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  1. Article ; Online: The reckoning of chromosomal instability: past, present, future.

    Lynch, Andrew / Bradford, Shermineh / Burkard, Mark E

    Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology

    2024  Volume 32, Issue 1, Page(s) 2

    Abstract: Quantitative measures of CIN are crucial to our understanding of its role in cancer. Technological advances have changed the way CIN is quantified, offering increased accuracy and insight. Here, we review measures of CIN through its rise as a field, ... ...

    Abstract Quantitative measures of CIN are crucial to our understanding of its role in cancer. Technological advances have changed the way CIN is quantified, offering increased accuracy and insight. Here, we review measures of CIN through its rise as a field, discuss considerations for its measurement, and look forward to future quantification of CIN.
    MeSH term(s) Humans ; Aneuploidy ; Chromosomal Instability ; Neoplasms/genetics
    Language English
    Publishing date 2024-02-17
    Publishing country Netherlands
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1161632-5
    ISSN 1573-6849 ; 0967-3849
    ISSN (online) 1573-6849
    ISSN 0967-3849
    DOI 10.1007/s10577-024-09746-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3873: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Classes of therapeutics to amplify the immune response.

    Hu, Yang / Burkard, Mark E

    Breast cancer research and treatment

    2021  Volume 191, Issue 2, Page(s) 277–289

    Abstract: Purpose: Conventional chemotherapies are a mainstay for metastatic breast cancers, though durable response is rare. Immunotherapies promise long-term responses thorough immune activation but have been underwhelming in breast cancer relative to other ... ...

    Abstract Purpose: Conventional chemotherapies are a mainstay for metastatic breast cancers, though durable response is rare. Immunotherapies promise long-term responses thorough immune activation but have been underwhelming in breast cancer relative to other cancer types. Here, we review the mechanisms of existing strategies including chemotherapies and how they may cause breast cancers to become immunogenic to identify potential biomarkers for combinations of conventional and immunotherapies.
    Conclusion: Mechanistic considerations should inform biomarker development and patient selection for therapeutic combinations of drugs to combine with immune-checkpoint inhibitors.
    MeSH term(s) Breast Neoplasms/drug therapy ; Female ; Humans ; Immunity ; Immunotherapy
    Language English
    Publishing date 2021-11-17
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 604563-7
    ISSN 1573-7217 ; 0167-6806
    ISSN (online) 1573-7217
    ISSN 0167-6806
    DOI 10.1007/s10549-021-06369-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1655: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  3. Article ; Online: Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer.

    Denu, Ryan A / Burkard, Mark E

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 11921

    Abstract: The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions including organization of the mitotic spindle to ensure faithful chromosome segregation during mitosis, cell polarization and migration, and ...

    Abstract The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions including organization of the mitotic spindle to ensure faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with more aggressive clinical features and worse patient outcomes. However, the causes of CA in human cancer are unclear. Many previous studies have identified mechanisms of CA in cellulo, such as overexpression of PLK4, but it is unclear how often these are the primary mechanism in human disease. To identify a primary cause of CA, we analyzed The Cancer Genome Atlas (TCGA) genomic and transcriptomic data for genes encoding the 367 proteins that localize to the centrosome (the "centrosome-ome"). We identified the following candidates for primary causes of CA: gain-of-function alterations of CEP19, CEP72, CTNNB1, PTK2, NDRG1, SPATC1, TBCCD1; and loss-of-function alterations of CEP76, MCPH1, NEURL4, and NPM1. In cellulo analysis of these candidates revealed that loss of MCPH1/microcephalin caused the most robust increase in centriole number. MCPH1 deep gene deletions are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. Mechanistic experiments demonstrated that loss of MCPH1 caused a CDK2-dependent increase in STIL levels at the centrosome to drive CA. We conclude that loss of MCPH1 is common in human cancer and is likely to be a cause of CA.
    MeSH term(s) Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Centrioles/metabolism ; Centrosome/metabolism ; Chromosomal Instability/genetics ; Cytoskeletal Proteins/genetics ; Gene Deletion ; Homozygote ; Humans ; Neoplasms/genetics ; Nucleophosmin ; Penetrance ; Proteome/metabolism ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Cell Cycle Proteins ; Cytoskeletal Proteins ; MCPH1 protein, human ; NPM1 protein, human ; Proteome ; Tumor Suppressor Protein p53 ; Nucleophosmin (117896-08-9)
    Language English
    Publishing date 2020-07-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-68629-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A survey of chromosomal instability measures across mechanistic models.

