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Pranee Winichagoon - One of the best experts on this subject based on the ideXlab platform.
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Update in Laboratory Diagnosis of Thalassemia.
Frontiers in molecular biosciences, 2020Co-Authors: Thongperm Munkongdee, Ping Chen, Pranee Winichagoon, Suthat Fucharoen, Kittiphong PaiboonsukwongAbstract:Alpha- and β-Thalassemias and abnormal hemoglobin (Hb) are common in tropical countries. These abnormal globin genes in different combinations lead to many thalassemic diseases including three severe Thalassemia diseases, i.e., homozygous β-Thalassemia, β-Thalassemia/Hb E, and Hb Bart's hydrops fetalis. Laboratory diagnosis of Thalassemia requires a number of tests including red blood cell indices and Hb and DNA analyses. Thalassemic red blood cell analysis with an automated hematology analyzer is a primary screening for Thalassemia since microcytosis and decreased Hb content of red blood cells are hallmarks of all thalassemic red blood cells. However, these two red blood cell indices cannot discriminate between Thalassemia trait and iron deficiency or between α- and β-thalassemic conditions. Today, Hb analysis may be carried out by either automatic high-performance liquid chromatography (HPLC) or capillary zone electrophoresis (CE) system. These two systems give both qualitative and quantitative analysis of Hb components and help to do Thalassemia prenatal and postnatal diagnoses within a short period. Both systems have a good correlation, but the interpretation under the CE system should be done with caution because Hb A2 is clearly separated from Hb E. In case of α-Thalassemia gene interaction, it can affect the amount of Hb A2/E. Thalassemia genotypes can be characterized by the intensities between alpha-/beta-globin chains or alpha-/beta-mRNA ratios. However, those are presumptive diagnoses. Only DNA analysis can be made for specific Thalassemia mutation diagnosis. Various molecular techniques have been used for point mutation detection in β-Thalassemia and large-deletion detection in α-Thalassemia. All of these techniques have some advantages and disadvantages. Recently, screening for both α- and β-Thalassemia genes by next-generation sequencing (NGS) has been introduced. This technique gives an accurate diagnosis of Thalassemia that may be misdiagnosed by other conventional techniques. The major limitation for using NGS in the screening of Thalassemia is its cost which is still expensive. All service labs highly recommend to select the technique(s) they are most familiar and most economic one for their routine use.
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Expression of microRNA-451 in normal and thalassemic erythropoiesis
Annals of Hematology, 2010Co-Authors: Saovaros Svasti, Pranee Winichagoon, Suthat Fucharoen, Shizuka Masaki, Tipparat Penglong, Tsukuru UmemuraAbstract:MicroRNAs (miRNAs) are negative regulators of gene expression that play an important role in hematopoiesis. Thalassemia, a defective globin synthesis leading to precipitate of excess unbound globins in red blood cell precursors, results in defective erythroid precursors and ineffective erythropoiesis. Expression pattern of miR-451, an erythroid-specific miRNA, was analyzed during differentiation of erythroid progenitors derived from normal and thalassemic peripheral blood CD34-positive cells, after 14 days of culture. A biphasic expression with transient up-regulation of miRNA-451 on day 3 of cultures was observed during thalassemic erythroid differentiation. In contrast, the expression pattern of the miR-451 in erythroid cells obtained from the other extravascular hemolytic anemia, i.e., hereditary spherocytosis patients showed no transient up-regulation of miR-451 on day 3 of cultures. Our results suggest that early erythroid progenitors in β-Thalassemia have a dysregulated miRNA-451 expression program, and analysis of microRNA is a relevant approach to determine abnormalities of erythropoiesis.
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Expression of microRNA-451 in normal and thalassemic erythropoiesis
Annals of Hematology, 2010Co-Authors: Saovaros Svasti, Pranee Winichagoon, Suthat Fucharoen, Shizuka Masaki, Tipparat Penglong, Yasunobu Abe, Tsukuru UmemuraAbstract:MicroRNAs (miRNAs) are negative regulators of gene expression that play an important role in hematopoiesis. Thalassemia, a defective globin synthesis leading to precipitate of excess unbound globins in red blood cell precursors, results in defective erythroid precursors and ineffective erythropoiesis. Expression pattern of miR-451, an erythroid-specific miRNA, was analyzed during differentiation of erythroid progenitors derived from normal and thalassemic peripheral blood CD34-positive cells, after 14 days of culture. A biphasic expression with transient up-regulation of miRNA-451 on day 3 of cultures was observed during thalassemic erythroid differentiation. In contrast, the expression pattern of the miR-451 in erythroid cells obtained from the other extravascular hemolytic anemia, i.e., hereditary spherocytosis patients showed no transient up-regulation of miR-451 on day 3 of cultures. Our results suggest that early erythroid progenitors in β-Thalassemia have a dysregulated miRNA-451 expression program, and analysis of microRNA is a relevant approach to determine abnormalities of erythropoiesis.
