Blood Cells Molecules and Diseases最新文献

{"title":"The role of PKC in X-ray-induced megakaryocyte apoptosis and thrombocytopenia","authors":"Fanbi Meng ,&nbsp;Shuang Chen ,&nbsp;Chunliang Liu ,&nbsp;Muhammad Shoaib Khan,&nbsp;Yan Yan,&nbsp;Jun Wan,&nbsp;Yue Xia,&nbsp;Chenglin Sun,&nbsp;Mengnan Yang,&nbsp;Renping Hu,&nbsp;Kesheng Dai","doi":"10.1016/j.bcmd.2023.102798","DOIUrl":"10.1016/j.bcmd.2023.102798","url":null,"abstract":"<div><p><span>Thrombocytopenia<span> is a critical complication after radiation therapy and exposure. Dysfunction of megakaryocyte<span><span> development and platelet production<span> are key pathophysiological stages in ionizing radiation (IR)-induced thrombocytopenia. </span></span>Protein kinase C<span> (PKC) plays an important role in regulating megakaryocyte development and platelet production. However, it remains unclear how PKC regulates IR-induced megakaryocyte apoptosis<span><span><span>. In this study, we found that pretreatment of PKC pan-inhibitor Go6983 delayed IR-induced megakaryocyte apoptosis, and inhibited IR-induced </span>mitochondrial membrane potential and </span>ROS production in CMK cells. Moreover, suppressing PKC activation inhibited cleaved caspase3 expression and reduced p38 phosphorylation levels, and IR-induced PKC activation might be regulated by p53. </span></span></span></span></span><em>In vivo</em><span> experiments confirmed that Go6983 promoted platelet count<span><span> recovery after 21 days of 3 Gy total body irradiation. Furthermore, Go6983 reduced megakaryocyte apoptosis, increased the number of megakaryocyte and </span>polyploid formation in bone marrow, and improved the survival rate of 6 Gy total body irradiation. In conclusion, our results provided a potential therapeutic target for IR-induced thrombocytopenia.</span></span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102798"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41182019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and animal models for the investigation of β-thalassemia","authors":"Antonella Nai ,&nbsp;Celia Cordero-Sanchez ,&nbsp;Emanuele Tanzi ,&nbsp;Alessia Pagani ,&nbsp;Laura Silvestri ,&nbsp;Simona Maria Di Modica","doi":"10.1016/j.bcmd.2023.102761","DOIUrl":"10.1016/j.bcmd.2023.102761","url":null,"abstract":"<div><p><span><span><span>β-Thalassemia is a genetic<span> form of anemia due to mutations in the β-globin gene, that leads to ineffective and extramedullary erythropoiesis, abnormal </span></span>red blood cells<span><span> and secondary iron-overload. The severity of the disease ranges from mild to lethal anemia based on the residual levels of globins<span><span><span> production. Despite being a monogenic disorder, the </span>pathophysiology of β-thalassemia is multifactorial, with different players contributing to the severity of anemia and secondary complications. As a result, the identification of effective therapeutic strategies is complex, and the </span>treatment of patients is still suboptimal. For these reasons, several models have been developed in the last decades to provide experimental tools for the study of the disease, including </span></span>erythroid cell lines, cultures of primary erythroid cells and </span></span>transgenic animals<span><span>. Years of research enabled the optimization of these models and led to decipher the mechanisms responsible for globins deregulation and ineffective erythropoiesis<span> in thalassemia, to unravel the role of </span></span>iron homeostasis in the disease and to identify and validate novel therapeutic targets and agents. Examples of successful outcomes of these analyses include iron restricting agents, currently tested in the clinics, several gene therapy vectors, one of which was recently approved for the treatment of most severe patients, and a promising gene editing strategy, that has been shown to be effective in a </span></span>clinical trial. This review provides an overview of the available models, discusses pros and cons, and the key findings obtained from their study.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102761"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9574537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe clinical picture in a cohort of six Brazilian children with hemoglobin Sβ-thalassemia IVS-I-5 G>A","authors":"Marcos Borato Viana ,&nbsp;Érica Louback Oliveira ,&nbsp;André Rolim Belisário","doi":"10.1016/j.bcmd.2023.102795","DOIUrl":"10.1016/j.bcmd.2023.102795","url":null,"abstract":"","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102795"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10201581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium flux alterations in erythrocytes from sickle cell mice: The relevance of mean corpuscular volume","authors":"Luis E.F. Almeida,&nbsp;Meghann L. Smith,&nbsp;Sayuri Kamimura,&nbsp;Sebastian Vogel,&nbsp;Zenaide M.N. Quezado","doi":"10.1016/j.bcmd.2023.102800","DOIUrl":"10.1016/j.bcmd.2023.102800","url":null,"abstract":"<div><p>Red blood cells (RBC) from patients with sickle cell disease (SCD) have elevated calcium levels at baseline, which are further elevated upon deoxygenation. Here we examined baseline calcium levels and calcium flux in RBCs from a mouse model of SCD mice. We found that akin to humans with SCD, sickle (HbSS) Townes mice, have higher baseline levels and increased calcium flux in RBCs compared to control (HbAA) animals. As HbSS mice, unlike humans with SCD, have high mean corpuscular volume compared with HbAA, we highlight the importance of adjusting biochemical results to number of RBCs rather than hematocrit during the analysis and interpretation of the results. Our findings add to the face validity of humanized sickle cell mice and support its use for studies of RBC calcium flux in SCD.