bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A151: Establishing assays to investigate combinations of fractioned radiotherapy with DNA damage response agents in vitro and in vivo to enable investigation of radiosensitization and improved anti-tumour responses
Authors: Bell Charlotte , Brown Stewart , Cantrell Amy , Farrington Paul , Garcia Miguel , Hodgson Ben , Ho Yin Xin , Jordan Allan , Katopodi Theoni , Kendrew Jane , Neo Wen Hao , Thomson Stuart , Walker Graeme E , Wright Emily 
Published: December 2023

Abstract
Introduction: Radiotherapy is a main treatment modality for multiple cancer types, with approximately half of all cancer patients receiving radiotherapy as part of their treatment regimen. In addition to direct cytotoxic effects on cancer cells, it is now appreciated that radiosensitization using specific drugs inhibiting DNA damage response (DDR) pathways can enhance the sensitivity of tissues or cells to radiation therapy. Establishing assays to screen for potential radiosensitizing compounds is therefore valuable to inform drug discovery research.
Methods: The MDA-MB-436 human breast cancer cell line was selected for assay optimization. DDR inhibitors of DNA-dependent protein kinase (DNA-PK) (AZD7648) and Poly-(ADP-Ribose)-Polymerase (PARP) (niraparib) were used as tool radiosensitizing compounds, as these proteins play key roles in the repair of radiation-induced DNA double strand breaks. Effects on cell viability, cell cycle progression and DDR biomarkers were determined under a variety of irradiation (IR) and compound conditions. In parallel, in vivo validation experiments were performed.
Results and Conclusions: Both AZD7648 and niraparib radiosensitize MDA-MB-436 cells to IR treatment. A dose of 2 Gray (Gy) reduced the observed anti-proliferative compound IC50 compared to IR treatment or compound treatment alone. Furthermore, combined treatment of 2 Gy IR with either DDR inhibitor induces S-phase cell cycle arrest and increases cell death. Analysis of DDR biomarkers confirms their induction by radiotherapy in combination with DDR inhibitors. Similar changes to DDR biomarker expression were also observed in the in vivo xenograft mouse model. In summary, in vitro and in vivo assays have been established to investigate radiosensitization through the combination of IR and DDR inhibitors. Furthermore, these assays can identify novel compounds acting via a synergistic mechanism.
Citation Format: Charlotte Bell, Stewart Brown, Amy Cantrell, Paul Farrington, Miguel Garcia, Ben Hodgson, Yin Xin Ho, Allan Jordan, Theoni Katopodi, Jane Kendrew, Wen Hao Neo, Stuart Thomson, Graeme E Walker, Emily Wright. Establishing assays to investigate combinations of fractioned radiotherapy with DNA damage response agents in vitro and in vivo to enable investigation of radiosensitization and improved anti-tumour responses [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A151.
Abstract B073: Characterization of selective, allosteric inhibitors of human XRN1
Authors: Lockbaum Gordon J , Sickmier E. Allen , Sparling Brian A , Knockenhauer Kevin , Holt Nicholas , Liu Julie , Lynes Maureen M , Grigoriu Simina , Duncan Kenneth W , Copeland Robert A , Boriack-Sjodin P. Ann 
Published: December 2023

Abstract
Background: 5′→3′ exoribonuclease 1 (XRN1) plays an important role in innate immunity by preventing double stranded RNA (dsRNA) accumulation. In addition, XRN1 has emerged as a potential target for drug discovery efforts as tumors with high interferon signaling are sensitive to XRN1 loss using genetic tools. To date, no XRN1-selective inhibitors have been disclosed. This study details characterization of two small-molecule inhibitors of XRN1, 3’-5’ adenosine diphosphate (pAp) and Compound 1, through biochemical, biophysical, and structural analysis.
Materials and Methods: Enzymatic and biophysical assays for XRN1 were developed, and characterization of XRN1 inhibitors was performed. To enable structure-based drug design, novel constructs of human XRN1 were designed and characterized for both catalytic activity and compound binding using biochemical and biophysical methods. In addition, cocrystal structures of XRN1 were determined for each inhibitor.
Results: pAp was found to be a potent, RNA-competitive inhibitor of XRN1 dsRNA degradation with similar activity for XRN2. Cocrystal structures of XRN1 with pAp confirm the nucleotide analog binds in the active site of the enzyme. Enzymatic and biophysical techniques indicate Compound 1 is also a substrate-competitive inhibitor with single-digit micromolar affinity for XRN1. However, Compound 1 is highly selective for XRN1 and does not bind or inhibit XRN2. High-resolution crystal structures indicate that Compound 1 binds in an allosteric binding site, confirming the mechanism of inhibition and selectivity profile determined by in vitro assays.
Conclusions: This work demonstrates XRN1 can be selectively inhibited by small-molecule inhibitors. Human XRN1 structures provide a tool for structure-based drug design efforts against this compelling oncology target.Conflict of Interests: All authors are current or former employees and shareholders of Accent Therapeutics, Inc.
Citation Format: Gordon J Lockbaum, E. Allen Sickmier, Brian A Sparling, Kevin Knockenhauer, Nicholas Holt, Julie Liu, Maureen M Lynes, Simina Grigoriu, Kenneth W Duncan, Robert A Copeland, P. Ann Boriack-Sjodin. Characterization of selective, allosteric inhibitors of human XRN1 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B073.
Abstract LB_B17: Single-cell analysis of dynamic remodeling of radiated TNBC cells
Authors: Ku Minhee , Kim Jin Sung , Koom Woong Sub , Yang Jaemoon 
Published: December 2023

