Publications by authors named "Jeremy D Rubinstein"

12 Publications

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Treatment of posttransplant lymphoproliferative disorder with poor prognostic features in children and young adults: Short-course EPOCH regimens are safe and effective.

Pediatr Blood Cancer 2021 May 21:e29126. Epub 2021 May 21.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.
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http://dx.doi.org/10.1002/pbc.29126DOI Listing
May 2021

Tolerance of dinutuximab therapy for treatment of high-risk neuroblastoma in two patients with end-stage renal disease on dialysis.

Pediatr Blood Cancer 2021 Mar 31;68(3):e28852. Epub 2020 Dec 31.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Autologous hematopoietic cell transplant (aHCT) has a significant survival advantage in patients with high-risk (HR) neuroblastoma. Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication and may result in chronic renal disease leading to delay in subsequent posttransplant therapy and limitations of treatment options. Dinutuximab represents an important therapeutic advance in the treatment of pediatric HR neuroblastoma, but historically has not been administered in patients with GFR < 60 mL/m /min. Here, we present the safe outcome of dinutuximab administration while on renal replacement therapy in two cases of HR neuroblastoma with end-stage renal disease secondary to TA-TMA.
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http://dx.doi.org/10.1002/pbc.28852DOI Listing
March 2021

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.

Blood Adv 2020 11;4(22):5745-5754

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, OH.

BK polyomavirus (BKPyV) infection is a major complication of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT). Treatment options are limited, poorly effective, and have significant toxicities. Cellular therapy using T cells directed against BKPyV is an emerging therapy, and we report efficacy in controlling BKPyV-associated disease in highly immunocompromised patients. Virus-specific T cells (VSTs) against BKPyV were manufactured using either blood from the patient's stem cell donor (donor-derived VSTs) or from unrelated donors (third-party VSTs). VSTs were used to treat BKPyV in 38 HSCT recipients and 3 SOT recipients between June 2017 and December 2019. Overall response rate was 86% in patients treated for BK viremia, 100% in patients treated for hemorrhagic cystitis, and 87% in patients treated for both BK viremia and hemorrhagic cystitis. No infusional toxicity, de novo graft-versus-host disease, or rejection of the organ occurred attributable to the VST infusion. BKPyV-specific immune responses were demonstrated by interferon-γ production by peripheral blood mononuclear cells postinfusion in response to BKPyV antigens. VSTs are a safe and potentially effective strategy to treat BKPyV and associated symptoms in recipients of HSCT and SOT. Cellular therapy should be considered for all patients with BKPyV and underlying immune suppression at risk of complications. This trial was registered at www.clinicaltrials.gov as #NCT02532452.
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http://dx.doi.org/10.1182/bloodadvances.2020003073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686882PMC
November 2020

Chimeric Antigen Receptor T Cell Therapy in Patients with Multiply Relapsed or Refractory Extramedullary Leukemia.

Biol Blood Marrow Transplant 2020 11 2;26(11):e280-e285. Epub 2020 Aug 2.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Autologous CD19-directed chimeric antigen receptor T lymphocyte (CAR-T) therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B cell precursor acute lymphoblastic leukemia (B-ALL). Experience using this therapy in pediatric patients with extramedullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). We infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel. Six patients had isolated central nervous system (CNS) leukemia, and 1 patient had an isolated testicular relapse. An initial complete response was seen in all patients, with 5 patients remaining in CAR-T-induced remission at a median of 18 months from first infusion. Reversible ICANS was seen in 1 patient with CNS leukemia. Durable B cell aplasia occurred in 3 patients, with a median time to B cell recovery of 6.5 months in the other patients. These data suggest that CAR-T therapy has promising safety and efficacy in treating EM leukemia, although definitive conclusions are limited by the small size of the cohort and limited follow-up period.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.036DOI Listing
November 2020

Chimeric antigen receptor T-cell therapy in patients with neurologic comorbidities.

