Pub Date : 2024-11-14DOI: 10.1016/j.retram.2024.103478
Abdullah Sezer , Öznur Kaya Güneş , Burçak Kurucu
Tatton-Brown-Rahman syndrome (TBRS) is characterized by overgrowth, cognitive deficiency, and distinctive facial features resulting from germline DNMT3A variants. This report describes a four-year-old female diagnosed with TBRS due to a de novo and novel heterozygous DNMT3A variant, NM_022552.5:c.1627G>C:p.(Gly543Arg). Alongside typical TBRS features, she had a history of hospitalization for immune thrombocytopenic purpura (ITP) at five months old. While ITP is clinically diagnosed and has multifactorial origins, studies have demonstrated its autoimmune and genetic components. DNMT3A protein, responsible for DNA methylation, regulates various cellular processes, including hematopoiesis and autoimmunity. It has been reported that ITP patients exhibit decreased expression of DNMT3A, and specific variants linked to decreased platelet counts have been identified in a murine model for TBRS. Additionally, some case reports have been described with multiple cytopenias and thrombocytopenia without hematologic malignancy. In conclusion, this report emphasizes for the first time the occurrence of ITP in a TBRS patient and suggests that autoimmune and hematologic disorders may need to be considered in the follow-up of these patients. However, further evidence is required to establish a direct correlation.
{"title":"DNMT3A-related overgrowth syndrome presenting with immune thrombocytopenic purpura","authors":"Abdullah Sezer , Öznur Kaya Güneş , Burçak Kurucu","doi":"10.1016/j.retram.2024.103478","DOIUrl":"10.1016/j.retram.2024.103478","url":null,"abstract":"<div><div>Tatton-Brown-Rahman syndrome (TBRS) is characterized by overgrowth, cognitive deficiency, and distinctive facial features resulting from germline <em>DNMT3A</em> variants. This report describes a four-year-old female diagnosed with TBRS due to a de novo and novel heterozygous <em>DNMT3A</em> variant, NM_022552.5:c.1627G>C:p.(Gly543Arg). Alongside typical TBRS features, she had a history of hospitalization for immune thrombocytopenic purpura (ITP) at five months old. While ITP is clinically diagnosed and has multifactorial origins, studies have demonstrated its autoimmune and genetic components. DNMT3A protein, responsible for DNA methylation, regulates various cellular processes, including hematopoiesis and autoimmunity. It has been reported that ITP patients exhibit decreased expression of <em>DNMT3A</em>, and specific variants linked to decreased platelet counts have been identified in a murine model for TBRS. Additionally, some case reports have been described with multiple cytopenias and thrombocytopenia without hematologic malignancy. In conclusion, this report emphasizes for the first time the occurrence of ITP in a TBRS patient and suggests that autoimmune and hematologic disorders may need to be considered in the follow-up of these patients. However, further evidence is required to establish a direct correlation.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"Article 103478"},"PeriodicalIF":3.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696196","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}
Pub Date : 2024-10-25DOI: 10.1016/j.retram.2024.103476
Giorgia Battipaglia, Nicola Polverelli, Joe Tuffnell, Patrizia Chiusolo, Marie Robin, Massimiliano Gambella, Annoek Broers, Elisa Sala, Jakob Passweg, Sabine Furst, Lone Smidtrup Friis, Remy Dulery, Moniek de Witte, Micha Srour, Maria Chiara Finazzi, Claudia Wehr, Arnon Nagler, Deborah Richardson, Wolfgang Bethge, Andrew Clark, Joanna Drozd-Sokolowska, Kavita Raj, Tomasz Czerw, Juan Carlos Hernández-Boluda, Donal P McLornan
Heterogeneous approaches exist in regard to the management of disease-related co-morbidities in potential allogeneic haematopoietic cell transplantation (allo-HCT) candidates with myelofibrosis (MF). The EBMT Chronic Malignancies Working Party launched an electronic survey to evaluate how MF-specific comorbidities are approached and whether they ultimately affect the decision to transplant. A total of 41/63 (65%) Centers, all of whom were experienced in the management of MF allo-HCT, responded. Responses were aggregated and reported in a comparative fashion. Screening for portal hypertension (PH) was routinely performed in 54% centers, never in 12% and guided by clinical manifestations in the remaining. Involvement of hepatologists/gastroenterologists was always/very often considered in patients with signs of PH prior to transplant. Centers reported that radiological evidence of PH did not routinely represent a formal contraindication for allo-HCT in most cases (78%). Of note, most centers (61%) did not perform routine screening for gastroesophageal varices; this was systematically considered or guided by clinical manifestations in only 7% and 32% centers, respectively. Presence of gastroesophageal varices was always (15%) or occasionally (19%) considered a formal contraindication to allo-HCT. A prior history of portal vein thrombosis never (78%) or occasionally (15%) represented a formal contraindication. Three Centers would not proceed to transplant in such cases. Less importance was assigned to non-portal splanchnic vein thrombosis (SVT), with all but one centre proceeding to transplant regardless of prior SVT. This survey highlights a considerable heterogeneity across responding centers in approaching MF-related comorbidities prior to transplant, suggesting that harmonisation guidelines are needed to address these issues in this patient population.
