626, 53.5 %), Hb Constant Spring (n = 415, 35.5 %), -α (n = 44, 3.8 %), Hb Paksé (n = 36, 3.1 %), and Hb Q-Thailand (n = 19, 1.6 %), were detected. Ten rarer α-thalassemia were identified, including a novel mutation, namely the Hb Chumphae (HBA2:c.32T>A). The Hb H-Lansing-Ramathibodi, Hb H-Jax, and Hb H-Chumphae are hitherto undescribed in this region. PCR-based diagnostic methods for these α-thalassemia defects were described.
CONCLUSIONS
This study confirms the diverse heterogeneity and genetic interactions causing Hb H disease in northeast Thailand. The results should prove useful for laboratory diagnosis and genetic counseling of this genetic disorder in the region.
PubMed: 38914363
DOI: 10.1016/j.cca.2024.119830 -
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 -
Chinese Neurosurgical Journal Jun 2024Glioblastoma are highly malignant type of primary brain tumors. Treatment for glioblastoma multiforme (GBM) generally involves surgery combined with chemotherapy and...
BACKGROUND
Glioblastoma are highly malignant type of primary brain tumors. Treatment for glioblastoma multiforme (GBM) generally involves surgery combined with chemotherapy and radiotherapy. However, the development of tumoral chemo- and radioresistance induces complexities in clinical practice. Multiple signaling pathways are known to be involved in radiation-induced cell survival. However, the role of alpha-thalassemia X-linked mutant retardation syndrome (ATRX), a chromatin remodeling protein, in GBM radioresistance remains unclear.
METHODS
In the present study, the ATRX mutation rate in patients with glioma was obtained from The Cancer Genome Atlas, while its expression analyzed using bioinformatics. Datasets were also obtained from the Gene Expression Omnibus, and ATRX expression levels following irradiation of GBM were determined. The effects of ATRX on radiosensitivity were investigated using a knockdown assays.
RESULTS
The present study demonstrated that the ATRX mutation rate in patients with GBM was significantly lower than that in patients with low-grade glioma, and that patients harboring an ATRX mutation exhibited a prolonged survival, compared with to those harboring the wild-type gene. Single-cell RNA sequencing demonstrated that ATRX counts increased 2 days after irradiation, with ATRX expression levels also increasing in U-251MG radioresistant cells. Moreover, the results of in vitro irradiation assays revealed that ATRX expression was increased in U-251MG cells, while ATRX knockdown was associated with increased levels of radiosensitivity.
CONCLUSIONS
High ATRX expression levels in primary GBM may contribute to high levels of radioresistance. Thus ATRX is a potential target for overcoming the radioresistance in GBM.
PubMed: 38898533
DOI: 10.1186/s41016-024-00371-6 -
Journal of Blood Medicine 2024To analyze the composition of abnormal hemoglobin and the relationship between genotype and phenotype by screening abnormal hemoglobin in a subpopulation of Guizhou,...
PURPOSE
To analyze the composition of abnormal hemoglobin and the relationship between genotype and phenotype by screening abnormal hemoglobin in a subpopulation of Guizhou, China.
PATIENTS AND METHODS
Routine blood evaluation, capillary electrophoresis of hemoglobin, and mutation of α - and β - thalassemia genes were evaluated in 19,976 individuals for thalassemia screening in Guizhou. Sanger sequencing of HBA1, HBA2 and HBB genes was performed in samples with abnormal bands or unexplained increases of normal bands. The types of abnormal hemoglobin were obtained by sequence analysis.
RESULTS
Abnormal hemoglobin was detected in 84 individuals (detection rate, 0.42%). Ten types each of α and β globin chain variants were detected, including most commonly Hb E, Hb New York and Hb Port Phillip. In this study, the abnormal Hb Mizuho was identified for the first time in a Chinese population, and a novel abnormal hemoglobin Hb Guiyang (HBA2: c.151C > A) was detected for the first time. Except for Hb Mizuho, other abnormal hemoglobin heterozygotes without thalassemia or iron deficiency had no significant hematological changes.
CONCLUSION
This study enriched the molecular epidemiological data of abnormal hemoglobin in Guizhou, China and provided reference data for genetic counseling and prenatal diagnosis of abnormal hemoglobin.
PubMed: 38895162
DOI: 10.2147/JBM.S458057