Pediatr Blood Cancer 2020 04 4;67(4):e28199. Epub 2020 Feb 4.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Chimeric antigen receptor T cells (CAR-T) are an effective and potentially durable treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR-T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life-threatening. Providers have exercised caution in providing CAR-T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR-T cell infusion after bridging therapy with conventional chemotherapy.
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http://dx.doi.org/10.1002/pbc.28199DOI Listing
April 2020

A case of submandibular desmoplastic small round cell tumor: Diagnostic and management approaches to an atypical presentation of a rare tumor.

Pediatr Blood Cancer 2020 04 11;67(4):e28178. Epub 2020 Jan 11.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

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http://dx.doi.org/10.1002/pbc.28178DOI Listing
April 2020

EBV-directed viral-specific T-lymphocyte therapy for the treatment of EBV-driven lymphoma in two patients with primary immunodeficiency and DNA repair defects.

Pediatr Blood Cancer 2020 03 18;67(3):e28126. Epub 2019 Dec 18.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.
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http://dx.doi.org/10.1002/pbc.28126DOI Listing
March 2020

Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation.

Dev Cell 2013 Dec;27(6):607-20

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address:

Megakaryocyte morphogenesis employs a "hypertrophy-like" developmental program that is dependent on P-TEFb kinase activation and cytoskeletal remodeling. P-TEFb activation classically occurs by a feedback-regulated process of signal-induced, reversible release of active Cdk9-cyclin T modules from large, inactive 7SK small nuclear ribonucleoprotein particle (snRNP) complexes. Here, we have identified an alternative pathway of irreversible P-TEFb activation in megakaryopoiesis that is mediated by dissolution of the 7SK snRNP complex. In this pathway, calpain 2 cleavage of the core 7SK snRNP component MePCE promoted P-TEFb release and consequent upregulation of a cohort of cytoskeleton remodeling factors, including α-actinin-1. In a subset of human megakaryocytic leukemias, the transcription factor GATA1 undergoes truncating mutation (GATA1s). Here, we linked the GATA1s mutation to defects in megakaryocytic upregulation of calpain 2 and of P-TEFb-dependent cytoskeletal remodeling factors. Restoring calpain 2 expression in GATA1s mutant megakaryocytes rescued normal development, implicating this morphogenetic pathway as a target in human leukemogenesis.
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http://dx.doi.org/10.1016/j.devcel.2013.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892434PMC
December 2013

Cyclic AMP signaling inhibits megakaryocytic differentiation by targeting transcription factor 3 (E2A) cyclin-dependent kinase inhibitor 1A (CDKN1A) transcriptional axis.

J Biol Chem 2012 Jun 17;287(23):19207-15. Epub 2012 Apr 17.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22903, USA.

Signaling via the intracellular second messenger cyclic AMP (cAMP) has long been implicated in the repression of megakaryocytic differentiation. However, the mechanisms by which cAMP signaling impairs megakaryopoiesis have never been elucidated. In a human CD34(+) cell culture model, we show that the adenylyl cyclase agonist forskolin inhibits megakaryocytic differentiation in a protein kinase A-dependent manner. Using this system to screen for downstream effectors, we identified the transcription factor E2A as a key target in a novel repressive signaling pathway. Specifically, forskolin acting through protein kinase A-induced E2A down-regulation and enforced expression of E2A overrode the inhibitory effects of forskolin on megakaryopoiesis. The dependence of megakaryopoiesis on critical thresholds of E2A expression was confirmed in vivo in haploinsufficient mice and ex vivo using shRNA knockdown in human progenitors. Using a variety of approaches, we further identified p21 (encoded by CDKN1A) as a functionally important megakaryopoietic regulator residing downstream of E2A. These results thus implicate the E2A-CDKN1A transcriptional axis in the control of megakaryopoiesis and reveal the lineage-selective inhibition of this axis as a likely mechanistic basis for the inhibitory effects of cAMP signaling.
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http://dx.doi.org/10.1074/jbc.M112.366476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365953PMC
June 2012

Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells.