{"title":"Evaluation and management of hepatic dysfunction, portal hypertension and portal/splanchnic vein thrombosis in patients with myelofibrosis undergoing allogeneic haematopoietic cell transplantation: A practice based survey on behalf of the Chronic Malignancies Working Party of the EBMT.","authors":"Giorgia Battipaglia, Nicola Polverelli, Joe Tuffnell, Patrizia Chiusolo, Marie Robin, Massimiliano Gambella, Annoek Broers, Elisa Sala, Jakob Passweg, Sabine Furst, Lone Smidtrup Friis, Remy Dulery, Moniek de Witte, Micha Srour, Maria Chiara Finazzi, Claudia Wehr, Arnon Nagler, Deborah Richardson, Wolfgang Bethge, Andrew Clark, Joanna Drozd-Sokolowska, Kavita Raj, Tomasz Czerw, Juan Carlos Hernández-Boluda, Donal P McLornan","doi":"10.1016/j.retram.2024.103476","DOIUrl":"https://doi.org/10.1016/j.retram.2024.103476","url":null,"abstract":"<p><p>Heterogeneous approaches exist in regard to the management of disease-related co-morbidities in potential allogeneic haematopoietic cell transplantation (allo-HCT) candidates with myelofibrosis (MF). The EBMT Chronic Malignancies Working Party launched an electronic survey to evaluate how MF-specific comorbidities are approached and whether they ultimately affect the decision to transplant. A total of 41/63 (65%) Centers, all of whom were experienced in the management of MF allo-HCT, responded. Responses were aggregated and reported in a comparative fashion. Screening for portal hypertension (PH) was routinely performed in 54% centers, never in 12% and guided by clinical manifestations in the remaining. Involvement of hepatologists/gastroenterologists was always/very often considered in patients with signs of PH prior to transplant. Centers reported that radiological evidence of PH did not routinely represent a formal contraindication for allo-HCT in most cases (78%). Of note, most centers (61%) did not perform routine screening for gastroesophageal varices; this was systematically considered or guided by clinical manifestations in only 7% and 32% centers, respectively. Presence of gastroesophageal varices was always (15%) or occasionally (19%) considered a formal contraindication to allo-HCT. A prior history of portal vein thrombosis never (78%) or occasionally (15%) represented a formal contraindication. Three Centers would not proceed to transplant in such cases. Less importance was assigned to non-portal splanchnic vein thrombosis (SVT), with all but one centre proceeding to transplant regardless of prior SVT. This survey highlights a considerable heterogeneity across responding centers in approaching MF-related comorbidities prior to transplant, suggesting that harmonisation guidelines are needed to address these issues in this patient population.</p>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"103476"},"PeriodicalIF":3.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512931","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}
Pub Date : 2024-10-23DOI: 10.1016/j.retram.2024.103477
Yifan Liu , Gangfeng Xiao , Yang Liu , Sanfang Tu , Bin Xue , Yadi Zhong , Cailu Zhang , Lili Zhou , Shiguang Ye , Yan Lu , Bing Xiu , Wenjun Zhang , Yi Ding , Jianfei Fu , Ping Li , Liang Huang , Xiu Luo , Aibin Liang
Burkitt lymphoma (BL) is a highly aggressive type of non-Hodgkin lymphomas that have a high likelihood of relapse and are highly refractory to initial treatment. While high-intensity chemotherapy has improved the outcomes, many adult patients still experience treatment failure, and effective salvage therapies are limited. This study retrospectively analyzed the outcomes of 21 relapsed or refractory (R/R) adult BL patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, combined or not with hematopoietic cell transplantation (HCT), across four Chinese hospitals. Patients were grouped based on treatment strategies: autologous HCT followed by CAR T-cell therapy (auto-HCT+CART group, n = 8), and CAR T-cell therapy alone (CART group, n = 13). The auto-HCT+CART group demonstrated superior outcomes, with an overall response rate (ORR) of 87.5 % and significantly higher 1-year overall survival (OS) and progression-free survival (PFS) rates compared to the CART group (p = 0.014 and p = 0.045, respectively). These findings suggest that combining auto-HCT with CAR-T therapy may enhance long-term disease control in R/R BL patients. These encouraging results highlight the need for further prospective studies to validate our data.
