bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A003: HPV infection causes dependence on alternative DNA damage response pathways providing cancer specific targets for radiosensitization
Authors: Goldstein Michael , Kotwal Akhil , Gabriel Nishanth , Buchser William , Sentmanat Monica , Markovina Stephanie , Schwarz Julie , Cui Xia 
Published: January 2024

Abstract
Targeted radiosensitization is an attractive approach to improving the efficacy of radiotherapy in cancer treatment. However, drugs targeting ubiquitous DNA damage response (DDR) pathways are not cancer specific and can increase radiation related side effects. Thus, there is an unmet clinical need for tumor specific molecular targets. To address this need we sought to identify DNA damage signaling pathways that are unique to cancer cells. We hypothesized that by expressing its genome in host cells high-risk Human Papilloma Virus (HPV) can rewire DNA damage signaling making HPV-positive tumor cells dependent on alternative pathways to survive radiation, which can be exploited for targeted radiosensitization of HPV-induced cancers. Using a CRISPR/Cas9 screen in cells that selectively express HPV16 proteins E6 or E7 we uncovered genes that cells rely on to survive radiation-induced DNA damage in the context of E6 or E7 expression. We demonstrate that targeting these newly identified genes sensitizes cancer cells to radiation specifically in the presence of E6 or E7. We provide mechanistic insights showing that E6 and E7 alter the cellular epigenome by inhibiting histone lysine acetylation and tri-methylation, respectively. In this setting, a member of a centromeric protein complex identified in the screen is critical for mitotic progression and survival in E6-expressing cells following radiation exposure. Deletion of this factor resulted in delayed mitotic progression, chromosomal missegregation and rapid post-mitotic death in irradiated HPV-positive cells, a phenotype that was mitigated by ablation of E6 expression. Furthermore, we identified an E3 ubiquitin ligase that promotes survival in E7-expressing cells following radiation exposure by alleviating perturbations during DNA replication. Together, we have uncovered DDR pathways that are critical for cell survival after radiation exposure specifically in HPV-positive cells. Our findings suggest that expression of viral proteins E6 and E7 rewires DNA damage signaling networks causing dependence on alternative response pathways. We propose that these pathways can be targeted for tumor-specific radiosensitization of HPV-induced cancers.
Citation Format: Michael Goldstein, Akhil Kotwal, Nishanth Gabriel, William Buchser, Monica Sentmanat, Stephanie Markovina, Julie Schwarz, Xia Cui. HPV infection causes dependence on alternative DNA damage response pathways providing cancer specific targets for radiosensitization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A003.
Abstract A012: Mre11 mediates cGAS activation and tumor suppression through ZBP1-dependent necroptosis in breast cancer
Authors: Jo Minguk , Kumar Rashmi J. , Lin Chien-Chu , Boyer Joshua A. , Shahir Jamshaid A. , Fagan-Solis Katerina , Simpson Dennis A. , Fan Cheng , Foster Christine E. , Goddard Anna M. , Lerner Lynn M. , Ellington Simon W. , Wang Qinhong , Wang Ying , Ho Alice Y. , Liu Pengda , Perou Charles M. , Zhang Qi , McGinty Robert K. , Purvis Jeremy E. , Gupta Gaorav P. 
Published: January 2024

