scholarly journals The meninges enhance leukemia survival in cerebral spinal fluid

2019 ◽  
Author(s):  
Patrick Basile ◽  
Leslie M. Jonart ◽  
Maryam Ebadi ◽  
Kimberly Johnson ◽  
Morgan Kerfeld ◽  
...  
Keyword(s):  
Cerebral Spinal Fluid ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Meningeal Cells ◽  
Short And Long Term

AbstractCentral nervous system (CNS) relapse is a common cause of treatment failure in patients with acute lymphoblastic leukemia (ALL) despite current CNS-directed therapies that are also associated with significant short and long-term toxicities. Herein, we showed that leukemia cells exhibit decreased proliferation, elevated reactive oxygen species (ROS), and increased cell death in CSF both in vitro and in vivo. However, interactions between leukemia and meningeal cells mitigated these adverse effects. This work expands our understanding of the pathophysiology of CNS leukemia and suggests novel therapeutic approaches for more effectively targeting leukemia cells in the CNS.

Lithium Restores Abnormal Platelet 5-HT Transport in Patients with Affective Disorders

1980 ◽  
Vol 136 (3) ◽  
pp. 235-238 ◽  
Author(s):  
Alec Coppen ◽  
Cynthia Swade ◽  
Keith Wood
Keyword(s):  
Blood Platelets ◽  
Lithium Treatment ◽  
Before And After ◽  
Short And Long Term ◽  
5 Ht Uptake ◽  
Depressive Patients ◽  
Rate Of Accumulation

SummaryKinetic analysis of the transport of 5-HT into the blood platelets of depressed patients and recovered depressive patients has shown that the rate of accumulation of 5-hydroxytryptamine (5-HT) is significantly decreased both before and after recovery from the illness. This abnormality is corrected by both short and long-term lithium treatment. As a corollary to these studies, the effect of lithium in vitro on 5-HT uptake has been studied and the results are opposite to those reported in vivo. These findings suggest that lithium acts indirectly, and possible mechanisms of its action are discussed.

scholarly journals Mesoporous Silicon: Short and Long Term, In Vitro and In Vivo Correlations of Cellular and Tissue Responses to Mesoporous Silicon Nanovectors (Small 9-10/2013)

Small ◽  
2013 ◽  
Vol 9 (9-10) ◽  
pp. 1721-1721
Author(s):  
Jonathan O. Martinez ◽  
Christian Boada ◽  
Iman K. Yazdi ◽  
Michael Evangelopoulos ◽  
Brandon S. Brown ◽  
...  
Keyword(s):  
Mesoporous Silicon ◽  
Tissue Responses ◽  
Short And Long Term

scholarly journals Long-term stable hematopoietic chimerism following marrow transplantation for acute lymphoblastic leukemia: a case report with in vitro marrow culture studies

Blood ◽  
1983 ◽  
Vol 62 (4) ◽  
pp. 869-872 ◽  
Author(s):  
JW Singer ◽  
A Keating ◽  
R Ramberg ◽  
R McGuffin ◽  
JE Sanders ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Host Cells ◽  
Marrow Graft ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Chimerism

Abstract This article describes the course of a patient who received an allogeneic marrow graft from his HLA-identical sister for acute lymphoblastic leukemia in second remission. In the second month after grafting, marrow aspirates showed the presence of 7%-10% lymphoblasts. In addition, cytogenetic examination indicated the persistence of host cells. Thereafter, the patient had morphologically normal marrow examinations, with no evidence for recurrent leukemia. In addition, stable hematopoietic chimerism in both the lymphoid and myeloid cell lines has persisted for over 5 yr. Between 20% and 50% of phytohemagglutinin-stimulated peripheral blood mononuclear cells were host-derived on repeated studies. A marrow sample 4 yr after transplantation was established in long-term culture and produced 2% host granulocyte-macrophage colonies at its inception, but 24% host colonies by week 4. Despite this persistent chimerism, no in vitro or in vivo abnormalities of hematopoiesis have been detected.