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Prevention and control of Thalassemia in Asia
Asian Biomedicine, 2007Co-Authors: Suthat Fucharoen, Pranee WinichagoonAbstract:Background: Thalassemia and abnormal hemoglobin are the most common inherited diseases. The only treatment readily available in most countries is regular blood transfusion and iron chelation that is recommended in severely anemic patients with iron overload. In the last 20 years there has been much progress in terms of diagnosing, preventing and managing Thalassemia. This has lead to the success of prevention and control of Thalassemia in many Mediterranean countries such as Cyprus, Italy and Greece. Objective: To introduce approaches that may be applied for the control of Thalassemia in developing countries including Asia where Thalassemias are very prevalent. Keywords: Asia, prevention, Thalassemia.
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Thalassemia and abnormal hemoglobin.
International Journal of Hematology, 2002Co-Authors: Suthat Fucharoen, Pranee WinichagoonAbstract:Thalassemia and abnormal hemoglobins are common genetic disorders in Asia. Thalassemia is not only an important public health problem but also a socio-economic problem of many countries in the region. The approach to deal with the thalassemic problem is to prevent and control birth of new cases. This requires an accurate identification of the couple at high risk for Thalassemia. However, the diagnosis of Thalassemia carrier states need several tests which are not practical for screening the population at large. Recently we have used two simple laboratory tests to screen for potential Thalassemia carriers and hemoglobin E individuals. There is also a new development in using the automatic HPLC to diagnose thalassemic diseases and the carriers. This system gives both qualitative and quantitative analysis of hemoglobin components in the same run with good precision and reproducibility. The system has been applied to study Thalassemia and abnormal Hb in adult and cord blood. This system has enabled us to do both prenatal and postnatal diagnosis of Thalassemia within the few minutes. However, none of these screening tests can accurately give specific diagnosis of the Thalassemia genotype. Specific Thalassemia mutation can be carried out by DNA analysis. Many DNA techniques have been used for point mutation detection and small deletion. For the last few years there is a development of DNA chip technology that has been applied for Thalassemia mutation as well. Clinically, Thalassemia is very heterogeneous in the manifestation. In spite of seemingly identical genotypes, severity of.beta thalassemic patients can vary greatly. Heterogeneity in the clinical manifestation of beta thalassemic diseases may occur from the nature of beta globin gene mutation, alpha Thalassemia gene interaction and difference in the amount of Hb F production which is partly associated with a specific beta globin haplotype. However, there is still some beta Thalassemia cases that have a mild clinical symptom without those known genetic fators interaction suggesting that there are other additional factors responsible for the mildness of the disease.
Mark D. Fleming - One of the best experts on this subject based on the ideXlab platform.
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RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-Thalassemia intermedia.
American journal of hematology, 2018Co-Authors: Paul J. Schmidt, Kaifeng Liu, Gary A. Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia Hettinger, James Butler, Mark D. FlemingAbstract:Diminished β-globin synthesis in β-Thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic Thalassemias. Splenectomy is often employed in patients with β-Thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of Tmprss6 in splenectomized β-Thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β-Thalassemia patients.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β Thalassemia intermedia
American Journal of Hematology, 2015Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-Thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-Thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β Thalassemia intermedia short title tmprss6 sirna and deferiprone combination therapy in mur
2014Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-Thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To further interrogate the efficacy of an RNAitherapeutic downregulating Tmprss6, β-thalassemic Hbb animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-Thalassemia intermedia. Page 2 of 13 John Wiley & Sons American Journal of Hematology This article is protected by copyright. All rights reserved.
Supan Fucharoen - One of the best experts on this subject based on the ideXlab platform.