Abstract
Oncogene-induced replication stress leads to endogenous DNA damage, activating the cGAS/STING signaling pathway, a critical player in tumor suppression. The exact mechanism underlying cGAS activation, however, remains unclear due to the continual inhibition of cGAS by its high-affinity interaction with the histone acidic patch (AP), which sterically prevents its activation by double-stranded DNA (dsDNA). In this investigation, we elucidate the significant role of the DNA double-strand break sensor, Mre11, in regulating cGAS activation and thereby inhibiting mammary tumorigenesis. Our data reveal that the binding of the Mre11-Rad50-Nbn (MRN) complex to nucleosome fragments is crucial to liberate cGAS from AP-mediated sequestration, facilitating its subsequent activation by dsDNA. Consequently, Mre11 emerges as a vital component in the cGAS activation process, responding to oncogenic stress, cytosolic dsDNA, and ionizing radiation. Moreover, we highlight the ramifications of Mre11-dependent cGAS activation which fosters ZBP1/RIPK3/MLKL-mediated necroptosis, a vital process in curtailing oncogenic proliferation and breast tumorigenesis. Significantly, our study identifies a strong correlation between the downregulation of ZBP1 in human triple-negative breast cancer and increased genomic instability, suppressed immune response, and adverse patient prognosis. Our findings firmly establish Mre11 as a pivotal mediator connecting DNA damage to cGAS activation, thereby facilitating tumor suppression through ZBP1-dependent necroptosis, offering a promising avenue for targeted breast cancer therapies.
Citation Format: Minguk Jo, Rashmi J. Kumar, Chien-Chu Lin, Joshua A. Boyer, Jamshaid A. Shahir, Katerina Fagan-Solis, Dennis A. Simpson, Cheng Fan, Christine E. Foster, Anna M. Goddard, Lynn M. Lerner, Simon W. Ellington, Qinhong Wang, Ying Wang, Alice Y. Ho, Pengda Liu, Charles M. Perou, Qi Zhang, Robert K. McGinty, Jeremy E. Purvis, Gaorav P. Gupta. Mre11 mediates cGAS activation and tumor suppression through ZBP1-dependent necroptosis in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A012.
Abstract A015: 53BP1 loss mediated PARP inhibitor resistance in BRCA1-deficient pancreatic cancer is overcome with immune checkpoint blockade
Authors: Patterson-Fortin Jeffrey , Sun Yajie , Han Sen , Li Zhe , Nowicka Zuzanna , Hirohashi Yuna , Kilgas Susan , Yi Jae Kyo , Spektor Alexander , Fendler Wojciech , Konstantinopoulos Panagiotis , D'Andrea Alan D. , Chowdhury Dipanjan 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by the presence of mutations in homologous recombination (HR) repair genes, including BRCA1 and BRCA2, in approximately 20% of diagnosed cases. 53BP1 (tumor protein p53 binding protein 1) nucleates the anti-end resection machinery at DNA double strand break (DSB)s thereby countering BRCA1 activity. Importantly, BRCA1-deficient PDACs that are typically sensitive to poly-ADP ribose polymerase inhibitors (PARPi) become resistant in the absence of 53BP1. Here, we demonstrate that loss of 53BP1 results in enhanced DNA end-resection, increased micronuclei, and cytoplasmic dsDNA, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, activating pro-inflammatory signaling. This not only enhances CD8+ T cell infiltration but also activates macrophages and natural killer (NK) cells culminating in tumor growth inhibition. Loss of 53BP1 correlates with response to immune checkpoint blockade (ICB) and improved overall survival. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Taken together, our findings provide a rationale for combining PARPi with ICB to overcome PARPi-resistance in BRCA1-deficient pancreatic cancers.
Citation Format: Jeffrey Patterson-Fortin, Yajie Sun, Sen Han, Zhe Li, Zuzanna Nowicka, Yuna Hirohashi, Susan Kilgas, Jae Kyo Yi, Alexander Spektor, Wojciech Fendler, Panagiotis Konstantinopoulos, Alan D. D'Andrea, Dipanjan Chowdhury. 53BP1 loss mediated PARP inhibitor resistance in BRCA1-deficient pancreatic cancer is overcome with immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A015.
Abstract A030: DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma
Authors: Abdali Umaiya , Saleem Saima 
Published: January 2024

Abstract
Differences in DNA repair capacity have been linked to the risk and prognosis of cancer. In specific types of cancer, certain variations known as Single Nucleotide Polymorphisms (SNPs) within DNA repair genes can influence the effectiveness of treatments. This phenomenon has been observed in patients with Oral Squamous Cell Carcinoma (OSCC), especially in those undergoing chemotherapy and radiation therapy. One such gene, Excision Repair Cross-Complementation 5 (ERCC5), contains a SNP (rs17655) G&gt;C, leading to a missense variation and a change in amino acid from D to H. This variation has been noted in various cancer types. Hence, this study aimed to investigate the presence of this DNA repair gene polymorphism (rs17655) and its association with OSCC. To achieve this goal, blood samples were collected from OSCC patients exposed to chemotherapy and radiation therapy, as well as from OSCC patients not exposed to these treatments, following approval from the relevant institutional review committees. Informed consent was obtained from 100 patients, and an equal number of age and gender-matched controls. Genomic DNA was extracted using the salting-out method and analyzed for quality and quantity through agarose gel electrophoresis and nanodrop spectrophotometry. Primers were designed using online primer designing software. Genetic variations were identified using Tetra Primers-Amplifies Refractory Mutation System Polymerase Chain Reaction (t-ARMS PCR), and the amplified products were visualized via agarose gel electrophoresis. The genotypic frequency analysis of rs17655 revealed a higher prevalence of the homozygous mutant type (CC) in the blood samples of OSCC patients, both exposed and non-exposed to chemotherapy and radiation therapy. In contrast, the homozygous wild type (GG) was more prevalent among the control group. Statistical analysis, including a chi-square test (χ 2 = 36.76, p &lt; 0.001) and odds ratio (10.27), demonstrated a significant association between the rs17655 polymorphism and oral squamous cell carcinoma, indicating an increased risk of OSCC due to this genetic variation. These genomic variants have the potential to serve as biomarkers for predicting clinical outcomes in OSCC patients undergoing chemotherapy and radiotherapy.
Citation Format: Umaiya Abdali, Saima Saleem. DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A030.
Abstract B029: Enhanced anticancer effects through synergistic targeting of DDX5 and DNA damage-related factors
Authors: Seo Hye-Ran , Ryu Hwani , Ahn Jiyeon 
Published: January 2024