{"title":"CAR T-cell therapy combined with autologous hematopoietic cell transplantation in patients with refractory/relapsed Burkitt Lymphoma","authors":"Yifan Liu , Gangfeng Xiao , Yang Liu , Sanfang Tu , Bin Xue , Yadi Zhong , Cailu Zhang , Lili Zhou , Shiguang Ye , Yan Lu , Bing Xiu , Wenjun Zhang , Yi Ding , Jianfei Fu , Ping Li , Liang Huang , Xiu Luo , Aibin Liang","doi":"10.1016/j.retram.2024.103477","DOIUrl":"10.1016/j.retram.2024.103477","url":null,"abstract":"<div><div>Burkitt lymphoma (BL) is a highly aggressive type of non-Hodgkin lymphomas that have a high likelihood of relapse and are highly refractory to initial treatment. While high-intensity chemotherapy has improved the outcomes, many adult patients still experience treatment failure, and effective salvage therapies are limited. This study retrospectively analyzed the outcomes of 21 relapsed or refractory (R/R) adult BL patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, combined or not with hematopoietic cell transplantation (HCT), across four Chinese hospitals. Patients were grouped based on treatment strategies: autologous HCT followed by CAR T-cell therapy (auto-HCT+CART group, <em>n</em> = 8), and CAR T-cell therapy alone (CART group, <em>n</em> = 13). The auto-HCT+CART group demonstrated superior outcomes, with an overall response rate (ORR) of 87.5 % and significantly higher 1-year overall survival (OS) and progression-free survival (PFS) rates compared to the CART group (<em>p</em> = 0.014 and <em>p</em> = 0.045, respectively). These findings suggest that combining auto-HCT with CAR-T therapy may enhance long-term disease control in R/R BL patients. These encouraging results highlight the need for further prospective studies to validate our data.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"Article 103477"},"PeriodicalIF":3.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142551935","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}
Pub Date : 2024-10-16DOI: 10.1016/j.retram.2024.103475
Masoumeh Asadi , Ali Dalir Ghaffari , Fatemeh Mohammadhasani
Introduction
Toxoplasma gondii (T. gondii) infects all warm-blooded animals, including humans. Currently, no effective treatments exist to prevent the generation of chronic tissue cysts in infected hosts. Therefore, developing a vaccine to protect to deal with toxoplasmosis is a promising strategy, as a single immunization could provide lifelong protective immunity. Rhoptry proteins (ROPs) play a vital role for the parasite's survival within host cells and perform critical functions during different phases of parasite invasion. Little is known about ROP41 gene. Nevertheless, Understanding the characteristics of ROP41 will enhance diagnostic and vaccine research.
Materials and Methods
The current article provides a comprehensive analysis of the essential components of the ROP41 protein, including its transmembrane domain, physico-chemical properties, subcellular location, tertiary and secondary structures, and potential T- and B-cell epitopes. These features were determined by many bioinformatics approaches to identify possible epitopes for developing a highly effective vaccine.
Results
ROP41 protein showed 36 possible post-translational modification regions. The ROP41 protein secondary structure contains 17.35 % extended strand, 33.47 % alpha-helix, and 49.18 % random coil. Also, ROP41 showed many possible B- and T-cell epitopes. According to the Ramachandran plot, 90.78 % of amino acid residues had been placed in favored, 3.28 % in outlier, and 5.94 % in allowed areas. Also, the allergenicity and antigenicity evaluation indicated that ROP41 is non-allergenic and immunogenic.
Conclusion
The current study offered critical basic and conceptual information on ROP41 to increase a successful vaccine in opposition to continual and acute toxoplasmosis for in addition in vivo assessments. Further research is necessary for the development of vaccines utilizing ROP41 alone or combined with various antigens.