scholarly journals Exploring Mechanistic Toxicity of Mixtures Using PBPK Modeling and Computational Systems Biology

2019 ◽  
Vol 174 (1) ◽  
pp. 38-50 ◽  
Author(s):  
Patricia Ruiz ◽  
Claude Emond ◽  
Eva D McLanahan ◽  
Shivanjali Joshi-Barr ◽  
Moiz Mumtaz
Keyword(s):  
Risk Assessment ◽  
Current Knowledge ◽  
Pbpk Modeling ◽  
Toxic Substances ◽  
Computational Systems Biology ◽  
Stream Data ◽  
Short And Long Term

Abstract Mixtures risk assessment needs an efficient integration of in vivo, in vitro, and in silico data with epidemiology and human studies data. This involves several approaches, some in current use and others under development. This work extends the Agency for Toxic Substances and Disease Registry physiologically based pharmacokinetic (PBPK) toolkit, available for risk assessors, to include a mixture PBPK model of benzene, toluene, ethylbenzene, and xylenes. The recoded model was evaluated and applied to exposure scenarios to evaluate the validity of dose additivity for mixtures. In the second part of this work, we studied toluene, ethylbenzene, and xylene (TEX)-gene-disease associations using Comparative Toxicogenomics Database, pathway analysis and published microarray data from human gene expression changes in blood samples after short- and long-term exposures. Collectively, this information was used to establish hypotheses on potential linkages between TEX exposures and human health. The results show that 236 genes expressed were common between the short- and long-term exposures. These genes could be central for the interconnecting biological pathways potentially stimulated by TEX exposure, likely related to respiratory and neuro diseases. Using publicly available data we propose a conceptual framework to study pathway perturbations leading to toxicity of chemical mixtures. This proposed methodology lends mechanistic insights of the toxicity of mixtures and when experimentally validated will allow data gaps filling for mixtures’ toxicity assessment. This work proposes an approach using current knowledge, available multiple stream data and applying computational methods to advance mixtures risk assessment.

scholarly journals CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 381-390
Author(s):  
J Kurtzberg ◽  
TA Waldmann ◽  
MP Davey ◽  
SH Bigner ◽  
JO Moore ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Therapeutic Approaches ◽  
Myeloid Leukemias ◽  
Cell Gene ◽  
In Vitro Data

Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic cell phenotype. The CD7+, CD4-, CD8- phenotype was associated with a distinct clinical entity with those affected predominantly male (either less than 35 years or greater than 65 years of age), with frequent mediastinal and/or thymic masses, skin and CNS disease, high peripheral WBC counts, and bone marrow blasts that were morphologically L1 or not ascribable to a specific lineage. These patients did not respond to conventional chemotherapeutic regimens for either acute lymphoid or myeloid leukemias. No common karyotype or T-cell gene rearrangement pattern could be defined. Importantly, seven of eight patient's leukemic cells studied were capable of multilineage (myeloid, erythroid, monocytoid, megakaryocytoid, and lymphoid) differentiation in vitro. Data is presented suggesting that CD7+, CD4-, CD8- leukemias, in many instances, are leukemias of immature hematopoietic cells. The development of novel therapeutic approaches to this form of leukemia will be necessary to alter its poor prognosis.

scholarly journals Results of CoALL 07-03 study childhood ALL based on combined risk assessment by in vivo and in vitro pharmacosensitivity

2019 ◽  
Vol 3 (22) ◽  
pp. 3688-3699 ◽  
Author(s):  
Franziska Schramm ◽  
Udo zur Stadt ◽  
Martin Zimmermann ◽  
Norbert Jorch ◽  
Arnulf Pekrun ◽  
...  
Keyword(s):  
Drug Testing ◽  
Drug Response ◽  
Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Childhood All ◽  
Long Term Outcome ◽  
Key Points

Key Points Report of the long-term outcome of children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03. Lack of correlation between in vitro and in vivo drug response as well as a lower predictive value of in vitro drug testing.

