26 results on '"O’Doherty, Una"'
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2. Increased Proliferative Drive of Lymphocytes in Sickle Cell Disease
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Ginda, Ashley, Zhang, Jingyue, Meng, Wenzhao, Kearns, Charlotte, Weissman, Samuel, Swiggard, Liam, Richards, Clarice, Moore, Jeffrey, Murter, Melissa, Luning Prak, Eline T., and O'Doherty, Una
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Introduction
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- 2023
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3. Clinical use of lentiviral vectors
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Milone, Michael and O’Doherty, Una
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Viral vectors provide an efficient means for modification of eukaryotic cells, and their use is now commonplace in academic laboratories and industry for both research and clinical gene therapy applications. Lentiviral vectors, derived from the human immunodeficiency virus, have been extensively investigated and optimized over the past two decades. Third-generation, self-inactivating lentiviral vectors have recently been used in multiple clinical trials to introduce genes into hematopoietic stem cells to correct primary immunodeficiencies and hemoglobinopathies. These vectors have also been used to introduce genes into mature T cells to generate immunity to cancer through the delivery of chimeric antigen receptors (CARs) or cloned T-cell receptors. CAR T-cell therapies engineered using lentiviral vectors have demonstrated noteworthy clinical success in patients with B-cell malignancies leading to regulatory approval of the first genetically engineered cellular therapy using lentiviral vectors. In this review, we discuss several aspects of lentiviral vectors that will be of interest to clinicians, including an overview of lentiviral vector development, the current uses of viral vectors as therapy for primary immunodeficiencies and cancers, large-scale manufacturing of lentiviral vectors, and long-term follow-up of patients treated with gene therapy products.
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- 2018
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4. Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia
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Aqui, Nicole and O'Doherty, Una
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Patients presenting with new or recurrent acute leukemia, particularly of the myeloid lineage, with WBC counts exceeding 100 × 109/L are often considered for leukocytapheresis, especially if they are experiencing symptoms of leukostasis. These symptoms are thought to occur because of blast aggregates and WBC thrombi in the circulation, which reduce blood flow. Leukostasis may cause various complications, including hyperviscosity syndrome, vascular occlusion resulting in intracranial hemorrhages and respiratory failure, and perivascular leukemic infiltrates. Leukostasis occurs more commonly with a high WBC count and with leukemias of monocytoid lineage such as acute myelomonocytic leukemia, which is a reflection of the nature of the leukemic blasts. Leukocytapheresis is used in an effort to quickly decrease a patient's circulating blast count, which can both prevent the development of leukostasis and provide symptomatic relief of leukostasis. However, the impact of leukocytapheresis on early- and long-term mortality is controversial, with several studies producing conflicting results. In this chapter, the pathophysiology of leukostasis, performance of leukocytapheresis, and efficacy of this treatment are reviewed.
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- 2014
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5. Comprehensive analysis of unique cases with extraordinary control over HIV replication
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Mendoza, Daniel, Johnson, Sarah A., Peterson, Bennett A., Natarajan, Ven, Salgado, Maria, Dewar, Robin L., Burbelo, Peter D., Doria-Rose, Nicole A., Graf, Erin H., Greenwald, Jamieson H., Hodge, Jessica N., Thompson, William L., Cogliano, Nancy A., Chairez, Cheryl L., Rehm, Catherine A., Jones, Sara, Hallahan, Claire W., Kovacs, Joseph A., Sereti, Irini, Sued, Omar, Peel, Sheila A., O'Connell, Robert J., O'Doherty, Una, Chun, Tae-Wook, Connors, Mark, and Migueles, Stephen A.
- Abstract
True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8+T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8+T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.
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- 2012
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6. Comprehensive analysis of unique cases with extraordinary control over HIV replication
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Mendoza, Daniel, Johnson, Sarah A., Peterson, Bennett A., Natarajan, Ven, Salgado, Maria, Dewar, Robin L., Burbelo, Peter D., Doria-Rose, Nicole A., Graf, Erin H., Greenwald, Jamieson H., Hodge, Jessica N., Thompson, William L., Cogliano, Nancy A., Chairez, Cheryl L., Rehm, Catherine A., Jones, Sara, Hallahan, Claire W., Kovacs, Joseph A., Sereti, Irini, Sued, Omar, Peel, Sheila A., O'Connell, Robert J., O'Doherty, Una, Chun, Tae-Wook, Connors, Mark, and Migueles, Stephen A.