导言：弓形虫（T. gondii）感染所有温血动物，包括人类。目前，还没有有效的治疗方法来预防受感染宿主体内慢性组织囊肿的产生。因此，开发一种疫苗来预防弓形虫病是一种很有前景的策略，因为一次免疫接种可提供终身保护性免疫。ROPtry蛋白（ROPs）对寄生虫在宿主细胞内的生存起着至关重要的作用，并在寄生虫入侵的不同阶段发挥关键功能。人们对 ROP41 基因知之甚少。然而，了解 ROP41 的特征将有助于诊断和疫苗研究：本文全面分析了 ROP41 蛋白的基本成分，包括其跨膜结构域、物理化学性质、亚细胞位置、三级和二级结构以及潜在的 T 细胞和 B 细胞表位。通过多种生物信息学方法确定了这些特征，以确定开发高效疫苗的可能表位：结果：ROP41蛋白显示了36个可能的翻译后修饰区域。ROP41蛋白的二级结构中，17.35%为延伸链，33.47%为α-螺旋，49.18%为随机线圈。此外，ROP41 还显示出许多可能的 B 细胞和 T 细胞表位。根据拉马钱德兰图，90.78%的氨基酸残基被置于有利区域，3.28%的氨基酸残基被置于离群区域，5.94%的氨基酸残基被置于允许区域。此外，过敏性和抗原性评估表明，ROP41 不具有过敏性和免疫原性：目前的研究提供了有关 ROP41 的重要基础和概念信息，以增加成功对抗持续性和急性弓形虫病疫苗的体内评估。有必要开展进一步研究，以开发单独使用 ROP41 或将其与各种抗原结合使用的疫苗。
{"title":"In silico analysis and structural vaccinology prediction of Toxoplasma gondii ROP41 gene via immunoinformatics methods as a vaccine candidate","authors":"Masoumeh Asadi , Ali Dalir Ghaffari , Fatemeh Mohammadhasani","doi":"10.1016/j.retram.2024.103475","DOIUrl":"10.1016/j.retram.2024.103475","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Toxoplasma gondii</em> (<em>T. gondii</em>) infects all warm-blooded animals, including humans. Currently, no effective treatments exist to prevent the generation of chronic tissue cysts in infected hosts. Therefore, developing a vaccine to protect to deal with toxoplasmosis is a promising strategy, as a single immunization could provide lifelong protective immunity. Rhoptry proteins (ROPs) play a vital role for the parasite's survival within host cells and perform critical functions during different phases of parasite invasion. Little is known about ROP41 gene. Nevertheless, Understanding the characteristics of ROP41 will enhance diagnostic and vaccine research.</div></div><div><h3>Materials and Methods</h3><div>The current article provides a comprehensive analysis of the essential components of the ROP41 protein, including its transmembrane domain, physico-chemical properties, subcellular location, tertiary and secondary structures, and potential T- and B-cell epitopes. These features were determined by many bioinformatics approaches to identify possible epitopes for developing a highly effective vaccine.</div></div><div><h3>Results</h3><div>ROP41 protein showed 36 possible post-translational modification regions. The ROP41 protein secondary structure contains 17.35 % extended strand, 33.47 % alpha-helix, and 49.18 % random coil. Also, ROP41 showed many possible B- and T-cell epitopes. According to the Ramachandran plot, 90.78 % of amino acid residues had been placed in favored, 3.28 % in outlier, and 5.94 % in allowed areas. Also, the allergenicity and antigenicity evaluation indicated that ROP41 is non-allergenic and immunogenic.</div></div><div><h3>Conclusion</h3><div>The current study offered critical basic and conceptual information on ROP41 to increase a successful vaccine in opposition to continual and acute toxoplasmosis for in addition in vivo assessments. Further research is necessary for the development of vaccines utilizing ROP41 alone or combined with various antigens.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"Article 103475"},"PeriodicalIF":3.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512932","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}
Pub Date : 2024-09-25DOI: 10.1016/j.retram.2024.103472
Meilin Tian , Le Ma , Jieping Chen , Qiang Gong
Delayed platelet engraftment (DPE) and thrombocytopenia are common complications following myeloablative conditioning in the advanced stage of allogeneic haematopoietic cell transplantation (allo-HCT), and they are associated with transplantation-related mortality and poor prognosis. Therefore, promoting haematopoietic reconstitution after allo-HCT plays a key role in improving patient outcomes. The aim of this retrospective study was to assess the effectiveness and safety of recombinant human thrombopoietin (rhTPO) in promoting haematopoietic reconstruction after allo-HCT. The study included 210 patients who underwent transplantation, with 158 in the rhTPO group and 52 in the control group. Of the total patient population, 120 were males and 90 were females, with a median age of 31 years (range=6 to 59 years). The results showed that the rhTPO group had a median platelet engraftment time that was 14.1 days shorter than that of the control group (14.1 days vs. 21.9 days; P < 0.001). The time for platelet count recovery to 50 × 10^9/L was also shorter in the rhTPO group than in the control group (21.7 days vs. 30.3 days; P < 0.001). Additionally, the granulocyte engraftment time was shorter in the rhTPO group (14.3 days vs. 18.2 days; P < 0.001). There was no significant difference in overall survival (OS) between the rhTPO group and the control group at 2 years after transplantation (77.2% vs. 65.4 %; P = 0.08). Furthermore, there were no significant differences in the amount of platelet transfusions, the rate of platelet engraftment, the rate of DPE, or the incidence of Grade 4 haemorrhage between the groups. Moreover, no adverse reactions were found in the rhTPO group. This study demonstrated that rhTPO administration after allo-HCT effectively reduced the time required for platelet and granulocyte engraftment and was safe.