Abstract
Dead-box RNA helicase 5 (DDX5) is a member of the DDX RNA helicase family, commonly overexpressed in most carcinomas and plays an important role in tumor development and malignant progression. While DDX5 functions as a helicase in cells, it also plays various other roles in DNA damage repair, and resistance to radiotherapy or anticancer drugs. However, due to the diverse functions of DDX5, the anticancer effects solely from inhibiting helicase function of DDX5 are limited. Here, we inhibited DDX5 along with other factors to investigate their impact on the immune response and assess the cell viability of cancer cells. Our findings reveal that inhibiting DDX5 and DNA damage-related factors simultaneously in TNBC cells leads to a significantly greater decrease in cell viability than DDX5 knockdown alone. Through MTT assays using siRNA libraries related to DNA damage, we confirmed that when RAD51 and XRCC5 were knocked down along with DDX5, cell viability decreased by more than 20%. Furthermore, we noted an enhancement in innate immune activity and a more pronounced reduction in cell viability when simultaneously targeting the DNA damage-related factors alongside DDX5. In conclusion, our study identifies an augmented anticancer effect through the concurrent targeting of DDX5 and other critical factors.
Citation Format: Hye-Ran Seo, Hwani Ryu, Jiyeon Ahn. Enhanced anticancer effects through synergistic targeting of DDX5 and DNA damage-related factors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B029.
Abstract B034: Polymorphisms in XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair genes elevate cervical cancer risk among Bangladeshi female population
Authors: Rahman Md. Mustafizur , Das Laboni , Rahman Sadia , Hossain Amir , Sultana Razia 
Published: January 2024

Abstract
Introduction and Objective: Cervical cancer is the second most common cancer in women worldwide and is both a preventable and a curable disease especially if identified at an early stage. Sequence variations in DNA repair genes can cause aberration in cellular functions leading to cancer. Genetic polymorphisms in XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) genes result in individual variation in their DNA repair capacity. The aim of this study was to identify the association between XRCC1 Arg399Gln and XRCC3 Thr241Met single nucleotide polymorphisms (SNPs) and susceptibility to cervical cancer in Bangladeshi populations. Methods: The case-control study comprised 124 cervical cancer patients and 148 healthy controls. Genomic DNAs were isolated from peripheral blood and genotyped for candidate SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. Results: For XRCC1, heterozygous Arg/Gln and combined heterozygous plus variant homozygous Gln/Gln genotypes showed 1.78-fold (95% CI 1.0037 to 2.8771, p=0.0484) and 1.8627-fold (95% CI 1.1470 to 3.0250, p = 0.0119) increased risk of cervical cancer, respectively, when compared with normal homozygous Arg/Arg genotype. The variant Gln allele was positively associated with cervical cancer by 1.68-fold increase (95% CI 1.1732 to 2.3980, p = 0.0046). Similarly, for XRCC3, Thr/Met heterozygous and combined Thr/Met + Met/Met genotypes were found to be associated with 1.6993-fold (95% CI 1.0398 to 3.0166, p=0.0354) and 1.8312-fold (95% CI 1.0890 to 3.0791, p = 0.0225) higher risk, respectively, when compared with normal homozygous Thr/Thr genotypes. The variant Met allele showed significant association with 1.71-fold increased risk. Conclusion: XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) polymorphisms may be associated with increased cervical cancer risk in Bangladeshi females.
Citation Format: Md. Mustafizur Rahman, Laboni Das, Sadia Rahman, Amir Hossain, Razia Sultana. Polymorphisms in XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair genes elevate cervical cancer risk among Bangladeshi female population [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B034.
Abstract IA003: Molecular and imaging biomarkers of PARP inhibitors for small cell lung cancer
Authors: Lok Benjamin H. 
Published: January 2024

Abstract
This presentation will briefly define the different types of biomarkers and subsequently will cover examples of response, predictive, and prognostic biomarkers from preclinical and clinical evidence for small cell lung cancer (SCLC). The talk will cover examples with translational relevance, including intrinsic molecular features associated with DNA damage repair and response to PARP inhibitors, with a focus on the SCLC-specific context. Additionally, it will delve into the use of positron emission tomography with a radiolabeled PARP inhibitor to assess pharmacodynamic response, and the utilization of liquid biopsy patient blood samples for interrogating the tumor methylome with prognostic associations. Future opportunities and directions both specific to the aforementioned examples and more generally will be discussed.
Citation Format: Benjamin H. Lok. Molecular and imaging biomarkers of PARP inhibitors for small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA003.
Abstract IA016: Replication-coupled and canonical DNA double strand breaks are processed by distinct mechanisms
Authors: Pavani Raphael , Tripathi Veenu , Zong Dali , Callen Elsa , Pankajam Ajith , Nussenzweig Andre , Wu Wei , Vrtis Kyle , Chari Raj , Walter Johannes C 
Published: January 2024