- Abstract
True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8+ T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8+ T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.
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- 2012
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7. A novel monoclonal antibody against human Argonaute proteins reveals unexpected characteristics of miRNAs in human blood cells.
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Nelson, Peter T, De Planell-Saguer, Mariangels, Lamprinaki, Stella, Kiriakidou, Marianthi, Zhang, Paul, O'Doherty, Una, and Mourelatos, Zissimos
- Abstract
Argonaute (Ago) proteins bind to microRNA (miRNAs) and short interfering RNAs (siRNAs) and form the core components of effector complexes that mediate miRNA and siRNA function. Currently, there is a paucity of reliable antibodies against mammalian Ago proteins, thus precluding studies of endogenous Ago proteins from tissues. Here we report the development of 2A8, a novel anti-Ago monoclonal antibody that recognizes human and mouse Ago proteins and efficiently immunoprecipitates miRNAs. We report the characterization of 2A8 and its use to clone miRNAs from human brain and from preparations of human polymorphonuclear leukocytes (neutrophils), which revealed a prevalent miRNA with unusual features.
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- 2007
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8. Long HIV Type 1 Reverse Transcripts Can Accumulate Stably within Resting CD4+ T Cells While Short Ones Are Degraded
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Swiggard, William J., O'Doherty, Una, McGain, David, Jeyakumar, Deepa, and Malim, Michael H.
- Abstract
We utilized quantitative methods to compare the efficiency of reverse transcription and stability of viral DNA within resting and activated T cells. Highly purified resting CD4+ T cells and activated T cells from healthy donors were spinoculated with HIV-1YU-2, then cultured in conditions that maintain both the viability and the quiescence of the resting cells. Spreading infection was suppressed, then kinetic PCR was used to relate the rates of synthesis of short (strong-stop, RU5) and long (gag or U3-gag second strand transfer) viral DNA to the mean number of virions initially bound to each type of cell. As shown previously, activated cells support an initial burst of high-level reverse transcription, which is then followed by a ~ 10-fold decay in cDNA levels over 4.5 days. In resting T cells, although the synthesis of late reverse transcripts was initially ~ 1000-fold less efficient than in activated T cells, the number of these cDNAs per bound input virion rose 10-fold as culture was extended to 4.5 days. The number of late reverse transcripts remained constant for 3 days after the addition of efavirinez, reflecting enhanced stability. In contrast, the short strong-step reverse transcripts were mostly degraded. Thus, late HIV-1 reverse transcripts can accumulate stably in resting T cells in the absence of detectable T cell activation. Defining the underlying basis for the stabilization of late reverse transcripts, and their associated nucleoprotein complexes, may be pertinent to the accumulation of reservoirs of latent HIV-1 in patients, and could provide a target for future therapies.
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- 2004
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9. A Sensitive, Quantitative Assay for Human Immunodeficiency Virus Type 1 Integration
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O'Doherty, Una, Swiggard, William J., Jeyakumar, Deepa, McGain, David, and Malim, Michael H.
- Abstract
ABSTRACTQuantitative methods to measure human immunodeficiency virus type 1 (HIV-1) integration promise to be important tools in dissecting the mechanisms whereby latent reservoirs of provirus are established, most notably in the resting T cells of patients receiving antiretroviral therapy. Here we describe a fluorescence-monitored, nested PCR assay that is able to quantify the relatively rare integration events that occur within these cells. Following DNA extraction, a nonkinetic preamplification step is performed with primers that bind genomic Aluelements and HIV-1 gagsequences, under conditions where primers, deoxynucleoside triphosphates, and enzyme are not limiting. This is followed by a kinetic PCR that quantitates HIV-1 long terminal repeat sequences. A T-cell-based integration standard which reflects the randomness of HIV-1 integration is also described. The assay is 10 to 100 times more sensitive than previously reported quantitative AluPCR-based integration assays. It is specific for integration events, since no proviruses are detected in cells infected either in the presence of an integrase inhibitor or with an integrase-deficient virus. This method promises to provide important new insights into the processes underlying the accumulation and persistence of latent HIV-1 reservoirs and may eventually be useful clinically in monitoring the eradication of latent virus by novel therapies.