{"title":"Effect and safety of recombinant human thrombopoietin on haematopoietic reconstitution after allogeneic haematopoietic cell transplantation","authors":"Meilin Tian , Le Ma , Jieping Chen , Qiang Gong","doi":"10.1016/j.retram.2024.103472","DOIUrl":"10.1016/j.retram.2024.103472","url":null,"abstract":"<div><div>Delayed platelet engraftment (DPE) and thrombocytopenia are common complications following myeloablative conditioning in the advanced stage of allogeneic haematopoietic cell transplantation (allo-HCT), and they are associated with transplantation-related mortality and poor prognosis. Therefore, promoting haematopoietic reconstitution after allo-HCT plays a key role in improving patient outcomes. The aim of this retrospective study was to assess the effectiveness and safety of recombinant human thrombopoietin (rhTPO) in promoting haematopoietic reconstruction after allo-HCT. The study included 210 patients who underwent transplantation, with 158 in the rhTPO group and 52 in the control group. Of the total patient population, 120 were males and 90 were females, with a median age of 31 years (range=6 to 59 years). The results showed that the rhTPO group had a median platelet engraftment time that was 14.1 days shorter than that of the control group (14.1 days vs. 21.9 days; <em>P</em> < 0.001). The time for platelet count recovery to 50 × 10^9/L was also shorter in the rhTPO group than in the control group (21.7 days vs. 30.3 days; <em>P</em> < 0.001). Additionally, the granulocyte engraftment time was shorter in the rhTPO group (14.3 days vs. 18.2 days; <em>P</em> < 0.001). There was no significant difference in overall survival (OS) between the rhTPO group and the control group at 2 years after transplantation (77.2% vs. 65.4 %; <em>P</em> = 0.08). Furthermore, there were no significant differences in the amount of platelet transfusions, the rate of platelet engraftment, the rate of DPE, or the incidence of Grade 4 haemorrhage between the groups. Moreover, no adverse reactions were found in the rhTPO group. This study demonstrated that rhTPO administration after allo-HCT effectively reduced the time required for platelet and granulocyte engraftment and was safe.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"Article 103472"},"PeriodicalIF":3.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.retram.2024.103474
Maryam Nabigol, Laya Khodayi Hajipirloo, Bentolhoda Kuhestani-dehaghi, Mehdi Allahbakhshian Farsani
Purpose of study
Despite the various therapeutic options introduced for AML treatment, therapy resistance and relapse are still the main obstacles. It is well known that alterations in the bone marrow microenvironment (BMM) play a crucial role in leukemia growth and the treatment failure of AML. Evidence shows that exosomes alter the components of BMM in a way that support leukemia survival, leading to chemoresistance. In this study, we evaluated the effect of AML exosomes on the biological functions of human bone marrow mesenchymal stromal cells (h BM-MSCs), especially alteration in the expression of the JAK/STAT signaling genes, as a leukemia-favoring pathway.
Method
Exosomes were isolated from the HL-60 cell line and characterized using flow cytometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS) technique. The exosome protein content was assessed using a bicinchoninic acid (BCA) protein assay kit in order to determine the concentration of exosomes. Subsequently, MSCs were treated with varying concentrations of AML exosomes, and data was obtained using MTT, cell cycle, apoptosis, and ki67 assays. Additionally, gene expression analysis was conducted through qRT-PCR.
Result
AML exosomes regulated the viability and survival of MSCs in a concentration-dependent manner. The qRT-PCR data revealed that treatment with AML exosomes at a concentration of 50 μg/mL led to a significant upregulation of JAK2, STAT3, and STAT5 genes in MSCs.
Conclusion
Because the JAK/STAT signaling pathway has been shown to play a role in the proliferation and survival of leukemic cells, our results suggest that AML exosomes stimulate MSCs to activate this pathway. This activation may impede AML cell apoptosis, potentially leading to chemoresistance and relapse.