Mol Neurodegener 2008 Dec 29;3:21. Epub 2008 Dec 29.

Center for the Study of Neurodegenerative Diseases and Morris K, Udall Parkinson's Disease Research Center of Excellence, University of Virginia, Charlottesville, Virginia, USA.

Background: Parkinson's disease, the most common adult neurodegenerative movement disorder, demonstrates a brain-wide pathology that begins pre-clinically with alpha-synuclein aggregates ("Lewy neurites") in processes of gut enteric and vagal motor neurons. Rostral progression into substantia nigra with death of dopamine neurons produces the motor impairment phenotype that yields a clinical diagnosis. The vast majority of Parkinson's disease occurs sporadically, and current models of sporadic Parkinson's disease (sPD) can utilize directly infused or systemic neurotoxins.

Results: We developed a differentiation protocol for human SH-SY5Y neuroblastoma that yielded non-dividing dopaminergic neural cells with long processes that we then exposed to 50 nM rotenone, a complex I inhibitor used in Parkinson's disease models. After 21 days of rotenone, ~60% of cells died. Their processes retracted and accumulated ASYN-(+) and UB-(+) aggregates that blocked organelle transport. Mitochondrial movement velocities were reduced by 8 days of rotenone and continued to decline over time. No cytoplasmic inclusions resembling Lewy bodies were observed. Gene microarray analyses showed that the majority of genes were under-expressed. qPCR analyses of 11 mtDNA-encoded and 10 nDNA-encoded mitochondrial electron transport chain RNAs' relative expressions revealed small increases in mtDNA-encoded genes and lesser regulation of nDNA-encoded ETC genes.

Conclusion: Subacute rotenone treatment of differentiated SH-SY5Y neuroblastoma cells causes process retraction and partial death over several weeks, slowed mitochondrial movement in processes and appears to reproduce the Lewy neuritic changes of early Parkinson's disease pathology but does not cause Lewy body inclusions. The overall pattern of transcriptional regulation is gene under-expression with minimal regulation of ETC genes in spite of rotenone's being a complex I toxin. This rotenone-SH-SY5Y model in a differentiated human neural cell mimics changes of early Parkinson's disease and may be useful for screening therapeutics for neuroprotection in that disease stage.
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http://dx.doi.org/10.1186/1750-1326-3-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631511PMC
December 2008

Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues.

Biochim Biophys Acta 2009 Jan 10;1792(1):68-74. Epub 2008 Oct 10.

Center for the Study of Neurodegenerative Diseases, University of Virginia, Charlottesville, Virginia, USA.

We have studied sporadic Parkinson's disease (sPD) from expression of patient mitochondrial DNA (mtDNA) in neural cells devoid of their own mtDNA, the "cybrid" model. In spite of reproducing several properties of sPD brain, it remains unclear whether sPD cybrid cells reflect more complex sPD brain bioenergetic pathophysiology. We characterized and correlated respiration of intact sPD cybrid cells with electron transport chain (ETC) protein assembly, complex I ETC gene expression and ETC protein levels in sPD brain. We also assayed expression for multiple ETC genes coded by mtDNA and nuclear DNA (nDNA) in sPD cybrid cells and brain. sPD cybrid cells have reduced levels of mtDNA genes, variable compensatory normalization of mitochondrial gene expression and show robust correlations with mitochondrial ETC gene expression in sPD brains. Relationships among ETC protein levels predict impaired complex I-mediated respiration in sPD brain. That sPD cybrid cells and sPD brain samples show very correlated regulation of nDNA and mtDNA ETC transcriptomes suggests similar bioenergetic physiologies. We propose that further insights into sPD pathogenesis will follow elucidation of mechanisms leading to reduced mtDNA gene levels in sPD cybrids. This will require characterization of the abnormalities and dynamics of mtDNA changes propagated through sPD cybrids over time.
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http://dx.doi.org/10.1016/j.bbadis.2008.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2655102PMC
January 2009