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102800"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89716867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcome of first or second transplantation using unrelated umbilical cord blood without ATG conditioning regimen for pediatric bone marrow failure disorders","authors":"Xia Chen ,&nbsp;Fang Liu ,&nbsp;Yuanyuan Ren ,&nbsp;Luyang Zhang,&nbsp;Yang Wan,&nbsp;Wenyu Yang,&nbsp;Xiaojuan Chen,&nbsp;Li Zhang,&nbsp;Yao Zou,&nbsp;Yumei Chen,&nbsp;Xiaofan Zhu,&nbsp;Ye Guo","doi":"10.1016/j.bcmd.2023.102793","DOIUrl":"10.1016/j.bcmd.2023.102793","url":null,"abstract":"<div><h3>Background</h3><p><span>Unrelated umbilical cord blood transplantation<span> (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary </span></span>treatment for transplant failure patients.</p></div><div><h3>Procedure</h3><p><span><span>We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or </span>Busulfan<span> (BU) + Fludarabine (FLU) + </span></span>Cyclophosphamide (CY).</p></div><div><h3>Results</h3><p>Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure<span> after first haploidentical stem cell transplantation at days +38 and +82.</span></p><p><span>All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %–99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil </span>engraftment<span><span> was 19 days (range, 12–30) and time to platelet engraftment was 32 days (range, 18–61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7–84.9 %), and 17.6 % (95 % CI: 2.6–37.9 %) of patients developed </span>chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %.</span></p></div><div><h3>Conclusion</h3><p>UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102793"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10131323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First report of a patient with homozygous hemoglobin Ernz: Evidence to support a non-pathogenic variant","authors":"Zohreh Shojaei ,&nbsp;Maryam Abiri ,&nbsp;Fatemeh Zafarghandi Motlagh ,&nbsp;Masoume Amini ,&nbsp;Samira Dabbagh Bagheri ,&nbsp;Sadaf Asnavandi ,&nbsp;Sedighe Asadi ,&nbsp;Hamideh Bagherian ,&nbsp;Sirous Zeinali","doi":"10.1016/j.bcmd.2023.102797","DOIUrl":"10.1016/j.bcmd.2023.102797","url":null,"abstract":"<div><p>Hemoglobin Ernz (Hb Ernz) is a missense variant in β-globin caused by a Threonine<span><span> to Asparagine substitution at the 123rd </span>amino acid<span><span> position and HBB c.371C &gt; A in gene level. Hb Ernz has been classified as Uncertain Significance (VUS) by ACMG due to limited reports and the absence of any homozygote<span> genotypes. In our study, we found eight cases of Hb Ernz by DNA sequencing of the β-globin gene during &gt;20 years of </span></span>Thalassemia Screening in individuals with borderline hematological parameters who were possible carriers of thalassemia or their spouses. We also report the first homozygote variant of Hb Ernz. Our findings suggest that the changes in hematological parameters observed in individuals with Hb Ernz are likely due to α-globin gene mutations rather than Hb Ernz itself. These findings support the reclassification of Hb Ernz as a benign variant in variant classification.</span></span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102797"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41190220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bach1 inhibitor HPP-D mediates γ-globin gene activation in sickle erythroid progenitors","authors":"Chithra D. Palani ,&nbsp;Xingguo Zhu ,&nbsp;Manickam Alagar ,&nbsp;Otis C. Attucks ,&nbsp;Betty S. Pace","doi":"10.1016/j.bcmd.2023.102792","DOIUrl":"10.1016/j.bcmd.2023.102792","url":null,"abstract":"<div><p><span><span><span><span>Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in </span>sickle hemoglobin production, chronic </span>hemolytic anemia<span>, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved </span></span>drugs<span> to treat SCD, hydroxyurea<span><span> is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, </span>chromatin immunoprecipitation assay<span> showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active </span></span></span></span>histone<span> marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102792"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10065919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of seven hox genes in zebrafish thrombopoiesis","authors":"Hemalatha Sundaramoorthi,&nbsp;Weam Fallatah,&nbsp;Jabila Mary,&nbsp;Pudur Jagadeeswaran","doi":"10.1016/j.bcmd.2023.102796","DOIUrl":"10.1016/j.bcmd.2023.102796","url":null,"abstract":"<div><p><span><span>Thrombopoiesis is the production of platelets from </span>megakaryocytes<span> in the bone marrow of mammals. In fish, thrombopoiesis involves the formation of thrombocytes without megakaryocyte-like precursors but derived from erythrocyte thrombocyte bi-functional precursor cells. One unique feature of thrombocyte differentiation involves the maturation of young