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- 2002
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10. cisExpression of DC-SIGN Allows for More Efficient Entry of Human and Simian Immunodeficiency Viruses via CD4 and a Coreceptor
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Lee, Benhur, Leslie, George, Soilleux, Elizabeth, O'Doherty, Una, Baik, Sarah, Levroney, Ernest, Flummerfelt, Karen, Swiggard, William, Coleman, Nicholas, Malim, Michael, and Doms, Robert W.
- Abstract
ABSTRACTDC-SIGN is a C-type lectin expressed on dendritic cells and restricted macrophage populations in vivo that binds gp120 and acts intransto enable efficient infection of T cells by human immunodeficiency virus type 1 (HIV-1). We report here that DC-SIGN, when expressed in ciswith CD4 and coreceptors, allowed more efficient infection by both HIV and simian immunodeficiency virus (SIV) strains, although the extent varied from 2- to 40-fold, depending on the virus strain. Expression of DC-SIGN on target cells did not alleviate the requirement for CD4 or coreceptor for viral entry. Stable expression of DC-SIGN on multiple lymphoid lines enabled more efficient entry and replication of R5X4 and X4 viruses. Thus, 10- and 100-fold less 89.6 (R5/X4) and NL4–3 (X4), respectively, were required to achieve productive replication in DC-SIGN-transduced Jurkat cells when compared to the parental cell line. In addition, DC-SIGN expression on T-cell lines that express very low levels of CCR5 enabled entry and replication of R5 viruses in a CCR5-dependent manner, a property not exhibited by the parental cell lines. Therefore, DC-SIGN expression can boost virus infection in cisand can expand viral tropism without affecting coreceptor preference. In addition, coexpression of DC-SIGN enabled some viruses to use alternate coreceptors like STRL33 to infect cells, whereas in its absence, infection was not observed. Immunohistochemical and confocal microscopy data indicated that DC-SIGN was coexpressed and colocalized with CD4 and CCR5 on alveolar macrophages, underscoring the physiological significance of these cisenhancement effects.
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- 2001
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11. Human Immunodeficiency Virus Type 1 Spinoculation Enhances Infection through Virus Binding
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O'Doherty, Una, Swiggard, William J., and Malim, Michael H.
- Abstract
ABSTRACTThe study of early events in the human immunodeficiency virus type 1 (HIV-1) life cycle can be limited by the relatively low numbers of cells that can be infected synchronously in vitro. Although the efficiency of HIV-1 infection can be substantially improved by centrifugal inoculation (spinoculation or shell vial methods), the underlying mechanism of enhancement has not been defined. To understand spinoculation in greater detail, we have used real-time PCR to quantitate viral particles in suspension, virions that associate with cells, and the ability of those virions to give rise to reverse transcripts. We report that centrifugation of HIV-1IIIBvirions at 1,200 × gfor 2 h at 25°C increases the number of particles that bind to CEM-SS T-cell targets by ~40-fold relative to inoculation by simple virus-cell mixing. Following subsequent incubation at 37°C for 5 h to allow membrane fusion and uncoating to occur, the number of reverse transcripts per target cell was similarly enhanced. Indeed, by culturing spinoculated samples for 24 h, ~100% of the target cells were reproducibly shown to be productively infected, as judged by the expression of p24gag. Because the modestgforces employed in this procedure were found to be capable of sedimenting viral particles and because CD4-specific antibodies were effective at blocking virus binding, we propose that spinoculation works by depositing virions on the surfaces of target cells and that diffusion is the major rate-limiting step for viral adsorption under routine in vitro pulsing conditions. Thus, techniques that accelerate the binding of viruses to target cells not only promise to facilitate the experimental investigation of postentry steps of HIV-1 infection but should also help to enhance the efficacy of virus-based genetic therapies.
