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  1. Article ; Online: Transcutaneous ultrasound-mediated gene delivery into canine livers achieves therapeutic levels of factor VIII expression.

    Manson, Megan A / Zhang, Feng / Novokhodko, Alexander / Chen, Chun-Yu / Parker, Maura / Loeb, Keith R / Kajimoto, Masaki / Campbell, Carley / Storb, Rainer F / Miao, Carol H

    Blood advances

    2022  Volume 6, Issue 12, Page(s) 3557–3568

    Abstract: A safe, effective, and inclusive gene therapy will significantly benefit a large population of patients with hemophilia. We used a minimally invasive transcutaneous ultrasound-mediated gene delivery (UMGD) strategy combined with microbubbles (MBs) to ... ...

    Abstract A safe, effective, and inclusive gene therapy will significantly benefit a large population of patients with hemophilia. We used a minimally invasive transcutaneous ultrasound-mediated gene delivery (UMGD) strategy combined with microbubbles (MBs) to enhance gene transfer into 4 canine livers. A mixture of high-expressing, liver-specific human factor VIII (hFVIII) plasmid and MBs was injected into the hepatic vein via balloon catheter under fluoroscopy guidance with simultaneous transcutaneous UMGD treatment targeting a specific liver lobe. Therapeutic levels of hFVIII expression were achieved in all 4 dogs, and hFVIII levels were maintained at a detectable level in 3 dogs throughout the 60-day experimental period. Plasmid copy numbers correlated with hFVIII antigen levels, and plasmid-derived messenger RNA (mRNA) was detected in treated livers. Liver transaminase levels and histology analysis indicated minimal liver damage and a rapid recovery after treatment. These results indicate that liver-targeted transcutaneous UMGD is promising as a clinically feasible therapy for hemophilia A and other diseases.
    MeSH term(s) Animals ; Dogs ; Factor VIII/genetics ; Factor VIII/therapeutic use ; Gene Transfer Techniques ; Genetic Therapy/methods ; Hemophilia A/genetics ; Hemophilia A/therapy ; Hemophilia A/veterinary ; Hemostatics ; Humans ; Liver/metabolism
    Chemical Substances Hemostatics ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2022-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2021006016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Contribution of measurable residual disease status to prediction accuracy of relapse and survival in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

    Rodríguez-Arbolí, Eduardo / Othus, Megan / Orvain, Corentin / Zarling, Lucas C / Sandmaier, Brenda M / Milano, Filippo / Schoch, Gary / Davis, Chris / Deeg, H Joachim / Appelbaum, Frederick R / Storb, Rainer / Walter, Roland B

    Haematologica

    2023  Volume 108, Issue 1, Page(s) 273–277

    MeSH term(s) Adult ; Humans ; Hematopoietic Stem Cell Transplantation ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/therapy ; Chronic Disease ; Recurrence ; Neoplasm, Residual ; Retrospective Studies ; Transplantation Conditioning
    Language English
    Publishing date 2023-01-01
    Publishing country Italy
    Document type Letter ; Research Support, N.I.H., Extramural
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2022.281631
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Prevention of graft-vs.-host disease.

    Rezvani, Andrew R / Storb, Rainer F

    Expert opinion on pharmacotherapy

    2012  Volume 13, Issue 12, Page(s) 1737–1750

    Abstract: Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematologic disorders. However, graft-vs.-host disease (GVHD) remains a major complication of allogeneic HCT and limits the ... ...

    Abstract Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematologic disorders. However, graft-vs.-host disease (GVHD) remains a major complication of allogeneic HCT and limits the success of this approach.
    Areas covered: This paper reviews recent developments in the prevention of acute and chronic GVHD. In the setting of acute GVHD prevention, recent trials of T-cell depletion using Fresenius-ATG are reviewed, as well as studies testing total lymphoid irradiation, mesenchymal stromal cells, rituximab, statins, sirolimus and other investigational agents. In the setting of chronic GVHD, results with Fresenius-ATG are reviewed, as well as B-cell depletion with rituximab, and the potential role of the B-cell regulatory cytokine BAFF in chronic GVHD is also discussed. Finally, the emerging role of resident skin and gut bacterial flora-the so-called microbiome-in the pathogenesis of GVHD is covered.
    Expert opinion: Current methods of acute GVHD prevention are highly successful, and a number of investigational approaches promise to further reduce the risk of this complication. By contrast, chronic GVHD is more poorly understood and more difficult to prevent. Future studies are required to delineate the roles of these approaches and to abrogate GVHD without sacrificing the beneficial immunologic graft-vs.-tumor effect.
    MeSH term(s) Animals ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation ; Humans ; Metagenome ; Transplantation, Homologous/immunology
    Language English
    Publishing date 2012-07-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2001535-5
    ISSN 1744-7666 ; 1465-6566
    ISSN (online) 1744-7666
    ISSN 1465-6566
    DOI 10.1517/14656566.2012.703652
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  4. Article ; Online: Utility of the Treatment-Related Mortality (TRM) score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