thrombocytes in circulation. In this study, we investigated the role of </span></span><em>hox</em> genes in zebrafish thrombopoiesis to model platelet production. We selected <em>hoxa10b</em>, <em>hoxb2a</em>, <em>hoxc5a</em>, <em>hoxd3a,</em> and <em>hoxc11b</em><span> from thrombocyte RNA expression data, and checked whether they are expressed in young or mature thrombocytes. We found </span><em>hoxa10b</em>, <em>hoxb2a</em>, <em>hoxc5a</em>, and <em>hoxd3a</em> were expressed in both young and mature thrombocytes and <em>hoxc11b</em> was expressed in only young thrombocytes. We then performed knockdowns of these 5 <em>hox</em> genes and found <em>hoxc11b</em><span><span> knockdown resulted in thrombocytosis and the rest showed </span>thrombocytopenia. To identify </span><em>hox</em> genes that could have been missed by the above datasets, we performed knockdowns 47 <em>hox</em> genes in the zebrafish genome and found <em>hoxa9a</em>, and <em>hoxb1a</em> knockdowns resulted in thrombocytopenia and they were expressed in both young and mature thrombocytes. In conclusion, our comprehensive knockdown study identified Hoxa10b, Hoxb2a, Hoxc5a, Hoxd3a, Hoxa9a, and Hoxb1a, as positive regulators and Hoxc11b<em>,</em> as a negative regulator for thrombocyte development.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102796"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse models of sickle cell disease: Imperfect and yet very informative","authors":"Sayuri Kamimura ,&nbsp;Meghann Smith ,&nbsp;Sebastian Vogel ,&nbsp;Luis E.F. Almeida ,&nbsp;Swee Lay Thein ,&nbsp;Zenaide M.N. Quezado","doi":"10.1016/j.bcmd.2023.102776","DOIUrl":"10.1016/j.bcmd.2023.102776","url":null,"abstract":"<div><p>The root cause of sickle cell disease<span> (SCD) has been known for nearly a century, however, few therapies to treat the disease are available. Over several decades of work, with advances in gene editing technology and after several iterations of mice with differing genotype/phenotype relationships, researchers have developed humanized SCD mouse models. However, while a large body of preclinical studies<span> has led to huge gains in basic science knowledge about SCD in mice, this knowledge has not led to the development of effective therapies to treat SCD-related complications in humans, thus leading to frustration with the paucity of translational progress in the SCD field. The use of mouse models to study human diseases is based on the genetic<span> and phenotypic similarities between mouse and humans (face validity). The Berkeley and Townes SCD mice express only human globin chains and no mouse hemoglobin. With this genetic composition, these models present many phenotypic similarities, but also significant discrepancies that should be considered when interpreting preclinical studies results. Reviewing genetic and phenotypic similarities and discrepancies and examining studies that have translated to humans and those that have not, offer a better perspective of construct, face, and predictive validities of humanized SCD mouse models.</span></span></span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102776"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10086615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and clinical characterization of two unrelated families with factor V deficiency, including a novel nonsense variant (p.Gln1532*)","authors":"Ke Zhang,&nbsp;Longying Ye,&nbsp;Yanhui Jin,&nbsp;Yuan Chen,&nbsp;Shuting Jiang,&nbsp;Haixiao Xie,&nbsp;Lihong Yang,&nbsp;Mingshan Wang","doi":"10.1016/j.bcmd.2023.102794","DOIUrl":"10.1016/j.bcmd.2023.102794","url":null,"abstract":"<div><h3>Background</h3><p>Factor V (FV) is an essential cofactor in the coagulation cascade. The characterization of novel mutations is advantageous for the clinical management of FV-deficient patients.</p></div><div><h3>Methods</h3><p>Coagulation screening and thrombin generation assay were performed with the plate-poor plasma. All 25 exons of the <em>F5</em><span> gene were amplified and sequenced. The ClustalX-2.1 software was applied to the multiple sequence alignment<span><span>. The possible adverse effects of mutations were investigated with online bioinformatics software and </span>protein modeling.</span></span></p></div><div><h3>Results</h3><p><span><span>Two unrelated families with FV deficiency were under investigation. Proband<span> A was an 18-year-old youth with recurrent epistaxis. Proband B was a 29-year-old woman who did not present with any bleeding symptoms. Three heterozygous mutations (p.Gln1532*, p.Phe218Ser, and p.Asp2222Gly) were detected. Interestingly, they were compound </span></span>heterozygotes and both contained the p.Asp2222Gly, a polymorphism. The thrombin generation assay showed that both patients had impaired ability of thrombin generation, and in particular, proband A was more severe. Conservation, </span>pathogenicity and protein modeling studies all indicated that these three mutations could cause deleterious effects on the function and structure of FV.</p></div><div><h3>Conclusion</h3><p>These three mutations are responsible for the FV-deficient in two pedigrees. Moreover, the nonsense variant p.Gln1532* is first reported in the world.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102794"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10110346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}