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- 2000
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12. The Dendritic Cell-T Cell Milieu of the Lymphoid Tissue of the Tonsil Provides a Locale in Which SIV Can Reside and Propagate at Chronic Stages of Infection
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Hu, Jinjie, Miller, Christopher J., O'Doherty, Una, Marx, Preston A., and Pope, Melissa
- Abstract
Previous studies described the presence of numerous human immunodeficiency virus (HIV)-positive cells within and just beneath the mucosal surfaces of the tonsillar tissue of HIV-1-infected individuals. The viruspositive cells were most abundant in the dendritic cell (DC)-T cell rich areas of the lymphoepithelia lining the crypts, and consisted of multinucleated syncytia that contained DCs. This suggested that such cells within the tonsillar tissue might represent a site for chronic virus replication in infected individuals. Using the simian immunodeficiency virus (SIV)-macaque system, we chose to study further the viral distribution within the tonsillar tissue of animals infected via the vaginal route 8-10 months earlier. Our initial studies demonstrated that in situ hybridization (ISH)-positive DCs and T cells could be identified within the genital mucosa and draining lymph nodes of these infected animals even at this chronic stage of infection. Here we specifically examined the distal mucosa-associated lymphoid tissues of the tonsil. ISH-positive cells were mostly restricted to the DC-rich T cell areas of the underlying lymphoid tissue. However, T cells were the most commonly infected cell type and virus-positive cells were rarely found within the epithelia. In isolated cell suspensions, ISH-positive lymphocytes were often tightly associated with ISH-negative DCs, although few ISH-positive lymphocytes were often tightly associated with ISH-negative DCs, although few ISH-positive DCs could be identified within these clusters. Therefore, the naturally occurring DC-T cell milieu of the lymphoid tissue of the tonsil provides a locale in which SIV can reside and propagate on a chronic basis, even many months after the animals were infected by virus crossing the genital mucosa.
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- 1999
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13. Susceptibility of dendritic cells to HIV‐1 infection in vitro
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Cameron, Paul U., Lowe, Melinda G., Crowe, Suzanne M., O'Doherty, Una, Pope, Melissa, Gezelter, Stuart, and Steinman, Ralph M.
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We review recent work on the extent of HIV‐1 infection of dendritic cells (DCs) and the consequences of exposure to virus. The reported levels of infection of DCs from blood have varied from “explosive” to “undetectable.” The only study that used sorted DCs demonstrated little if any infectability, which may not be surprising given the very low levels of CD4 on the populations that were studied. HIV‐1‐pulsed, highly purified DCs function as potent antigen‐presenting cells during the mixed leukocyte reaction and responses to superantigens. At the same time that the HIV‐1‐pulsed DCs stimulate CD4+T cells in DC‐T clusters, the virus is transferred to the responding lymphocytes and a vigorous productive infection of the T cells takes place. This pool of transferable HIV‐1 is short lived in cultured human blood DCs and likely reflects the capacity of these cells to internalize and recycle vesicles in the endocytic pathway, as revealed with experiments using 0.1‐μm fluorescent latex beads. Current efforts are directed to analyzing the interaction of HIV‐1 with several populations of DCs that express higher levels of CD4. These include DCs studied in fresh, uncultured blood, as well as skin, thymus, and tonsil DCs. In each case, entry and reverse transcription of HIV‐1 are seen, but again, coculture with T cells is required for a productive infection to take place. We conclude that DCs could play a critical role in the pathogenesis of HIV‐1 infection, but that the interaction with CD4+T cells is a critical variable in analyzing the extent of productive infection and its consequences. J. Leukoc. Biol.56: 257–265; 1994.
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- 1994
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14. Efficient Interaction of HIV-1 with Purified Dendritic Cells via Multiple Chemokine Coreceptors
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Granelli-Piperno, Angela, Moser, Bernhard, Pope, Melissa, Chen, Dongling, Wei, Yang, Isdell, Frank, O'Doherty, Una, Paxton, William, Koup, Richard, Mojsov, Svetlana, Bhardwaj, Nina, Clark-Lewis, Ian, Baggiolini, Marco, and Steinman, Ralph M.
