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  1. Article ; Online: Exploring DNA Repair Mechanisms in Cancer Biology: Critical Insights and Open Questions.

    Gupta, Gaorav P / Rothenberg, Eli

    Journal of molecular biology

    2023  Volume 436, Issue 1, Page(s) 168377

    MeSH term(s) Humans ; DNA Damage ; DNA Repair ; Neoplasms/genetics
    Language English
    Publishing date 2023-11-29
    Publishing country Netherlands
    Document type Editorial
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168377
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  2. Article ; Online: Polymerase θ inhibition steps on the cGAS pedal.

    Smith, Chelsea M / Gupta, Gaorav P

    The Journal of clinical investigation

    2023  Volume 133, Issue 11

    Abstract: Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by ... ...

    Abstract Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.
    MeSH term(s) Animals ; Mice ; DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; Recombinational DNA Repair ; Neoplasms/genetics
    Chemical Substances DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2023-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI170660
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  3. Article ; Online: Spatially Localized Immunotherapy: A Perfect Combination With Radiation Therapy?

    Wang, Qinhong / Gupta, Gaorav P

    International journal of radiation oncology, biology, physics

    2021  Volume 110, Issue 2, Page(s) 507–509

    MeSH term(s) Combined Modality Therapy ; Humans ; Immunologic Factors ; Immunotherapy
    Chemical Substances Immunologic Factors
    Language English
    Publishing date 2021-03-16
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2021.02.046
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  4. Article ; Online: Polymerase θ inhibition steps on the cGAS pedal

    Chelsea M. Smith / Gaorav P. Gupta

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 11

    Abstract: Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by ... ...

    Abstract Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.
    Keywords Medicine ; R
    Subject code 616
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Introduction: Progress Towards Genomically-directed Radiosensitization.

    Gupta, Gaorav P / Bindra, Ranjit S

    Seminars in radiation oncology

    2021  Volume 32, Issue 1, Page(s) 1–2

    Abstract: Radiation therapy continues to break down technological barriers to deliver ionizing radiation with exceptional anatomical precision. However, some tumor types and subtypes exhibit intrinsic biological resistance to radiotherapy, which can result in ... ...

    Abstract Radiation therapy continues to break down technological barriers to deliver ionizing radiation with exceptional anatomical precision. However, some tumor types and subtypes exhibit intrinsic biological resistance to radiotherapy, which can result in unsuccessful tumor eradication or symptom palliation. Radiation resistance can result from alterations in diverse genetic, epigenetic, and metabolic pathways. Therapeutic targeting of these tumor-specific alterations may provide tumor-selective radiosensitization with relative sparing of adjacent normal tissues. This issue of Seminars in Radiation Oncology presents a series of articles that describe recent progress towards genomically-directed radiosensitization.
    MeSH term(s) Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/radiotherapy ; Radiation Oncology ; Radiation Tolerance ; Radiation, Ionizing
    Language English
    Publishing date 2021-12-03
    Publishing country United States
    Document type Editorial
    ZDB-ID 1146999-7
    ISSN 1532-9461 ; 1053-4296
    ISSN (online) 1532-9461
    ISSN 1053-4296
    DOI 10.1016/j.semradonc.2021.09.009
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  6. Article ; Online: Mechanisms of Immune Sensing of DNA Damage.

    Goddard, Anna M / Cho, Min-Guk / Lerner, Lynn M / Gupta, Gaorav P

    Journal of molecular biology

    2023  Volume 436, Issue 4, Page(s) 168424

    Abstract: Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the activation of the immune system to eliminate cells with persistent DNA damage. Recent ...

    Abstract Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the activation of the immune system to eliminate cells with persistent DNA damage. Recent research has shed light on a complex array of nucleic acid sensors crucial for innate immune activation in response to oncogenic stress-associated DNA damage, a process vital for suppressing tumor formation. Yet, these immune sensing pathways may also be co-opted to foster tolerance of chromosomal instability, thereby driving cancer progression. This review aims to provide an updated overview of how the innate immune system detects and responds to DNA damage. An improved understanding of the regulatory intricacies governing this immune response may uncover new avenues for cancer prevention and therapeutic intervention.
    MeSH term(s) Humans ; DNA Damage/immunology ; DNA Repair ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Innate Immunity Recognition
    Language English
    Publishing date 2023-12-29
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168424
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  7. Article ; Online: Cell composition inference and identification of layer-specific spatial transcriptional profiles with POLARIS.