Abstract
The dynamic rearrangement of the cellular cytoskeletal network and changes in cellular stiffness play crucial roles in the progression of malignant tumors, including those with invasive and metastatic traits. Despite the acknowledged connections, the inherent complexity of cancer and the various microenvironments that individual cells experience during treatment have hindered comprehensive investigations into therapeutic responses, particularly at the individual cell level. Notably, the emergence of large DNA damage-induced cells following radiotherapy in the challenging-to-treat triple-negative breast cancer (TNBC) subtype suggests potential concurrent alterations in cellular mechanics. This study dives into the complex interplay among radiation therapy, cytoskeletal architecture, and cellular stiffness at the level of individual cells. By utilizing atomic force microscopy (AFM) as a quantitative and non-invasive technique, we discerned how cancer cells respond to radiation treatment based on their cytoskeletal properties. Our findings revealed a clear correlation between radiation therapy and disruptions in cytoskeletal integrity, along with a simultaneous increase in cellular stiffness. These observed changes could potentially indicate impending cell death or a reduced tendency for metastasis. Building on these insights, we propose that assessing cytoskeletal features through AFM holds potential for tailoring personalized radiation therapy approaches, depending on the distinct responses exhibited by cancer cells post-treatment. This shift in approach, guided by mechanics, underscores the capacity to enhance treatment effectiveness while minimizing unintended damage. By shedding light on the intricate interplay between radiation-induced cellular responses and mechanical properties, this study lays the foundation for innovative strategies that leverage cytoskeletal attributes to customize and optimize therapeutic interventions for TNBC and potentially other malignancies.
Citation Format: Minhee Ku, Jin Sung Kim, Woong Sub Koom, Jaemoon Yang. Single-cell analysis of dynamic remodeling of radiated TNBC cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B17.
Abstract A095: Rural disparities in telemedicine use among cancer survivors during the COVID-19 pandemic
Authors: Lee Minjee , Tsai Meng-Han 
Published: December 2023

Abstract
Background: The COVID-19 pandemic has led to significant changes in the delivery of healthcare across the world, including the widespread adoption of telemedicine. This study examined the prevalence of telemedicine use by rurality and determined whether rurality was associated with its use among cancer survivors in the United States (US). Methods: The 2021 National Health Interview Survey (NHIS) was used to examine the use of telemedicine among cancer survivors during the pandemic. Our primary outcome is telemedicine use and rurality is our main exposure of interest. Other covariates of interest include demographics, health-related factors (number of comorbidities, self-rated health), and types of cancer history. Descriptive statistics and multiple logistic regression models were used to examine the mentioned association. Results: Among 27,500 eligible cancer survivors, 51.6% (14,140 participants) of them reported telemedicine use. The use of telemedicine varied by rurality, with 41.4% of rural cancer survivors using telemedicine compared to 58.4% of cancer survivors in large central metropolitan areas (p&lt;0.001). Rural cancer survivors had significantly lower odds of using telemedicine during the pandemic compared to metropolitan cancer survivors. Cancer survivors residing in rural were 0.58 times less likely (95% CI, 0.43 to 0.78) and cancer survivors residing in medium and small metropolitan areas were 0.72 times less likely (95% CI, 0.56 to 0.93) to report telemedicine use compared to cancer survivors residing in large central metropolitan areas. Conclusion: Significant rural disparities in telemedicine use were evident among cancer survivors. Rural cancer survivors were less likely to use telemedicine during the COVID-19 pandemic. To ensure equitable access to telemedicine, continued reimbursement for telemedicine services, but additional efforts are needed to improve access to and utilization of healthcare for rural cancer survivors.
Citation Format: Minjee Lee, Meng-Han Tsai. Rural disparities in telemedicine use among cancer survivors during the COVID-19 pandemic [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A095.
Abstract B108: Racial disparities in survival among oral cavity and pharynx cancer patients treated with immunotherapy: Insights from the US National Cancer Database (NCDB)
Authors: Yang Danting , Karanth Shama 
Published: December 2023