    Lynch, Andrew R / Bradford, Shermineh / Zhou, Amber S / Oxendine, Kim / Henderson, Les / Horner, Vanessa L / Weaver, Beth A / Burkard, Mark E

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 16, Page(s) e2309621121

    Abstract: Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation ... ...

    Abstract Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation rates remain challenging to assess in human cancer despite an array of available measures. We evaluated measures of CIN by comparing quantitative methods using specific, inducible phenotypic CIN models of chromosome bridges, pseudobipolar spindles, multipolar spindles, and polar chromosomes. For each, we measured CIN fixed and timelapse fluorescence microscopy, chromosome spreads, six-centromere FISH, bulk transcriptomics, and single-cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples significantly correlated (R = 0.72;
    MeSH term(s) Humans ; Cell Line, Tumor ; Chromosomal Instability/genetics ; Neoplasms ; Centromere ; Karyotyping ; Gene Expression Profiling ; Chromosome Segregation ; Aneuploidy
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2309621121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: Shared Knowledge in Precision Cancer Care.

    Burkard, Mark E / Golden, Robert N

    WMJ : official publication of the State Medical Society of Wisconsin

    2018  Volume 117, Issue 4, Page(s) 178–179

    MeSH term(s) Cooperative Behavior ; Diffusion of Innovation ; Health Services Accessibility ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Patient Selection ; Precision Medicine ; Quality of Life ; Wisconsin
    Language English
    Publishing date 2018-11-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 441051-8
    ISSN 1098-1861 ; 0043-6542
    ISSN 1098-1861 ; 0043-6542
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 225: Show issues Location:
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  6. Article ; Online: MACROD2, an Original Cause of CIN?

    Jin, Ning / Burkard, Mark E

    Cancer discovery

    2018  Volume 8, Issue 8, Page(s) 921–923

    MeSH term(s) Chromosomal Instability ; Colorectal Neoplasms/genetics ; DNA Repair Enzymes ; Genes, Tumor Suppressor ; Haploinsufficiency ; Humans ; Hydrolases ; Poly (ADP-Ribose) Polymerase-1
    Chemical Substances MACROD2 protein, human ; PARP1 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Hydrolases (EC 3.-) ; DNA Repair Enzymes (EC 6.5.1.-)
    Language English
    Publishing date 2018-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-18-0674
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
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  7. Article: Breast cancer immunotherapy: current biomarkers and the potential of

    Skala, Melissa C / Ayuso, Jose M / Burkard, Mark E / Deming, Dustin A

    Current opinion in biomedical engineering

    2021  Volume 21

    Abstract: Breakthroughs in metastatic breast cancer care require new model systems that can identify the unique features and vulnerabilities of each cancer. Primary tumor cultures are proposed to efficiently screen multiple treatment options in a patient-specific ... ...

    Abstract Breakthroughs in metastatic breast cancer care require new model systems that can identify the unique features and vulnerabilities of each cancer. Primary tumor cultures are proposed to efficiently screen multiple treatment options in a patient-specific strategy to maximize therapeutic benefit, minimize toxicity, and enable mechanistic insights that inspire future biomarkers for patient selection. To realize the potential of patient-specific cultures, new tools are needed to capture cell-by-cell variability in behavior and dynamic response to treatments in living 3D specimens. Potential bioengineering tools that can achieve this include optical microscopy to image single-cell dynamics and microphysiological
    Language English
    Publishing date 2021-09-20
    Publishing country England
    Document type Journal Article
    ISSN 2468-4511
    ISSN 2468-4511
    DOI 10.1016/j.cobme.2021.100348
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Exceptional Response to Crizotinib With Subsequent Response to Cabozantinib in Metastatic, ROS1-GOPC Fusion-Mutated Breast Cancer.