{"title":"Effect of AML-exosomes on the cellular and molecular properties of bone marrow mesenchymal stromal cells: Expression of JAK/STAT signaling genes","authors":"Maryam Nabigol, Laya Khodayi Hajipirloo, Bentolhoda Kuhestani-dehaghi, Mehdi Allahbakhshian Farsani","doi":"10.1016/j.retram.2024.103474","DOIUrl":"10.1016/j.retram.2024.103474","url":null,"abstract":"<div><h3>Purpose of study</h3><div>Despite the various therapeutic options introduced for AML treatment, therapy resistance and relapse are still the main obstacles. It is well known that alterations in the bone marrow microenvironment (BMM) play a crucial role in leukemia growth and the treatment failure of AML. Evidence shows that exosomes alter the components of BMM in a way that support leukemia survival, leading to chemoresistance. In this study, we evaluated the effect of AML exosomes on the biological functions of human bone marrow mesenchymal stromal cells (h BM-MSCs), especially alteration in the expression of the JAK/STAT signaling genes, as a leukemia-favoring pathway.</div></div><div><h3>Method</h3><div>Exosomes were isolated from the HL-60 cell line and characterized using flow cytometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS) technique. The exosome protein content was assessed using a bicinchoninic acid (BCA) protein assay kit in order to determine the concentration of exosomes. Subsequently, MSCs were treated with varying concentrations of AML exosomes, and data was obtained using MTT, cell cycle, apoptosis, and ki67 assays. Additionally, gene expression analysis was conducted through qRT-PCR.</div></div><div><h3>Result</h3><div>AML exosomes regulated the viability and survival of MSCs in a concentration-dependent manner. The qRT-PCR data revealed that treatment with AML exosomes at a concentration of 50 μg/mL led to a significant upregulation of JAK2, STAT3, and STAT5 genes in MSCs.</div></div><div><h3>Conclusion</h3><div>Because the JAK/STAT signaling pathway has been shown to play a role in the proliferation and survival of leukemic cells, our results suggest that AML exosomes stimulate MSCs to activate this pathway. This activation may impede AML cell apoptosis, potentially leading to chemoresistance and relapse.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"73 1","pages":"Article 103474"},"PeriodicalIF":3.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376302","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}
Pub Date : 2024-09-20DOI: 10.1016/j.retram.2024.103473
Junjie Cao , Xianxu Zhuang , Renzhi Pei , Ying Lu , Peipei Ye , Dong Chen , Xiaohong Du , Shuangyue Li , Xuhui Liu
Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells have become the preferred source of hematopoietic stem cells. We compared the effectiveness of G-CSF and pegylated G-CSF (peg-G-CSF) for hematopoietic stem cell mobilization in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) donors, and evaluated the transplant outcomes. We conducted a matched retrospective cohort study. Donors mobilized with peg-G-CSF (n = 70) and G-CSF (n = 70). 140 consecutive patients diagnosed with acute leukemia who underwent haplo-HSCT were included in this study. The findings revealed that the peg-G-CSF cohort exhibited significantly elevated myeloid-derived suppressor cells (MDSCs) levels in their grafts when compared to the G-CSF cohort (P < 0.001). The 100-day cumulative incidence (CI) of grade III-IV acute graft-versus-host disease (GVHD) and 1-year CI of moderate-to-severe chronic GVHD were 4.3% vs 14.3 % (P = 0.047) and 11.2% vs 27.4 % (P = 0.023), in the peg-G-CSF group and G-CSF group. Patients reveiving mobilized stem cell with peg-G-CSF had a significantly greater likelihood of 1-year GVHD-free relapse-free survival (GRFS) compared to patients reveiving mobilized stem cell with G-CSF (74.9% vs 37.9 %, P < 0.001). The higher graft MDSCs proportion was associated with lower grade II-IV aGVHD, cGVHD (P < 0.05) and higher GRFS in the univariate analysis (P < 0.05). Multivariate analysis showed that MDSCs proportion higher than 11.36 % (HR, 0.305; 95 % CI, 0.154–0.606; P = 0.001) and peg-G-CSF for stem cell mobilization (HR, 0.466; 95 % CI, 0.251–0.865; P = 0.016) were independent prognostic factors of GRFS. The superior survival rates observed in recipients of peg-G-CSF-mobilized cells are likely due to reduced acute GVHD, potentially mediated by the increased MDSCs within the grafts.