Abstract
Purpose: Survival rates for oral cavity and oropharynx cancers vary by race, with Non-Hispanic(NH)-Black patients experiencing relatively lower survival rates compared to NH-White patients. While the potential for improving survival with immunotherapy has been demonstrated in clinical trials, it remains unclear whether racial disparities persist in patients treated with this novel approach. We aimed to evaluate the association between race and all-cause mortality among oral and pharynx cancer patients who received immunotherapy. Methods: This study utilized the National Cancer Database (NCDB) to investigate racial disparities in survival after immunotherapy among patients diagnosed with oral cavity and pharynx cancers between 2013 and 2017. Multivariable Cox proportional hazards models were employed to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) by race/ethnicity. Results: The study cohort included 7,714 patients, consisting of 7,011 NH-White patients and 703 NH-Black patients. During the follow-up period, mortality occurred in 45.5% of NH-White patients and 59.5% of NH-Black patients. After adjusting for sociodemographic, clinical, and treatment factors, NH-Black patients had a higher risk of death compared to NH-White patients (HR: 1.24; 95% CI: 1.11, 1.38). Additionally, the study found no significant differences in the interaction between race and Charlson-Deyo comorbidity score or race and area-level median income. Conclusion: This study suggests that urgent action is needed to address these disparities to improve outcomes for NH-Black patients with oral cavity and pharynx cancers.
Citation Format: Danting Yang, Shama Karanth. Racial disparities in survival among oral cavity and pharynx cancer patients treated with immunotherapy: Insights from the US National Cancer Database (NCDB) [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B108.
Abstract C038: BRCA2 haploinsufficiency driven neoplastic events in the fallopian tube epithelia
Authors: Ravix Jovanka , Paudel Iru , Sowamber Ramlogan , Pulivendala Gauthami , Lombard David , George Sophia 
Published: December 2023

Abstract
One in 70 women will develop ovarian cancer over their lifetime in the US and epithelial ovarian cancer (EOC) remains the deadliest gynecological cancer. EOC is a heterogenous disease and high-grade serous carcinoma (HGSOC) is the most common histotype. It is genetically unstable due to pathogenic variants in BRCA1, BRCA2, PALB2, ATM, and RAD51 genes involved in DNA damage response and repair which are part of the hereditary breast and ovarian cancer syndrome (HBOC). In women with a BRCA1 or BRCA2 mutation undergoing risk-reducing surgery, 3-17% have pre-neoplastic and neoplastic lesions in their fallopian tubes. These lesions, known as serous tubal intra-epithelial carcinoma (STIC), display differential loss of heterozygosity of BRCA1/2. New insights into BRCA2 function could provide novel opportunities for preventative interventions in individuals with this mutation, and perhaps new treatment opportunities for HGSC associated with BRCA2 heterozygosity. We have identified distinct metabolic and mitochondrial deficits in BRCA2 mutation carriers compared to BRCA1 carriers and non-carriers. Fallopian tube epithelial cell lines derived from BRCA2 mutation carriers showed increased levels of mitochondrial respiration and activity followed by BRCA1 mutation carriers and non-carriers. Transmission electron microscopy of BRCA2 mutation carriers showed increased disrupted mitochondrial networks when compared to wild type, suggesting that mutation status may contribute to increased mitochondrial fission. These observations reveal an entirely new aspect of BRCA2 biology and further studies will disaggregate the effects of BRCA2 on mitochondrial function, versus DNA damage repair. Ultimately, this work will provide new insight into the adaptive changes within FT cells which promote neoplastic transformation and inform how high-grade serous carcinoma (HGSC) cells distinctively respond to microenvironmental stimuli.
Citation Format: Jovanka Ravix, Iru Paudel, Ramlogan Sowamber, Gauthami Pulivendala, David Lombard, Sophia George. BRCA2 haploinsufficiency driven neoplastic events in the fallopian tube epithelia [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C038.
Abstract C046: Aryl hydrocarbon receptor activity may lead to the downstream transcription of several genes relevant to prostate cancer progression, apoptosis and lipid metabolism
Authors: Khamit-Kush Kofi K. , Powell Joann B. , Handy Jeffrey A. , Bowen Nathan J. , Wu Daqing , Odero-Marah Valerie 
Published: December 2023