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HIV-1 actively replicates in dendritic cell (DC)-T cell cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that HIV-1 begins reverse transcription much more efficiently in DCs than T cells, even though T cells have higher levels of CD4 and gp120 binding. DCs isolated from skin or from blood precursors behave similarly. Several M-tropic strains and the T-tropic strain IIIB enter DCs efficiently, as assessed by the progressive formation of the early products of reverse transcription after a 90-min virus pulse at 37°C. However, few late gag-containing sequences are detected, so that active viral replication does not occur. The formation of these early transcripts seems to follow entry of HIV-1, rather than binding of virions that contain viral DNA. Early transcripts are scarce if DCs are exposed to virus on ice for 4 h, or for 90 min at 37°C, conditions which allow virus binding. Also the early transcripts once formed are insensitive to trypsin. The entry of a M-tropic isolates is blocked by the chemokine RANTES, and the entry of IIIB by SDF-1. RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors. Entry of M-tropic but not T-tropic virus is ablated in DCs from individuals who lack a functional CCR5 receptor. DCs express more CCR5 and CXCR4 mRNA than T cells. Therefore, while HIV-1 does not replicate efficiently in mature DCs, viral entry can be active and can be blocked by chemokines that act on known receptors for M- and T-tropic virus.
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- 1996
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15. Heavy metal protease takes a tiki torch to HIV assembly
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O’Doherty, Una and Freed, Eric
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The plasma membrane–associated metalloprotease TRABD2A degrades the HIV Gag polyprotein and restricts virion assembly.
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- 2019
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16. Quantitation of Integrated HIV Provirus by Pulsed-Field Gel Electrophoresis and Droplet Digital PCR
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Lada, Steven M., Huang, Karissa, VanBelzen, D. Jake, Montaner, Luis J., O'Doherty, Una, and Richman, Douglas D.
- Abstract
We utilized pulsed-field gel electrophoresis (PFGE) to purify high-molecular-weight DNA from HIV-infected cells. This purification, in combination with our previously described droplet digital PCR (ddPCR) assay, was used to develop a method to quantify proviral integrated HIV DNA free of lower-molecular-weight species of HIV DNA.
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- 2018
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17. More Efficient Exchange of Sickle Red Blood Cells Can be Achieved By Exchanging the Densest Red Blood Cells
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Thibodeaux, Suzanne, Irwin, Leah, Jamensky, Lita, Schell, Kevin, and O'Doherty, Una
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No relevant conflicts of interest to declare.
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- 2016
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18. More Efficient Exchange of Sickle Red Blood Cells Can be Achieved By Exchanging the Densest Red Blood Cells
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Thibodeaux, Suzanne, Irwin, Leah, Jamensky, Lita, Schell, Kevin, and O'Doherty, Una
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Background: In sickle cell disease, it is well established that cells containing two mutated hemoglobins (SS) are denser than cells containing wild-type hemoglobin. We asked whether we could more efficiently exchange red blood cells (RBCs) in sickle cell anemia patients by exploiting the denser property of RBCs containing hemoglobin SS compared to wild-type RBCs.
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- 2016
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19. Rapid Prediction of Peripheral Blood CD34 Counts Using a Multiple Regression Model Derived from Automated Hematology Analyzer Cell Population Data
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Porturas, Thomas, Sell, Mary, Irwin, Leah, O'Doherty, Una, and Villa, Carlos Hipolito
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No relevant conflicts of interest to declare.
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- 2015
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20. Rapid Prediction of Peripheral Blood CD34 Counts Using a Multiple Regression Model Derived from Automated Hematology Analyzer Cell Population Data
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Porturas, Thomas, Sell, Mary, Irwin, Leah, O'Doherty, Una, and Villa, Carlos Hipolito
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Background: Although peripheral blood CD34+ stem cell counts by flow cytometry correlate well with yields, the time, complexity, and cost associated with flow cytometry limits its utility. Rapid, cost-effective, surrogate predictors (with <1hr turnaround) would allow for same-visit analyses and alteration of collection and mobilization strategies, particularly for the optimal use of time-sensitive and costly agents such as plerixafor. We previously demonstrated that morphologic parameters of neutrophil-like cells measured by hematology analyzers correlated with CD34 counts. We aimed to improve these models by using multiple regression analyses on data from a common hematology analyzer.