Abstract
Single strand breaks (SSBs), including DNA nicks, are the most common form of endogenous DNA damage. If they are not resolved before the passage of a replication fork, current models suggest that SSBs are converted to single-ended double strand breaks (seDSBs) and repaired by homologous recombination (HR). Here we show that when a replication fork encounters a Cas9-induced nick on the leading strand, the replisome is rapidly dislodged, and a highly resected seDSB is generated. In contrast, a Cas9-induced nick on the lagging strand rarely gives rise to a resected seDSB, either because Cas9 is actively evicted and the nick sealed prior to the arrival of the fork or because the nick is concealed as the replisome traverses the lesion, resulting in a double ended DSB (deDSB). Unlike canonical DSBs, end-resection at collapsed forks is BRCA1-independent. Instead, BRCA1 antagonizes 53BP1 to promote RAD51 filament formation and recombination. In the absence of strand invasion, exemplified by BRCA1-, RAD51-, and BRCA2- deficiencies, replication-coupled seDSBs are converted deDSBs by a converging fork. Together, our results demonstrate how nicks can give rise to DSBs in a strand asymmetrical manner, with implications for cancer-associated rearrangements and therapies that target the replication fork.
Citation Format: Raphael Pavani, Veenu Tripathi, Dali Zong, Elsa Callen, Ajith Pankajam, Andre Nussenzweig, Wei Wu, Kyle Vrtis, Raj Chari, Johannes C Walter. Replication-coupled and canonical DNA double strand breaks are processed by distinct mechanisms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA016.
Maledia Broadcasting: Getting Ready to Go on Air
Authors: Purani Keyoor , Premi Priya , Thomas Joffi 
Published: January 2024

This case focuses on the positioning strategy development for a new regional television channel of Maledia Broadcasting Network (MBN), a venture of the Kerala-based media group from India, Model Publication Trust. It also introduces the concept of perceptual maps for brand positioning and addresses brand extension. In 2011, MBN prepared to launch a Malayalam news channel. Samjad, Deputy CEO of the new company, faced the challenge of determining the channel’s positioning strategy. This task involved not only differentiation but also redefining competition in India’s dynamic and competitive broadcasting industry. The decision would impact marketing aspects such as the brand name and channel identity. This case offers opportunities to explore qualitative aspects of audience behaviour beyond competitive data, helping marketing students gain insights and analyse the competitive landscape in the industry to make strategic marketing decisions.
What care do people with dementia receive at the end of life? Lessons from a retrospective clinical audit of deaths in hospital and other settings
Authors: Triandafilidis Zoi , Carr Sally , Davis Daneill , Chiu Simon , Leigh Lucy , Jeong Sarah , Wong Daniel , Hensby Jacinta , Lewis Suzanne , Attia John , Goodwin Nicholas 
Published: January 2024

Abstract
Background
The need for better end-of-life care for people with dementia has been acknowledged. Existing literature suggests that people dying with dementia have less access to palliative care, yet little is known about the care provided to people with dementia at the end of life. This study aimed to establish evidence related to end-of-life care for people dying with dementia in hospital compared to other settings.

Methods
A retrospective clinical audit of people who had a diagnosis of dementia and had accessed services within a local health district, who died between 2015 and 2019, was conducted. A total of 705 people were identified, and a subset of 299 people randomly selected for manual audit. Chi-square p-values were used to compare the place of death, and a t-test or non-parametric test was used to assess the significance of the difference, as appropriate. Measures of functional decline within one month of death were assessed using mixed effects logistic regression models.

Results
The characteristics of people differed by place of death, with people who died in hospital more likely to be living at home and to not have a spouse. Less than 1 in 5 people had advance care directives or plans. Many were still being actively treated at the time of death: almost half of people who died in hospital had an investigation in their final 72 hours, less than half of people were coded as receiving palliative care at death, and more than 2 in 3 people did not get access to specialist palliative care. Declining function was associated with the terminal phase.

Conclusion
This study provides novel insights for those providing end-of-life care for people with dementia. Healthcare professionals and policy makers should consider how demographic characteristics relate to the places people with dementia receive end-of-life care. The care provided to people with dementia in the last year of their life highlights the need for more support to prepare advance care documentation and timely consideration for palliative care. Changes in markers of nutritional status and function in people with advanced dementia may help with identification of terminal phases.