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genotype and phenotype characterizations in a large cohort of β Thalassemia heterozygote with different forms of α Thalassemia in northeast thailand
Blood Cells Molecules and Diseases, 2011Co-Authors: Supawadee Yamsri, Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Nattaya Saeung, Supan FucharoenAbstract:Abstract In order to update the molecular basis of β-Thalassemia and describe hematological features among different mutations and the concurrent of α- and β-Thalassemias, 849 unrelated β-Thalassemia heterozygotes recruited in northeast Thailand during a prevention and control program were studied. β- and α-Thalassemia mutations were investigated using the polymerase chain reaction (PCR)-based technologies and hematological parameters were recorded using standard methods. Seventeen different mutations including both β 0 - and β + -Thalassemias were identified. Eight of these 17 β-Thalassemia alleles accounted for 97.4%, others were found at lower frequencies ( 2 and Hb F levels in individuals with the 3.4 kb deletion were significantly higher than those with other mutations. Interaction of each β-Thalassemia mutation with α-Thalassemia did not affect the diagnostic ranges of Hb A 2 and Hb F, though the significantly increased MCV and MCH was noted. These findings underline the heterogeneity of β-Thalassemia and the importance of hematological and molecular analyses of both α-and β-Thalassemias in the diagnosis and genetic counseling of the couples at-risk of having babies with severe Thalassemia diseases in the region.
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Thalassemia screening in Thailand
Journal of medical technology, 2010Co-Authors: Goonnapa Fucharoen, Supan FucharoenAbstract:The objective of Thalassemia screening in Thailand is to identify a - Thalassemia 1, b - Thalassemia and Hb E carriers. Those with these Thalassemia genes will be given appropriate genetic counseling in a prevention and control program. The aim is to prevent birth of new case with three severe Thalassemia diseases including homozygous a - Thalassemia 1, homozygous b - Thalassemia and b - Thalassemia / Hb E disease. In general, two screening strategies are performed. In the first approach, a and b - Thalassemias are screened for using a one tube osmotic fragility test (OF-test) and Hb E was identified by DCIP precipitation test (DCIP test). Alternatively, screening can be done using a combined RBC indices (mean cell hemoglobin; MCH and/or mean cell volume; MCV) and a DCIP test. While positive sample at this preliminary screening will be investigated further by Hb and DNA analyses, no further test is required for those with negative result. Both screening strategies can be done effectively but application depends on laboratory facilities and technical skill of the personnel. However, quality of Thalassemia screening in routine practice needs to be evaluated regularly in order to minimize false negative result.
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a reliable screening protocol for Thalassemia and hemoglobinopathies in pregnancy an alternative approach to electronic blood cell counting
American Journal of Clinical Pathology, 2005Co-Authors: Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Supan Fucharoen, Thawalwong Ratanasiri, Pattara Sanchaisuriya, Yossombat Changtrakul, Uthai Ukosanakarn, Wichai Ussawaphark, Frank P SchelpAbstract:Primary screening for Thalassemia and hemoglobinopathies usually involves an accurate blood count using an expensive electronic blood cell counter A cheaper alternative method was tested by using a modified osmotic fragility (OF) test and a modified dichlorophenolindophenol (DCIP) test. Altogether 423 pregnant Thai women participated in this project. Hemoglobin patterns and globin genotypes were determined using an automated high-performance liquid chromatography analyzer and polymerase chain reaction analysis of alpha- and beta-globin genes. Among the 423 subjects, 264 (62.4%) carried Thalassemia genes. The combined OF and DCIP tests detected all pregnant carriers of the 3 clinically important Thalassemias, ie, alpha0-Thalassemia, beta-Thalassemia, and hemoglobin E with a sensitivity of 100.0%, specificity of 87.1%, positive predictive value of 84.5%, and negative predictive value of 100.0%, which show more effectiveness than these values for the standard method based on RBC counts. A combination of modified OF and DCIP tests should prove useful and applicable to prenatal screening programs for Thalassemia and hemoglobinopathies in communities with limited facilities and economic resources.
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Simultaneous PCR detection of β – Thalassemia and α – Thalassemia 1 (SEA type) in prenatal diagnosis of complex Thalassemia syndrome
Clinical biochemistry, 2001Co-Authors: Nirut Siriratmanawong, Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Thawalwong Ratanasiri, Supan FucharoenAbstract:Abstract Objective: To establish a rapid PCR method for simultaneous detection of β-Thalassemia and α-Thalassemia 1 genes for diagnosis of complex αβ-Thalassemia syndrome. Design and methods: Using multiplex allele specific PCR approach, we evaluated a simultaneous detection of the SEA type α-Thalassemia 1 and the common Southeast Asian β-Thalassemia and hemoglobin E genes. The system was tested on known cases of double heterozygote for α- and β-Thalassemias and in a prenatal diagnosis of complex αβ-Thalassemia syndrome. Results: Co-inheritance of α-Thalassemia 1 (SEA type) with each of the common β-Thalassemia genes in Southeast Asian and with hemoglobin E could be identified in a single PCR reaction. A successful application of this simultaneous detection system in prenatal diagnosis of a complex Thalassemia syndrome caused by an EFBart’s disease was demonstrated in a Thai family. Conclusion: We have shown that correct diagnosis of double heterozygosity for α-Thalassemia 1 and β-Thalassemia or hemoglobin E could be obtained using a simultaneous multiplex PCR. These rapid PCR assays would facilitate characterization and prenatal diagnosis of complex Thalassemia syndromes in the regions where both α- and β-Thalassemias and hemoglobin E are common.
