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Pathway-centric generalizable computational framework uncovers pathway markers governing chemoresistance across cancers

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TitleInfo
Title
Pathway-centric generalizable computational framework uncovers pathway markers governing chemoresistance across cancers
Name (type = personal)
NamePart (type = family)
Epsi
NamePart (type = given)
Nusrat
NamePart (type = date)
1990
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Epsi, Nusrat, 1990-
Role
RoleTerm (authority = RULIB); (type = text)
author
Name (type = personal)
NamePart (type = family)
Mitrofanova
NamePart (type = given)
Antonina
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Antonina Mitrofanova
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Srinivasan
NamePart (type = given)
Shankar
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Shankar Srinivasan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Coffman
NamePart (type = given)
Frederick
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Frederick Coffman
Affiliation
Advisory Committee
Role
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internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
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NamePart
School of Health Professions
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school
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Text
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theses
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2020
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2020-08
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract
Background: Despite recent advances in discovering a wide array of novel chemotherapy agents, identification of patients with poor and favorable treatment response prior to treatment administration remains a major challenge in clinical oncology and cancer management.

Methods: We have developed a genome-wide systematic computational framework to uncover an interplay between transcriptomic and epigenomic mechanisms that elucidate the complexity of chemotherapy response in cancer patients. Our approach integrates transcriptomic (i.e., mRNA expression) and epigenomic (i.e., DNA methylation) patient profiles to uncover molecular pathways with significant alterations on transcriptomic and epigenomic levels that can distinguish favorable from poor treatment response.
Results: We have tested our approach on patients with lung adenocarcinoma who received a carboplatin and paclitaxel combination chemotherapy (i.e., carboplatin-paclitaxel), a standard-of-care for treating advanced lung cancer. Our integrative approach identified seven molecular pathways with significant alterations on transcriptomic and epigenomic levels that distinguish favorable from poor carboplatin-paclitaxel response, including chemokine receptors bind chemokines, mRNA splicing, G alpha (s) signalling events, immune network for IgA production, etc. We have demonstrated that these pathways can classify patients based on their risk to developing carboplatin- paclitaxel resistance in an independent patient cohort (log-rank p-value = 0.0081) and their predictive ability is independent of and is not affected by (i) signatures of lung cancer aggressiveness, and (ii) commonly utilized covariates, such as age, gender, and disease stage at diagnosis (adjusted hazard ratio = 14.0). To demonstrate generalizability of our approach, we have applied our algorithm across additional chemotherapy regimens (i.e., cisplatin-vinorelbine, oxaliplatin-fluorouracil) and cancer types (i.e., lung squamous cell carcinoma, and colorectal adenocarcinoma); and have demonstrated our method’s ability to accurately predict patients’ treatment response.
Conclusions: We propose that our approach can be utilized to identify transcriptomic and epigenomic altered pathways implicated in primary chemoresponse and effectively classify patients who would benefit from specific chemotherapy regimens or are at risk of resistance, which will significantly improve personalized therapeutic strategies and informed clinical decision making.
Subject (authority = local)
Topic
pathCHEMO
Subject (authority = RUETD)
Topic
Biomedical Informatics
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_11022
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application/pdf
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text/xml
Extent
1 online resource (ix, 79 pages)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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TitleInfo
Title
School of Health Professions ETD Collection
Identifier (type = local)
rucore10007400001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-1f56-7885
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Epsi
GivenName
Nusrat
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-06-22 17:22:42
AssociatedEntity
Name
Nusrat Epsi
Role
Copyright holder
Affiliation
Rutgers University. School of Health Professions
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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2020-07-08T10:37:27
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2020-07-08T10:37:27
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