    Chen, Jiawen / Luo, Tianyou / Jiang, Minzhi / Liu, Jiandong / Gupta, Gaorav P / Li, Yun

    Science advances

    2023  Volume 9, Issue 9, Page(s) eadd9818

    Abstract: Spatial transcriptomics (ST) technology, providing spatially resolved transcriptional profiles, facilitates advanced understanding of key biological processes related to health and disease. Sequencing-based ST technologies provide whole-transcriptome ... ...

    Abstract Spatial transcriptomics (ST) technology, providing spatially resolved transcriptional profiles, facilitates advanced understanding of key biological processes related to health and disease. Sequencing-based ST technologies provide whole-transcriptome profiles but are limited by the non-single cell-level resolution. Lack of knowledge in the number of cells or cell type composition at each spot can lead to invalid downstream analysis, which is a critical issue recognized in ST data analysis. Methods developed, however, tend to underuse histological images, which conceptually provide important and complementary information including anatomical structure and distribution of cells. To fill in the gaps, we present POLARIS, a versatile ST analysis method that can perform cell type deconvolution, identify anatomical or functional layer-wise differentially expressed (LDE) genes, and enable cell composition inference from histology images. Applied to four tissues, POLARIS demonstrates high deconvolution accuracy, accurately predicts cell composition solely from images, and identifies LDE genes that are biologically relevant and meaningful.
    MeSH term(s) Gene Expression Profiling ; Spatial Analysis ; Technology
    Language English
    Publishing date 2023-03-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.add9818
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  8. Article ; Online: Increasing Nonresearch-Related Industry Funding in Radiation Oncology: Cause for Concern?

    Royce, Trevor J / Gupta, Gaorav P / Chera, Bhisham S

    International journal of radiation oncology, biology, physics

    2020  Volume 109, Issue 1, Page(s) 26–28

    MeSH term(s) Conflict of Interest ; Humans ; Industry ; Physicians ; Radiation Oncologists ; Radiation Oncology ; United States
    Language English
    Publishing date 2020-12-11
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2020.09.003
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  9. Article ; Online: Breast conservation therapy versus mastectomy for breast cancer.

    Royce, Trevor J / Gupta, Gaorav P / Marks, Lawrence B

    The Lancet. Oncology

    2020  Volume 21, Issue 4, Page(s) 492–493

    MeSH term(s) Breast Neoplasms/pathology ; Breast Neoplasms/radiotherapy ; Breast Neoplasms/surgery ; Decision Making ; Female ; Humans ; Mastectomy/methods ; Mastectomy/trends ; Mastectomy, Segmental ; Radiotherapy, Adjuvant
    Language English
    Publishing date 2020-04-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2049730-1
    ISSN 1474-5488 ; 1470-2045
    ISSN (online) 1474-5488
    ISSN 1470-2045
    DOI 10.1016/S1470-2045(20)30172-8
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  10. Article ; Online: Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining.

    Ramsden, Dale A / Carvajal-Garcia, Juan / Gupta, Gaorav P

    Nature reviews. Molecular cell biology

    2021  Volume 23, Issue 2, Page(s) 125–140

    Abstract: Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway - alternative end joining (a-EJ) - ...

    Abstract Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway - alternative end joining (a-EJ) - has long resisted elucidation. In this Review, we highlight recent progress in our understanding of a-EJ, especially the assignment of DNA polymerase theta (Polθ) as the predominant mediator of a-EJ in most eukaryotes, and discuss a potential molecular mechanism by which Polθ-mediated end joining (TMEJ) occurs. We address possible cellular functions of TMEJ in resolving DSBs that are refractory to repair by non-homologous end joining (NHEJ), DSBs generated following replication fork collapse and DSBs present owing to stalling of repair by homologous recombination. We also discuss how these context-dependent cellular roles explain how TMEJ can both protect against and cause genome instability, and the emerging potential of Polθ as a therapeutic target in cancer.
    MeSH term(s) Animals ; DNA End-Joining Repair ; DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Humans ; Models, Biological ; Mutation/genetics ; Neoplasms/enzymology ; Neoplasms/genetics ; DNA Polymerase theta
    Chemical Substances DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2021-09-14
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-021-00405-2
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