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- 2015
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21. Stem Cell Mobilization With Plerixafor + G-CSF In Comparison To Cyclophosphamide + G-CSF and Time-To-Progression After Autologous Stem Cell Transplantation For Multiple Myeloma
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Garfall, Alfred L., Dougherty, Andrew, Vogl, Dan T., Weiss, Brendan M, Cohen, Adam D, Porter, David L., O'Doherty, Una, Mangan, Patricia, Cunningham, Kathleen, Siegel, Don L., and Stadtmauer, Edward A.
- Abstract
G-CSF in combination with either cyclophosphamide (G-Cy) or plerixafor (G-P) safely mobilizes hematopoietic stem cells of adequate quality and quantity for auto-SCT in patients with multiple myeloma. Few studies have examined the impact of mobilization regimen on post-transplant disease control, particularly since the availability of plerixafor.We retrospectively compared time-to-progression (TTP) after single melphalan-conditioned (140-200 mg/m2) auto-SCT in a single-institution cohort in which stem cells were mobilized with either cyclophosphamide 3 gm/m2 + G-CSF 10 mcg/kg/day x 10-14 days (G-Cy, n=93) or G-CSF 10 mcg/kg/day x 5-9 days with addition of plerixafor 240 mcg/kg/day starting on day 5 (G-P, n=55). Choice of mobilization regimen was according to physician preference. All patients had symptomatic multiple myeloma and had completed induction therapy with a regimen containing bortezomib and/or lenalidomide/thalidomide. Transplants conducted from January 2010 to May 2013, when commercially-available plerixafor was first used at our institution, were included in the analysis. Patients receiving tandem or salvage transplants and patients receiving investigational therapies in conjunction with transplant were excluded. Maintenance therapy was prescribed at the discretion of the treating physician. Progression was scored according to IMWG criteria.The G-Cy and G-P cohorts were well matched for age, gender, and baseline multiple myeloma prognostic factors (see table). Cytogenetic data and beta-2-microglobulin measurements were not consistently available at baseline. Patients receiving G-P were more likely to have a >60 day interval between mobilization and transplant (P<0.0001) and >1 year interval between diagnosis and transplant (P=0.05). At time of transplant, hemoglobin was lower in the G-Cy group (P=0.0003), and platelet count was lower in the G-P group (P=0.035). Renal function at time of transplant was similar between the two groups. Patients in the G-P group were more likely to have received dose-reduced melphalan (<200 mg/m2) (p=0.03). The G-P group had higher ALC at day +15, which has been reported previously as a favorable prognostic factor for progression-free and overall survival. Median follow-up was 22 months. TTP was significantly different in the two groups (p=0.0095, log-rank test); median TTP was 25 months in the G-Cy group vs. 13 months in the G-P group (see figure). The difference in TTP remained significant when patients were excluded from the analysis who were transplanted more than 1 year after diagnosis (median TTP 26 vs. 13 months, P=0.0136 by log-rank test) or who were transplanted more than 60 days after mobilization (TTP 25 vs 13 months, P=0.0017 by log-rank test). Other variables that were significantly correlated with inferior TTP included IgA isotype (p=0.022) and receipt of >1 induction regimen (p=0.0077). In a univariate Cox regression, mobilization with G-P was associated with a hazard ratio of 2.1 (95% CI 1.2-3.9, p=0.011) for progression. In a multivariate Cox regression incorporating presence of IgA isotype, receipt of >1 induction regimen, mobilization regimen, age at transplant, time from diagnosis to transplant, time from mobilization to transplant, receipt of reduced melphalan dose, creatinine/hemoglobin/platelet count at time of transplant, ALC on day +15, and receipt of maintenance therapy, the association between G-P and inferior TTP was preserved (hazard ratio 2.8, 95% CI 1.3-6.0, p=0.007). The only other statistically significant variable was receipt of >1 induction regimen (hazard ratio 2.3, 95% CI 1.3-4.4, p=0.008). Receipt of maintenance therapy had a protective effect that approached statistical significance (hazard ratio 0.58, 95% CI 0.33-1.03, P=0.065). There were no significant differences in overall survival between the G-Cy and G-P groups.Hematopoietic stem cell mobilization with G-P was associated with significantly shorter post-transplant TTP compared to G-Cy in this single-institution cohort of multiple myeloma patients. We cannot conclude whether this association is due to effects of the mobilization regimen or confounding variables not accounted for in our analysis. This association warrants examination in a larger, multi-institution cohort.Stadtmauer: Sanofi: Consultancy.