Live Cell Imaging Captures Immune Cell-Mediated Killing of Precursor-B Acute Lymphoblastic Leukemia Cells Targeted with Anti-CD19 (Medi-551) Antibodies: Support for Macrophage and NK Cell In Vivo Activity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1522-1522
Author(s):  
Ksenia Matlawska-Wasowska ◽  
Dennis Cook ◽  
Samuel R. Stevens ◽  
Elizabeth K. Ward ◽  
Ronald Herbst ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Lymphoblastic Leukemia ◽  
Live Cell ◽  
Fluorescent Imaging ◽  
Leukemia Cells ◽  
Strong Activity ◽  
Effector Cells

Abstract Abstract 1522 Precursor-B acute lymphoblastic leukemia (pre-B ALL) is the most common malignancy in children and can be cured in a majority of patients. However, cure remains elusive in approximately 20% of patients for reasons that are not well understood. Importantly, survivors commonly develop morbidities that result from dose-intensified treatment with cytotoxic drugs. Here, we investigate the tumoricidal effects of a novel humanized anti-CD19 monoclonal antibody (Medi-551). The a-fucosylated form of this antibody has increased affinity to human FcgammaRIII (CD16) receptor, present on the surface of NK cells and macrophages, mediating antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Medi-551/CD19 complexes internalize slowly and thus remain accessible for effector cells for prolonged periods. We evaluated in vitro ADCC and ADCP activities of primary human NK cells and macrophages (effector cells) against four pre-B ALL cell lines (697, Nalm 6, MHH-Call 3, RS 4;11), as well as freshly isolated patient blasts. We report results of live cell fluorescent imaging studies, characterizing the formation of immunological synapses between Medi 551-bound target leukemia cells and effector cells, as well as the kinetics of both NK-mediated killing and macrophage phagocytosis. The number of the CD19 receptors present on the cell surface is shown to be a factor in effector-mediated killing of Medi-551 targeted leukemia cells. Further, genetic polymorphisms in FcgammaRIII (158 F/V, V/V or F/F) affected in vitro ADCC and ADCP activities with FcgammaRIII 158 V homo- or heterozygotes showing the strongest activity. We also evaluated the efficacy of Medi-551 in a human pre-B ALL murine xenograft model. SCID mice were engrafted with 697 pre-B ALL cells and received either vehicle alone or Medi-551 (3 mg/kg; twice weekly for a total of 5 doses); treatment was started at day 5 after engraftment. Medi-551 treatment markedly lowered disease burden in blood, liver and bone marrow. The lack of cure is consistent with impaired roles for NK cells in this model, since murine NK cells lack FcgammaRIV. Experiments are in progress to improve the model through adoptive transfer of human NK cells. Taken together, the in vitro and in vivo data show that Medi-551 has strong activity against pre-B ALL and support a move forward to early phase trials in this disease. Disclosures: No relevant conflicts of interest to declare.

The Poison Oligonucleotide F10 Is Efficiently Taken Up By, and Highly Effective Against, Acute Lymphoblastic Leukemia While Sparing Normal Hematopoietic Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2674-2674
Author(s):  
Timothy Pardee ◽  
Jamie Jennings-Gee ◽  
Kristin Stadelman ◽  
David L. Caudell ◽  
William Gmeiner
Keyword(s):  
Board Of Directors ◽  
Median Survival ◽  
Survival Benefit ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Advisory Committees ◽  
Previously Treated ◽  
Human Hscs