Suthat Fucharoen - One of the best experts on this subject based on the ideXlab platform.
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Update in Laboratory Diagnosis of Thalassemia.
Frontiers in molecular biosciences, 2020Co-Authors: Thongperm Munkongdee, Ping Chen, Pranee Winichagoon, Suthat Fucharoen, Kittiphong PaiboonsukwongAbstract:Alpha- and β-Thalassemias and abnormal hemoglobin (Hb) are common in tropical countries. These abnormal globin genes in different combinations lead to many thalassemic diseases including three severe Thalassemia diseases, i.e., homozygous β-Thalassemia, β-Thalassemia/Hb E, and Hb Bart's hydrops fetalis. Laboratory diagnosis of Thalassemia requires a number of tests including red blood cell indices and Hb and DNA analyses. Thalassemic red blood cell analysis with an automated hematology analyzer is a primary screening for Thalassemia since microcytosis and decreased Hb content of red blood cells are hallmarks of all thalassemic red blood cells. However, these two red blood cell indices cannot discriminate between Thalassemia trait and iron deficiency or between α- and β-thalassemic conditions. Today, Hb analysis may be carried out by either automatic high-performance liquid chromatography (HPLC) or capillary zone electrophoresis (CE) system. These two systems give both qualitative and quantitative analysis of Hb components and help to do Thalassemia prenatal and postnatal diagnoses within a short period. Both systems have a good correlation, but the interpretation under the CE system should be done with caution because Hb A2 is clearly separated from Hb E. In case of α-Thalassemia gene interaction, it can affect the amount of Hb A2/E. Thalassemia genotypes can be characterized by the intensities between alpha-/beta-globin chains or alpha-/beta-mRNA ratios. However, those are presumptive diagnoses. Only DNA analysis can be made for specific Thalassemia mutation diagnosis. Various molecular techniques have been used for point mutation detection in β-Thalassemia and large-deletion detection in α-Thalassemia. All of these techniques have some advantages and disadvantages. Recently, screening for both α- and β-Thalassemia genes by next-generation sequencing (NGS) has been introduced. This technique gives an accurate diagnosis of Thalassemia that may be misdiagnosed by other conventional techniques. The major limitation for using NGS in the screening of Thalassemia is its cost which is still expensive. All service labs highly recommend to select the technique(s) they are most familiar and most economic one for their routine use.
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Impaired bone formation and osteopenia in heterozygous β^IVSII-654 knockin thalassemic mice
Histochemistry and Cell Biology, 2011Co-Authors: Kanogwun Thongchote, Suthat Fucharoen, Saovaros Svasti, Mayurachat Sa-ardrit, Nateetip Krishnamra, Narattaphol CharoenphandhuAbstract:β-Thalassemia caused by the C→T mutation at nucleotide 654 of the intron 2 (β^IVSII-654) results in aberrant splicing of β-globin RNA, leading to an almost absence of β-globin synthesis. Although trabecular and cortical bone loss was previously reported in β-thalassemic mice with deletion of β-globin gene, the microscopic changes in trabecular structure in β^IVSII-654 thalassemic mice remained elusive. Here, we investigated the macroscopic and microscopic bone changes in 12-week-old β^IVSII-654 knockin thalassemic mice by dual-energy X-ray absorptiometry (DXA) and histomorphometric analysis, respectively. DXA revealed a decrease in bone mineral density in the lumbar vertebrae and tibial metaphysis, but not in the femoral diaphysis, suggesting that β^IVSII-654 Thalassemia predominantly led to osteopenia at the trabecular site, but not the cortical site. Further histomorphometric analysis of the tibial secondary spongiosa showed that trabecular bone volume was significantly decreased with the expansion of marrow cavity. Decreases in osteoblast surface, osteoid surface, mineral apposition rate, mineralizing surface, and mineralized volume were also observed. Moreover, trabecular bone resorption was markedly enhanced as indicated by increases in the osteoclast surface and eroded surface. It could be concluded that β^IVSII-654 Thalassemia impaired bone formation and enhanced bone resorption, thereby leading to osteopenia especially at the trabecular sites, such as the tibial metaphysis.
