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Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia./
Author:	Clapp, Geoffrey Douglas.
Description:	1 online resource (139 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
Contained By:	Dissertation Abstracts International77-12B(E).
Subject:	Applied mathematics. -
Online resource:	click for full text (PQDT)
ISBN:	9781339866574

Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia.
Clapp, Geoffrey Douglas.

Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia. - 1 online resource (139 pages)

Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.

Thesis (Ph.D.)

Includes bibliographical references

This item is not available from ProQuest Dissertations & Theses.

Although tyrosine kinase inhibitors (TKIs) such as imatinib have transformed chronic myelogenous leukemia (CML) into a chronic condition, these therapies are not curative in the majority of cases. Most patients must continue TKI therapy indefinitely, a requirement that is both expensive and that compromises a patient's quality of life. While TKIs are known to reduce leukemic cells' proliferative capacity and to induce apoptosis, their effects on leukemic stem cells, the immune system, and the microenvironment are not fully understood. A more complete understanding of their global therapeutic effects would help us to identify any limitations of TKI monotherapy and to address these issues through novel combination therapies.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9781339866574Subjects--Topical Terms:

1069907
Applied mathematics.
Index Terms--Genre/Form:

554714
Electronic books.

Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia.
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245 1 0 $a Applying mathematical models to study the role of the immune system in chronic myelogenous leukemia.
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300 $a 1 online resource (139 pages)
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500 $a Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
500 $a Adviser: Doron Levy.
502 $a Thesis (Ph.D.) $c University of Maryland, College Park $d 2016.
504 $a Includes bibliographical references
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Although tyrosine kinase inhibitors (TKIs) such as imatinib have transformed chronic myelogenous leukemia (CML) into a chronic condition, these therapies are not curative in the majority of cases. Most patients must continue TKI therapy indefinitely, a requirement that is both expensive and that compromises a patient's quality of life. While TKIs are known to reduce leukemic cells' proliferative capacity and to induce apoptosis, their effects on leukemic stem cells, the immune system, and the microenvironment are not fully understood. A more complete understanding of their global therapeutic effects would help us to identify any limitations of TKI monotherapy and to address these issues through novel combination therapies.
520 $a Mathematical models are a complementary tool to experimental and clinical data that can provide valuable insights into the underlying mechanisms of TKI therapy. Previous modeling efforts have focused on CML patients who show biphasic and triphasic exponential declines in BCR-ABL ratio during therapy. However, our patient data indicates that many patients treated with TKIs show fluctuations in BCR-ABL ratio yet are able to achieve durable remissions. To investigate these fluctuations, we construct a mathematical model that integrates CML with a patient's autologous immune response to the disease. In our model, we define an immune window, which is an intermediate range of leukemic concentrations that lead to an effective immune response against CML. While small leukemic concentrations provide insufficient stimulus, large leukemic concentrations actively suppress a patient's immune system, thus limiting it's ability to respond. Our patient data and modeling results suggest that at diagnosis, a patient's high leukemic concentration is able to suppress their immune system. TKI therapy drives the leukemic population into the immune window, allowing the patient's immune cells to expand and eventually mount an efficient response against the residual CML. This response drives the leukemic population below the immune window, causing the immune population to contract and allowing the leukemia to partially recover. The leukemia eventually reenters the immune window, thus stimulating a sequence of weaker immune responses as the two populations approach equilibrium.
520 $a We hypothesize that a patient's autologous immune response to CML may explain the fluctuations in BCR-ABL ratio that are regularly seen during TKI therapy. These fluctuations may serve as a signature of a patient's individual immune response to CML. By applying our modeling framework to patient data, we are able to construct an immune profile that can then be used to propose patient-specific combination therapies aimed at further reducing a patient's leukemic burden. Our characterization of a patient's anti-leukemia immune response may be especially valuable in the study of drug resistance, treatment cessation, and combination therapy.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2018
538 $a Mode of access: World Wide Web
650 4 $a Applied mathematics. $3 1069907
650 4 $a Medicine. $3 644133
650 4 $a Immunology. $3 592892
655 7 $a Electronic books. $2 local $3 554714
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690 $a 0564
690 $a 0982
710 2 $a ProQuest Information and Learning Co. $3 1178819
710 2 $a University of Maryland, College Park. $b Applied Mathematics and Scientific Computation. $3 1180467
773 0 $t Dissertation Abstracts International $g 77-12B(E).
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10128656 $z click for full text (PQDT)