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- 2013
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22. Stem Cell Mobilization With Plerixafor + G-CSF In Comparison To Cyclophosphamide + G-CSF and Time-To-Progression After Autologous Stem Cell Transplantation For Multiple Myeloma
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Garfall, Alfred L., Dougherty, Andrew, Vogl, Dan T., Weiss, Brendan M, Cohen, Adam D, Porter, David L., O'Doherty, Una, Mangan, Patricia, Cunningham, Kathleen, Siegel, Don L., and Stadtmauer, Edward A.
- Abstract
G-CSF in combination with either cyclophosphamide (G-Cy) or plerixafor (G-P) safely mobilizes hematopoietic stem cells of adequate quality and quantity for auto-SCT in patients with multiple myeloma. Few studies have examined the impact of mobilization regimen on post-transplant disease control, particularly since the availability of plerixafor.
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- 2013
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23. The Optimal Timing for Stem Cell Collection After Induction Therapy for Patients with Multiple Myeloma
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Nazha, Aziz, Vogl, Dan T., O'Doherty, Una, Mangan, Patricia, Cunningham, Kathleen, Luger, Selina, Porter, David L., Schuster, Stephen J., Gardler, Marie, Sell, Mary, Siegel, Don L., and Stadtmauer, Edward A
- Abstract
High dose chemotherapy and stem cell transplant remains an integral part of the therapy for Multiple Myeloma patients under age of 70. The collection of sufficient number of stem cells for one or more transplant is however sometimes a challenge. Moreover, the optimal timing for stem cell collection after induction chemotherapies is controversial. The standard recommendation is for stem cell collection after 4–6 cycles of non-alkylator regimen, however studies to support this practice are limited.We conducted a retrospective analysis of 366 patients who were diagnosed with multiple myeloma and mobilized at the Hospital of University of Pennsylvania between January 2002 and December 2008. Patients who did not meet the initial inclusion criteria were those who had induction regimens containing an alkalytor agent or whose regimens were not well documented and were excluded from futher analysis (85). Every 4 cycles of any non-alkalytor agent was considered to be one treatment session for the purpose of this analysis. 245 patients received 1 or 2 treatment sessions and 36 received > 2. All patients were mobilized with either Cyclophosphamide/G-CSF (CY/G-CSF), Plerixafor/G-CSF (AMD/G-CSF), or G-CSF alone.The mean number of collected CD 34+ cells (CD 34+) was 9.22 × 106 CD34+/Kg in the patients who received 1 or 2 sessions and 6.87 × 1106 CD34+/Kg in the patients who received > 2 sessions (P= 0.005). The number of the patients who collected > 6 × 106 CD34+/Kg was 63%(153/246), 53%(19/36) respectively, (p= 0.005). The patients who mobilized with either CY/G-CSF or AMD/G-CSF collected higher number of CD34+ than the patients mobilized with G-CSF alone in both groups. (Table 1, 2.)The mean number of collected stem cells was 7.14 × 106 CD34+/Kg in the patients who received more than 2 sessions of different regimens and 6.26 × 106 CD34+/Kg in the patients who received > 2 sessions of the same regimen.The patients who mobilized after fewer than 8 cycles of non-alkylator agents (2 sessions) collected a higher number of CD 34+ than those with greater than 8 cycles. CY/G-CSF or AMD/G-CSF are similar and superior to G-CSF alone in the more heavily treated patients. The patients who received multiple sessions of the same regimen have similar outcome compared to those who received multiple different regimens suggesting that the duration of the treatment may impact stem cell collection more than the content of the regimen. Prospective studies in this regards are warranted.No relevant conflicts of interest to declare.