{"title":"The transplantation effect of pegylated granulocyte colony-stimulating factor mobilized hematopoietic stem cells may be superior to that of G-CSF mobilized hematopoietic stem cells in haploidentical allogeneic hematopoietic cell transplantation","authors":"Junjie Cao , Xianxu Zhuang , Renzhi Pei , Ying Lu , Peipei Ye , Dong Chen , Xiaohong Du , Shuangyue Li , Xuhui Liu","doi":"10.1016/j.retram.2024.103473","DOIUrl":"10.1016/j.retram.2024.103473","url":null,"abstract":"<div><div>Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells have become the preferred source of hematopoietic stem cells. We compared the effectiveness of G-CSF and pegylated G-CSF (peg-G-CSF) for hematopoietic stem cell mobilization in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) donors, and evaluated the transplant outcomes. We conducted a matched retrospective cohort study. Donors mobilized with peg-G-CSF (<em>n</em> = 70) and G-CSF (<em>n</em> = 70). 140 consecutive patients diagnosed with acute leukemia who underwent haplo-HSCT were included in this study. The findings revealed that the peg-G-CSF cohort exhibited significantly elevated myeloid-derived suppressor cells (MDSCs) levels in their grafts when compared to the G-CSF cohort (<em>P</em> < 0.001). The 100-day cumulative incidence (CI) of grade III-IV acute graft-versus-host disease (GVHD) and 1-year CI of moderate-to-severe chronic GVHD were 4.3% vs 14.3 % (<em>P</em> = 0.047) and 11.2% vs 27.4 % (<em>P</em> = 0.023), in the peg-G-CSF group and G-CSF group. Patients reveiving mobilized stem cell with peg-G-CSF had a significantly greater likelihood of 1-year GVHD-free relapse-free survival (GRFS) compared to patients reveiving mobilized stem cell with G-CSF (74.9% vs 37.9 %, <em>P</em> < 0.001). The higher graft MDSCs proportion was associated with lower grade II-IV aGVHD, cGVHD (<em>P</em> < 0.05) and higher GRFS in the univariate analysis (<em>P</em> < 0.05). Multivariate analysis showed that MDSCs proportion higher than 11.36 % (HR, 0.305; 95 % CI, 0.154–0.606; <em>P</em> = 0.001) and peg-G-CSF for stem cell mobilization (HR, 0.466; 95 % CI, 0.251–0.865; <em>P</em> = 0.016) were independent prognostic factors of GRFS. The superior survival rates observed in recipients of peg-G-CSF-mobilized cells are likely due to reduced acute GVHD, potentially mediated by the increased MDSCs within the grafts.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"72 4","pages":"Article 103473"},"PeriodicalIF":3.2,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318689","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}
Relapsed/refractory (r/r) acute myeloid leukemia (AML) is associated with poor prognosis. CD19 is a B-cell marker, is aberrantly expressed in AML, mostly with t(8; 21)(q22; q22.1). Here we report the results of a phase 2 study giving point of care produced CD19 CAR T- cells for r/r AML with aberrant expression of CD19 (NCT04257175). Lymphodepletion included fludarabine and cyclophosphamide The response was evaluated by bone marrow (BM) aspiration on day 28. Six patients (5 adults and 1 child) were included. Median number of previous chemotherapy lines was 4 (range, 3–8) and four patients received CAR T-cells 8–18 months post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytokine release syndrome (CRS) of any grade occurred in all patients, and 1 patient had grade 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients at low grades. Tocilizumab was administered to 2 patients and corticosteroids to 3 patients. Four patients achieved a complete remission (CR), while 2/6 progressed (PD). Three patients (2 with CR and 1 with PD) underwent allo-HSCT (it was the second transplant in 2) 2–5 months post CAR T-cells infusion. The median duration of response in patients achieving CR was 8.5 (range; 3–14) months. However, all patients eventually died within 5 (1–18) months.
In conclusion, CD19 CAR T- cell treatment for AML is feasible and safe. However, the response is short and should be followed by allo-HSCT. Hopefully, future long term results will be improved by combining the CAR T- cell therapy with the emerging novel effective anti-leukemic compounds.
复发/难治性（r/r）急性髓性白血病（AML）预后不良。CD19 是一种 B 细胞标志物，在急性髓细胞白血病中异常表达，主要是 t(8; 21)(q22; q22.1)。在此，我们报告了一项针对CD19异常表达的r/r AML（NCT04257175）的2期研究结果，该研究在治疗点生产CD19 CAR T-细胞。淋巴清除包括氟达拉滨和环磷酰胺，第28天通过骨髓（BM）抽吸评估反应。共纳入 6 名患者（5 名成人和 1 名儿童）。既往化疗次数中位数为4次（3-8次），4名患者在异基因造血干细胞移植（allo-HSCT）后8-18个月接受了CAR T细胞治疗。所有患者都出现了任何级别的细胞因子释放综合征（CRS），其中一名患者出现了3级CRS。2名患者出现了低度免疫效应细胞相关神经毒性综合征（ICANS）。2 名患者使用了托珠单抗，3 名患者使用了皮质类固醇。4名患者获得完全缓解（CR），2/6的患者病情进展（PD）。3名患者（2名CR患者和1名PD患者）在CAR T细胞输注后2-5个月接受了异基因造血干细胞移植（2名患者是第二次移植）。获得CR的患者的中位反应持续时间为8.5个月（3-14个月）。然而，所有患者最终都在 5（1-18）个月内死亡。总之，CD19 CAR T 细胞治疗急性髓细胞白血病是可行且安全的。然而，这种疗法的反应时间较短，应在治疗后进行同种异体造血干细胞移植（allo-HSCT）。希望通过将 CAR T 细胞疗法与新出现的有效抗白血病化合物相结合，能改善未来的长期疗效。