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Expression of microRNA-451 in normal and thalassemic erythropoiesis
Annals of Hematology, 2010Co-Authors: Saovaros Svasti, Pranee Winichagoon, Suthat Fucharoen, Shizuka Masaki, Tipparat Penglong, Tsukuru UmemuraAbstract:MicroRNAs (miRNAs) are negative regulators of gene expression that play an important role in hematopoiesis. Thalassemia, a defective globin synthesis leading to precipitate of excess unbound globins in red blood cell precursors, results in defective erythroid precursors and ineffective erythropoiesis. Expression pattern of miR-451, an erythroid-specific miRNA, was analyzed during differentiation of erythroid progenitors derived from normal and thalassemic peripheral blood CD34-positive cells, after 14 days of culture. A biphasic expression with transient up-regulation of miRNA-451 on day 3 of cultures was observed during thalassemic erythroid differentiation. In contrast, the expression pattern of the miR-451 in erythroid cells obtained from the other extravascular hemolytic anemia, i.e., hereditary spherocytosis patients showed no transient up-regulation of miR-451 on day 3 of cultures. Our results suggest that early erythroid progenitors in β-Thalassemia have a dysregulated miRNA-451 expression program, and analysis of microRNA is a relevant approach to determine abnormalities of erythropoiesis.
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Expression of microRNA-451 in normal and thalassemic erythropoiesis
Annals of Hematology, 2010Co-Authors: Saovaros Svasti, Pranee Winichagoon, Suthat Fucharoen, Shizuka Masaki, Tipparat Penglong, Yasunobu Abe, Tsukuru UmemuraAbstract:MicroRNAs (miRNAs) are negative regulators of gene expression that play an important role in hematopoiesis. Thalassemia, a defective globin synthesis leading to precipitate of excess unbound globins in red blood cell precursors, results in defective erythroid precursors and ineffective erythropoiesis. Expression pattern of miR-451, an erythroid-specific miRNA, was analyzed during differentiation of erythroid progenitors derived from normal and thalassemic peripheral blood CD34-positive cells, after 14 days of culture. A biphasic expression with transient up-regulation of miRNA-451 on day 3 of cultures was observed during thalassemic erythroid differentiation. In contrast, the expression pattern of the miR-451 in erythroid cells obtained from the other extravascular hemolytic anemia, i.e., hereditary spherocytosis patients showed no transient up-regulation of miR-451 on day 3 of cultures. Our results suggest that early erythroid progenitors in β-Thalassemia have a dysregulated miRNA-451 expression program, and analysis of microRNA is a relevant approach to determine abnormalities of erythropoiesis.
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Prevention and control of Thalassemia in Asia
Asian Biomedicine, 2007Co-Authors: Suthat Fucharoen, Pranee WinichagoonAbstract:Background: Thalassemia and abnormal hemoglobin are the most common inherited diseases. The only treatment readily available in most countries is regular blood transfusion and iron chelation that is recommended in severely anemic patients with iron overload. In the last 20 years there has been much progress in terms of diagnosing, preventing and managing Thalassemia. This has lead to the success of prevention and control of Thalassemia in many Mediterranean countries such as Cyprus, Italy and Greece. Objective: To introduce approaches that may be applied for the control of Thalassemia in developing countries including Asia where Thalassemias are very prevalent. Keywords: Asia, prevention, Thalassemia.
Paul J. Schmidt - One of the best experts on this subject based on the ideXlab platform.
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RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-Thalassemia intermedia.
American journal of hematology, 2018Co-Authors: Paul J. Schmidt, Kaifeng Liu, Gary A. Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia Hettinger, James Butler, Mark D. FlemingAbstract:Diminished β-globin synthesis in β-Thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic Thalassemias. Splenectomy is often employed in patients with β-Thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of Tmprss6 in splenectomized β-Thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β-Thalassemia patients.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β Thalassemia intermedia
American Journal of Hematology, 2015Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-Thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-Thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β Thalassemia intermedia short title tmprss6 sirna and deferiprone combination therapy in mur
2014Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-Thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-Thalassemia intermedia. To further interrogate the efficacy of an RNAitherapeutic downregulating Tmprss6, β-thalassemic Hbb animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-Thalassemia intermedia. Page 2 of 13 John Wiley & Sons American Journal of Hematology This article is protected by copyright. All rights reserved.