    Zarling, Lucas C / Othus, Megan / Sandmaier, Brenda M / Milano, Filippo / Schoch, Gary / Davis, Chris / Bleakley, Marie / Deeg, H Joachim / Appelbaum, Frederick R / Storb, Rainer / Walter, Roland B

    Leukemia

    2022  Volume 36, Issue 6, Page(s) 1563–1574

    Abstract: There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single-institution data from 861 adults with AML, ... ...

    Abstract There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single-institution data from 861 adults with AML, we retrospectively examined the Treatment-Related Mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the four TRM score quartiles (at 3 years: 9% [95% confidence interval: 5-13%] in Q1 vs. 28% [22-34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20-32%] in Q1 vs. 37% [30-43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59-72%] in Q1 vs. 36% [29-42%] in Q4; OS at 3 years: 72% [66-78%] in Q1 vs. 39% [33-46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.
    MeSH term(s) Adult ; Disease-Free Survival ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Leukemia, Myeloid, Acute/therapy ; Prognosis ; Recurrence ; Retrospective Studies ; Transplantation Conditioning ; Transplantation, Homologous
    Language English
    Publishing date 2022-04-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-022-01574-5
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    Zs.A 2295: Show issues Location:
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  5. Article ; Online: Mesenchymal stromal cells: a new tool against graft-versus-host disease?

    Baron, Frédéric / Storb, Rainer

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2011  Volume 18, Issue 6, Page(s) 822–840

    Abstract: Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical ... ...

    Abstract Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical use as prevention and/or treatment for severe graft-versus-host disease (GVHD). Although a number of phase I-II studies have suggested that MSC infusion was safe and might be effective for preventing or treating acute GVHD, definitive proof of their efficacy remains lacking thus far. Multicenter randomized studies are ongoing to more precisely assess the impact of MSC infusion on GVHD prevention/treatment, whereas further research is performed in vitro and in animal models with the aims of determining the best way to expand MSCs ex vivo as well as the most efficient dose and schedule of MSCs administration. After introducing GVHD, MSC biology, and results of MSC infusion in animal models of allogeneic hematopoietic cell transplantation, this article reviews the results of the first clinical trials investigating the use of MSC infusion as prevention or treatment of GVHD.
    MeSH term(s) Animals ; Clinical Trials as Topic ; Disease Models, Animal ; Dogs ; Graft vs Host Disease/immunology ; Graft vs Host Disease/prevention & control ; Graft vs Host Disease/therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cell Transplantation/statistics & numerical data ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/immunology ; Mice ; Transplantation, Homologous
    Language English
    Publishing date 2011-09-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1474865-4
    ISSN 1523-6536 ; 1083-8791
    ISSN (online) 1523-6536
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2011.09.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Separation of graft-vs.-tumor effects from graft-vs.-host disease in allogeneic hematopoietic cell transplantation.

    Rezvani, Andrew R / Storb, Rainer F

    Journal of autoimmunity

    2008  Volume 30, Issue 3, Page(s) 172–179

    Abstract: Allogeneic hematopoietic cell transplantation (HCT) is an increasingly widely used treatment modality in hematological malignancies. Alloreactivity mediated by donor T cells (and, in some settings, by donor natural killer cells) can produce durable ... ...

    Abstract Allogeneic hematopoietic cell transplantation (HCT) is an increasingly widely used treatment modality in hematological malignancies. Alloreactivity mediated by donor T cells (and, in some settings, by donor natural killer cells) can produce durable immunologic control or eradication of residual malignancy after allogeneic HCT. However, graft-vs.-tumor (GVT) effects are variably effective and are often accompanied by deleterious alloreactivity against normal host tissue, manifesting as graft-vs.-host disease (GVHD). A major focus of current research in HCT is the separation of beneficial GVT effects from GVHD. Here we review a number of approaches currently under investigation to specifically augment GVT effects, including the identification of minor histocompatibility antigens (mHA), adoptive immunotherapy with tumor-specific or mHA-specific cytotoxic T lymphocytes, vaccination of the donor or recipient to stimulate tumor-specific immunity, and adoptive transfer of natural killer cells. In addition, we review strategies being investigated to specifically suppress GVHD while sparing GVT, including the manipulation and infusion of regulatory T cells, the use of novel pharmacologic and biologic agents, and the use of mesenchymal stem cells. Ultimately, advances in separation of GVT from GVHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies.
    MeSH term(s) Adoptive Transfer ; Animals ; Graft vs Host Disease/immunology ; Graft vs Host Disease/prevention & control ; Graft vs Tumor Effect/immunology ; Hematologic Neoplasms/immunology ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Killer Cells, Natural/immunology ; Killer Cells, Natural/transplantation ; Mesenchymal Stem Cell Transplantation ; Minor Histocompatibility Antigens/immunology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/transplantation ; Transplantation Conditioning ; Transplantation Immunology ; Transplantation, Homologous
    Chemical Substances Minor Histocompatibility Antigens
    Language English
    Publishing date 2008-01-31
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 639452-8
    ISSN 0896-8411
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2007.12.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model.