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- 2010
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24. The Optimal Timing for Stem Cell Collection After Induction Therapy for Patients with Multiple Myeloma
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Nazha, Aziz, Vogl, Dan T., O'Doherty, Una, Mangan, Patricia, Cunningham, Kathleen, Luger, Selina, Porter, David L., Schuster, Stephen J., Gardler, Marie, Sell, Mary, Siegel, Don L., and Stadtmauer, Edward A
- Abstract
Abstract 2252
- Published
- 2010
- Full Text
- View/download PDF
25. Plerixafor and G-CSF Versus Cyclophosphamide and G-CSF for Stem Cell Mobilization in Patients with Multiple Myeloma.
- Author
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Nazha, Aziz, Cook, Rachel, Vogl, Dan T., Mangan, Patricia A., Hummel, Kimberly, Cunningham, Kathleen, Luger, Selina, Porter, David, Schuster, Stephen J., O'Doherty, Una, Sell, Mary, Siegel, Don L., and Stadtmauer, Edward A.
- Abstract
High dose melphalan and autologus stem cell transplant remains an effective treatment for patients with either early or refractory multiple myeloma (MM). Collection of sufficient numbers of stem cells for more than one transplant is optimal. G-CSF with chemotherapy, particularly cyclophosphamide (CY/G-CSF), has been a widely used and effective regimen for stem cell collection in MM. Plerixafor, a CXCR4 antagonist, when combined with G-CSF has been shown in a large randomized clinical trial to be superior to G-CSF alone. A comparison of plerixifor/G-CSF to CY/G-CSF is presented here.We performed a single institution retrospective analysis of 365 patients with MM who underwent stem cell mobilization and harvest at the University of Pennsylvania Abramson Cancer Center from January 2002 to December 2007. All patients were harvested early in the course of their disease. 76 patients were excluded from this analysis (23 had incomplete data on induction regimen, 19 had incomplete data on stem cell collection, 16 had incomplete data on mobilization regimen, 10 underwent allogeneic transplants, 2 had bone marrow rather than peripheral blood harvests, 2 had stem cells collected at an outside institution, 2 had chemotherapy mobilization other than CY and 2 had medical complications prior to harvest and after mobilization). Therefore, 289 patients were included in the analysis; 16 received plerixafor/G-CSF, 198 received CY/G-CSF, and 75 received G-CSF alone.The median number of collected stem cells was 7.95 × 106 CD34+/kg in plerixafor/G-CSF group, 7.7 × 106 CD34+/kg in Cy/G-CSF group and 4.5 × 106 CD34+/kg in G-CSF alone group. The median number of apheresis days was 2 days, 2 days and 4 days respectively. The percentage of the patients who collected ≥ 6 × 106 CD34+/kg in < 3 apheresis was 63% (10/16), 62% (123/198) and 19% (14/75) respectively. The percentage of the patients who collected ≥ 6 × 106CD34+/kg <5 apheresis was 81% (13/16), 69% (136/198) and 23% (17/75) respectively. The mean CD34+/kg collected erither after CY/G-CSF or plerixafor/G-CSF was higher than G-CSF alone (p<0.0001 for each analysis).This analysis suggests that plerixafor/G-CSF and CY/G-CSF mobilization result in similar and adequate stem cell harvest numbers for autologous stem cell transplantation for MM. Both approaches are superior to G-CSF alone. The choice of plerixafor/G-CSF vs CY/G-CSF for stem cell mobilization will therefore depend on further analysis of the relative costs, toxicities and long term outcome of these regimens.Stadtmauer: genzyme: Consultancy.
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- 2009
- Full Text
- View/download PDF
26. Plerixafor and G-CSF Versus Cyclophosphamide and G-CSF for Stem Cell Mobilization in Patients with Multiple Myeloma.
- Author
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Nazha, Aziz, Cook, Rachel, Vogl, Dan T., Mangan, Patricia A., Hummel, Kimberly, Cunningham, Kathleen, Luger, Selina, Porter, David, Schuster, Stephen J., O'Doherty, Una, Sell, Mary, Siegel, Don L., and Stadtmauer, Edward A.
- Abstract
Abstract 2146
- Published
- 2009
- Full Text
- View/download PDF
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