Abstract
The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is both upregulated and constitutively active in high-grade prostate cancer. AhR activity has also been reported to contribute to proliferation and potentially disease progression in C4-2 cells (Powell et al. 2015). To determine if the aryl hydrocarbon receptor mediates transcription of genes pertinent to cancer progression, we performed an RNA-seq analysis in C4-2 AhR knockdown cells and the vehicle control. When a fold-change cutoff of ±1.5 and an adjusted p-value (p-adj) &lt;0.05 were used, data analyses revealed several differentially expressed genes (DEGS), i.e. LEPROT, CHAC1/2, GDF11/15, CDKN2, FAS, FASTKD, ATF1/3, CCNL2, and CCNG2 with known functions involving the cell cycle, apoptosis, epigenetic modifications, tumor aggressiveness, and interestingly – lipid metabolism. Recent evidence demonstrates significant changes in the expression profile of many of these genes in response to treatment with chemotherapeutics, specifically bromocriptine (Wu et al 2023). In murine models AhR has been shown to promote diet-induced obesity coupled with metabolic dysregulation leading to obesity, which has been reported to cause malignant behaviors in prostate cancer. Leptin, a pleiotropic obesity-associated adipokine, is significantly overexpressed in mCRPC tissues. Our lab previously reported an integrative bioinformatics analysis using TCGA data (n=498) to explore the role of AHR and leptin receptor (LEPR) in prostate cancer, which revealed AHR and LEPR mRNA expression positively correlate in a subset of prostate cancer patients (P&lt;0.05, Pearson: 0.68, R^2=0.46). We also confirmed AhR inhibits bortezomib and docetaxel -mediated apoptosis of C4-2 cells (data not shown). Further understanding of the potential interactions between metabolism and drug treatment should lead to a better understanding of the complex network of factors influencing prostate cancer progression and lead to more effective therapeutics for patients.
Citation Format: Kofi K. Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan J. Bowen, Daqing Wu, Valerie Odero-Marah. Aryl hydrocarbon receptor activity may lead to the downstream transcription of several genes relevant to prostate cancer progression, apoptosis and lipid metabolism [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C046.
Abstract C049: Genomic correlates with ancestry in lung squamous cell carcinoma
Authors: Jain Sejal , Yao Alexandria , Momen-Heravi Fatemeh , Allen-Gipson Diane , Zhang Xiaoyang , Henick Brian S. , Carrot-Zhang Jian , Taylor Alison M. 
Published: December 2023

Abstract
Outcome data from lung squamous cell carcinoma (SCC) show significantly lower overall and progression-free survival in Black patients. However, whether any genomic factors correlate with race and ancestry in this lung SCC, and whether this may contribute to disparities, has not been elucidated. We analyzed clinically annotated genomic data from 501 lung SCC tumor samples in the Cancer Genome Atlas (TCGA), with available ancestry admixture data. Here, we analyzed clinical data, gene expression profiles, mutations, and copy number changes to identify significantly differential events between tumors from patients of European (EUR) or African (AFR) ancestry. In tumors from AFR patients, we identified more frequent gain of chromosome arm 8q and/or the chr8q24 locus, where the oncogene MYC and its enhancers are located. 8q24 gain is associated both with global AFR ancestry and local AFR ancestry. Furthermore, expression of MYC targets is significantly increased in AFR samples relative to EUR samples, all of which suggest a role for the MYC pathway in differential cancer progression. MYC activity correlates with decreased immune infiltration and gene signaling, and patients with AFR ancestry are more likely to have decreased immune infiltrate and pathway activity. Our findings are consistent with observations in prostate cancer; this is the first study to find MYC enhancer amplification correlating with African ancestry in lung SCC. We are currently testing additional cohorts, including AACR GENIE, to validate these findings. Future studies will elucidate patient-specific treatment modalities.
Citation Format: Sejal Jain, Alexandria Yao, Fatemeh Momen-Heravi, Diane Allen-Gipson, Xiaoyang Zhang, Brian S. Henick, Jian Carrot-Zhang, Alison M. Taylor. Genomic correlates with ancestry in lung squamous cell carcinoma [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C049.