    Zhang, Shihong / Black, R Graeme / Kohli, Karan / Hayes, Brian J / Miller, Cassandra / Koehne, Amanda / Schroeder, Brett A / Abrams, Kraig / Schulte, Brian C / Alexiev, Borislav A / Heimberger, Amy B / Zhang, Ali / Jing, Weiqing / Ng, Juliana Chi Kei / Shinglot, Himaly / Seguin, Bernard / Salter, Alexander I / Riddell, Stanley R / Jensen, Michael C /
    Gottschalk, Stephen / Moore, Peter F / Torok-Storb, Beverly / Pollack, Seth M

    Molecular cancer therapeutics

    2022  Volume 21, Issue 6, Page(s) 999–1009

    Abstract: One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model ... ...

    Abstract One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.
    MeSH term(s) Animals ; B7 Antigens ; Cell Line, Tumor ; Dogs ; Humans ; Receptors, Chimeric Antigen ; Sarcoma/drug therapy ; T-Lymphocytes ; Xenograft Model Antitumor Assays
    Chemical Substances B7 Antigens ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2022-04-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-21-0726
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    Zs.A 5750: Show issues Location:
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  8. Article ; Online: Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML.

    Paras, Gabrielle / Morsink, Linde M / Othus, Megan / Milano, Filippo / Sandmaier, Brenda M / Zarling, Lucas C / Palmieri, Raffaele / Schoch, Gary / Davis, Chris / Bleakley, Marie / Flowers, Mary E D / Deeg, H Joachim / Appelbaum, Frederick R / Storb, Rainer / Walter, Roland B

    Blood

    2022  Volume 139, Issue 11, Page(s) 1694–1706

    Abstract: In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk ... ...

    Abstract In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in first or second remission after myeloablative conditioning (MAC; n = 515) or non-MAC (n = 295) who underwent multiparameter flow cytometry-based MRD testing before as well as 20 to 40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85 of 104; 81.7%) than non-MAC (33 of 57; 57.9%) regimen (P = .002). Although non-MAC regimens were less likely to clear MRD, if they did, the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P = .020), RFS (P = .002), and OS (P = .001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared with the isolated use of pre-HCT MRD status or post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments in patients with AML.
    MeSH term(s) Adult ; Flow Cytometry ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/etiology ; Leukemia, Myeloid, Acute/therapy ; Neoplasm, Residual/etiology ; Retrospective Studies ; Transplantation Conditioning
    Language English
    Publishing date 2022-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021014804
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  9. Article: ROS-Scavenging Enzymes as an Antioxidant Response to High Concentration of Anthracene in the Liverwort

    Spinedi, Nahuel / Storb, Romina / Aranda, Elisabet / Romani, Facundo / Svriz, Maya / Varela, Santiago A / Moreno, Javier E / Fracchia, Sebastian / Cabrera, Juan / Batista-García, Ramón Alberto / Ponce de León, Inés / Scervino, J Martín

    Plants (Basel, Switzerland)

    2021  Volume 10, Issue 7

    Abstract: Marchantia ... ...

    Abstract Marchantia polymorpha
    Language English
    Publishing date 2021-07-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704341-1
    ISSN 2223-7747
    ISSN 2223-7747
    DOI 10.3390/plants10071478
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  10. Article ; Online: Graft-versus-host-disease after double cord blood transplantation: a new look at its characteristics.

    Milano, Filippo / Delaney, Colleen / Storb, Rainer

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2013  Volume 19, Issue 6, Page(s) 847–848

    MeSH term(s) Cord Blood Stem Cell Transplantation ; Female ; Gastrointestinal Tract/immunology ; Graft vs Host Disease/therapy ; HLA Antigens/immunology ; Hematologic Neoplasms/therapy ; Humans ; Male ; Myeloablative Agonists/therapeutic use ; Transplantation Conditioning
    Chemical Substances HLA Antigens ; Myeloablative Agonists
    Language English
    Publishing date 2013-06
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 1474865-4
    ISSN 1523-6536 ; 1083-8791
    ISSN (online) 1523-6536
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2013.04.006
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