Abstract The development of imatinib to target the BCR-ABL kinase in chronic phase (CP) CML has changed the natural history of the disease. This success generated much enthusiasm for the approach in the more genetically complex acute lymphoblastic leukemia (ALL). Unfortunately, the durable responses seen in CP CML are not reproduced in BCR-ABL positive ALL. Indeed, all previous attempts to target a single oncogenic pathway in acute leukemias have resulted in transient responses with frequent relapse. An alternative approach is to use agents that target “final common pathways”, i.e. processes that must be accomplished to produce additional leukemia cells regardless of driving mutations. In this paradigm, agents are not judged by differential expression of a target, but by the degree of differential uptake. One pathway to exploit is the known increased uptake of oligonucleotides by ALL cells. F10 is a poison deoxy-oligonucleotide that is a 10mer of the thymidylate synthase (TS) inhibitory 5-fluorouracil (5-FU) metabolite, 5-fluoro-2’-deoxyuridine-5’-O-monophosphate. We sought to determine the uptake and activity of F10 against preclinical ALL models. Using fluorescently labeled F10, we determined that uptake by the human ALL cell lines DG75 and SUP-B15 was rapid and had a profound temperature dependence consistent with an active process. Both cell lines demonstrated increased uptake compared to normal, lineage- depleted marrow cells from C57Bl/6 mice. Using a syngeneic, BCR-ABL-expressing murine ALL model, we confirmed rapid uptake of F10 in vivo. Furthermore, preliminary experiments suggested normal human HSCs have decreased uptake compared to primary patient samples. Consistent with this decreased uptake, F10 treatment did not alter the ability of human HSCs to engraft in immunodeficient mice. F10 treatment resulted in robust induction of apoptosis that could not be equaled by 100 fold more 5-FU. IC50 values for F10 against B6 ALL, Jurkat, DG75, Molt-4, CCRF-CEM, and SUP-B15 were in the picomolar to nanomolar range, with an average value of 2.15 nM (range 0.12 to 5.4 nM). For comparison we also tested 5-FU, doxorubicin, and cytarabine. In all cases, F10 was the most potent agent; over 1000 times more potent than 5-FU. In vivo, F10 treatment was associated with a significant increase in survival in a BCR-ABL driven, syngeneic ALL mouse model (p= 0.0001 by log rank test). Survival was dose-dependent, with median survival extended by 3, 9 or 15 days for 4, 6, or 9 doses, respectively. F10 also protected mice from leukemia-induced weight loss during and for several days after treatment. To confirm the in vivo activity of F10, we treated a separately derived syngeneic model expressing the T315I variant of BCR-ABL. As in the previous model, F10 significantly prolonged survival (p=0.0013). To further extend these results and confirm F10's activity against human ALL cells, we treated DG75, Jurkat, and SUP-B15 xenograft models. As in the murine models, F10 caused regression of disease with several animals cured and resulted in a significant survival benefit (p=0.0112). As the uptake and mechanism of action of F10 is unique we sought to determine the in vivo efficacy of F10 on ALL previously treated with cytarabine. When mice injected with previously treated ALL cells were treated with cytarabine a median survival benefit of only one day (11 vs 12 days) was observed. In contrast F10 treatment resulted in a median survival of 31 days, similar to the survival seen in previously untreated ALL. F10 exposure results in trapped topoisomerase I (Topo1) cleavage complexes in vitro. To determine if this occurs in vivo, we treated leukemic C57Bl/6 or nude mice harboring ALL xenografts with F10. After 24 hours, leukemia cells were harvested and assayed for trapped Topo1 complexes. F10 treatment resulted in detectable trapped Topo1 complexes in both the xenograft and syngeneic models. In summary, F10 exhibited remarkable activity against human and murine ALL cells in vitro and in vivo by inducing apoptosis and trapping Topo1 complexes. These data demonstrate agents that target “final common pathways” but with differential uptake can be safe and effective, even against genetically complex and aggressive leukemias. Disclosures: Pardee: Salzburg Therapeutics: Membership on an entity’s Board of Directors or advisory committees. Gmeiner:Salzburg Therapeutics: Membership on an entity’s Board of Directors or advisory committees.

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