{"title":"Point of care CD19 chimeric antigen receptor (CAR) T-cells for relapsed/refractory acute myeloid leukemia (AML) with aberrant CD19 antigen expression","authors":"Ivetta Danylesko , Noga Shem-Tov , Ronit Yerushalmi , Elad Jacoby , Amos Toren , Roni Shouval , Orit Itzhaki , Abraham Avigdor , Avichai Shimoni , Arnon Nagler","doi":"10.1016/j.retram.2024.103471","DOIUrl":"10.1016/j.retram.2024.103471","url":null,"abstract":"<div><div>Relapsed/refractory (r/r) acute myeloid leukemia (AML) is associated with poor prognosis. CD19 is a B-cell marker, is aberrantly expressed in AML, mostly with t(8; 21)(q22; q22.1). Here we report the results of a phase 2 study giving point of care produced CD19 CAR T- cells for r/r AML with aberrant expression of CD19 (NCT04257175). Lymphodepletion included fludarabine and cyclophosphamide The response was evaluated by bone marrow (BM) aspiration on day 28. Six patients (5 adults and 1 child) were included. Median number of previous chemotherapy lines was 4 (range, 3–8) and four patients received CAR T-cells 8–18 months post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytokine release syndrome (CRS) of any grade occurred in all patients, and 1 patient had grade 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients at low grades. Tocilizumab was administered to 2 patients and corticosteroids to 3 patients. Four patients achieved a complete remission (CR), while 2/6 progressed (PD). Three patients (2 with CR and 1 with PD) underwent allo-HSCT (it was the second transplant in 2) 2–5 months post CAR T-cells infusion. The median duration of response in patients achieving CR was 8.5 (range; 3–14) months. However, all patients eventually died within 5 (1–18) months.</div><div>In conclusion, CD19 CAR T- cell treatment for AML is feasible and safe. However, the response is short and should be followed by allo-HSCT. Hopefully, future long term results will be improved by combining the CAR T- cell therapy with the emerging novel effective anti-leukemic compounds.</div></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"72 4","pages":"Article 103471"},"PeriodicalIF":3.2,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300836","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}
Pub Date : 2024-09-01DOI: 10.1016/j.retram.2024.103464
Antonio Milano , Giuliana Lando , Giulia Di Maggio , Giorgia Cornacchini , Giovanni Grillo , Roberto Cairoli , Silvano Rossini , Roberto Crocchiolo
Background
While the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results.
Methods
We here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLA-mismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies.
Results
The survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donor-specific anti-HLA antibodies was 21 months (95 % CI: 9–42) vs. 61 months (95 % CI: 17–77) among the anti-HLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, p = 0.01). No pattern of death causes was found
Conclusions
In this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts.
{"title":"Impaired survival of patients with non donor-specific anti-HLA antibodies before HLA-mismatched allogeneic stem cell transplantation","authors":"Antonio Milano , Giuliana Lando , Giulia Di Maggio , Giorgia Cornacchini , Giovanni Grillo , Roberto Cairoli , Silvano Rossini , Roberto Crocchiolo","doi":"10.1016/j.retram.2024.103464","DOIUrl":"10.1016/j.retram.2024.103464","url":null,"abstract":"<div><h3>Background</h3><p>While the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results.</p></div><div><h3>Methods</h3><p>We here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLA-mismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies.</p></div><div><h3>Results</h3><p>The survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donor-specific anti-HLA antibodies was 21 months (95 % CI: 9–42) vs. 61 months (95 % CI: 17–77) among the anti-HLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, <em>p</em> = 0.01). No pattern of death causes was found</p></div><div><h3>Conclusions</h3><p>In this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts.</p></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"72 3","pages":"Article 103464"},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142128416","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}
Pub Date : 2024-08-17DOI: 10.1016/j.retram.2024.103466
Simon Planken , Ann De Becker , Tessa Kerre , Hélène Schoemans , Frédéric Baron , Carlos Graux , Ivan Van Riet , Chantal Lechanteur , Etienne Baudoux , Rik Schots , Yves Beguin , Transplant Committee of the Belgian Hematology Society.
Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects.
The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival.
Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported.
In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation.
{"title":"Feasibility of co-transplantation of umbilical cord blood and third-party mesenchymal stromal cells after (non)myeloablative conditioning in patients with hematological malignancies","authors":"Simon Planken , Ann De Becker , Tessa Kerre , Hélène Schoemans , Frédéric Baron , Carlos Graux , Ivan Van Riet , Chantal Lechanteur , Etienne Baudoux , Rik Schots , Yves Beguin , Transplant Committee of the Belgian Hematology Society.","doi":"10.1016/j.retram.2024.103466","DOIUrl":"10.1016/j.retram.2024.103466","url":null,"abstract":"<div><p>Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects.</p><p>The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival.</p><p>Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported.</p><p>In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation.</p></div>","PeriodicalId":54260,"journal":{"name":"Current Research in Translational Medicine","volume":"72 4","pages":"Article 103466"},"PeriodicalIF":3.2,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098238","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}
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