    O'Neil, Sean R / Weber, Garrett A / Deming, Dustin A / Burkard, Mark E / Kenny, Paraic A / Richmond, Craig S / Parsons, Benjamin M

    JCO precision oncology

    2023  Volume 7, Page(s) e2300174

    MeSH term(s) Humans ; Crizotinib ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Anilides ; Neoplasms ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
    Chemical Substances cabozantinib (1C39JW444G) ; Crizotinib (53AH36668S) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; Anilides ; ROS1 protein, human (EC 2.7.10.1) ; GOPC protein, human ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
    Language English
    Publishing date 2023-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.23.00174
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference.

    Lynch, Andrew R / Arp, Nicholas L / Zhou, Amber S / Weaver, Beth A / Burkard, Mark E

    eLife

    2022  Volume 11

    Abstract: ... segregation-is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rate ...

    Abstract Chromosomal instability (CIN)-persistent chromosome gain or loss through abnormal mitotic segregation-is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rate, a measure of CIN, can inform prognosis and is a promising biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by selection against aneuploid cells, which reduces observable diversity. We developed a framework to measure CIN, accounting for karyotype selection, using simulations with various levels of CIN and models of selection. To identify the model parameters that best fit karyotype data from single-cell sequencing, we used approximate Bayesian computation to infer mis-segregation rates and karyotype selection. Experimental validation confirmed the extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (18.5 ± 0.5/division). Extending this approach to clinical samples revealed that inferred rates fell within direct observations of cancer cell lines. This work provides the necessary framework to quantify CIN in human tumors and develop it as a predictive biomarker.
    MeSH term(s) Aneuploidy ; Bayes Theorem ; Chromosomal Instability/genetics ; Chromosome Aberrations ; Chromosome Segregation/genetics ; Humans ; Karyotype ; Neoplasms/genetics ; Systems Analysis
    Language English
    Publishing date 2022-04-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.69799
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: A survey of CIN measures across mechanistic models.

    Lynch, Andrew R / Bradford, Shermineh / Zhou, Amber S / Oxendine, Kim / Henderson, Les / Horner, Vanessa L / Weaver, Beth A / Burkard, Mark E

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation ... ...

    Abstract Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation rates remain challenging to assess in human cancer despite an array of available measures. We evaluated measures of CIN by comparing quantitative methods using specific, inducible phenotypic CIN models of chromosome bridges, pseudobipolar spindles, multipolar spindles, and polar chromosomes. For each, we measured CIN fixed and timelapse fluorescence microscopy, chromosome spreads, 6-centromere FISH, bulk transcriptomics, and single cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples correlated well (R=0.77; p<0.01) and sensitively detect CIN. Cytogenetics approaches include chromosome spreads and 6-centromere FISH, which also correlate well (R=0.77; p<0.01) but had limited sensitivity for lower rates of CIN. Bulk genomic DNA signatures and bulk transcriptomic scores, CIN70 and HET70, did not detect CIN. By contrast, single-cell DNA sequencing (scDNAseq) detects CIN with high sensitivity, and correlates very well with imaging methods (R=0.83; p<0.01). In summary, single-cell methods such as imaging, cytogenetics, and scDNAseq can measure CIN, with the latter being the most comprehensive method accessible to clinical samples. To facilitate comparison of CIN rates between phenotypes and methods, we propose a standardized unit of CIN: Mis-segregations per Diploid Division (MDD). This systematic analysis of common CIN measures highlights the superiority of single-cell methods and provides guidance for measuring CIN in the clinical setting.
    Language English
    Publishing date 2023-06-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.15.544840
    Database MEDical Literature Analysis and Retrieval System OnLINE

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