bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 1 from Incident Cardiovascular Disease Risk among Older Asian, Native Hawaiian and Pacific Islander Breast Cancer Survivors
Authors: Hashibe Mia , Wei Mei , Lee Catherine J. , Tao Randa , Koric Alzina , Wang Jing , Daud Anees , Tay Djin , Shen Jincheng , Lee Yuan-chin A. , Chang Chun-Pin E.
Published: January 2024

This table shows the number of patients who had CVD before cancer diagnosis.
Table S6 from Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study
Authors: Yang Zhanghuan , He Hao , He Guangxu , Zeng Chudai , Hu Qian
Published: January 2024

Statistical Power of Identified Association Calculated With mRnd
Supplementary Figure 2 from Male-Pattern Vertex Baldness Trajectories, Chest Hair Patterns, and Odds of Overall and Aggressive Prostate Cancer
Authors: Salmon Charlotte , Mesidor Miceline , Rousseau Marie-Claude , Richard Hugues , Weiss Deborah , Spence Andrea R. , Parent Marie-Elise
Published: January 2024

Supplementary Figure 2. Directed acyclic graph of the association between chest hair amount and prostate cancer.
In green, variables of interest. In orange, potential confounding factors (due to the paucity of reports on risk factors in the literature, we elected to take a conservative approach and limited adjustments to age and ancestry).
Table S4 from Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study
Authors: Yang Zhanghuan , He Hao , He Guangxu , Zeng Chudai , Hu Qian
Published: January 2024

Summary of F Statistic and Variance Explained of Each Hematological Trait
Table S3 from Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study
Authors: Yang Zhanghuan , He Hao , He Guangxu , Zeng Chudai , Hu Qian
Published: January 2024

Instrument Variants for Each Hematological Trait
Table S17 from Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study
Authors: Yang Zhanghuan , He Hao , He Guangxu , Zeng Chudai , Hu Qian
Published: January 2024

Reverse Causal Effects Estimated for Four Hematological Traits
Table S14 from Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study
Authors: Yang Zhanghuan , He Hao , He Guangxu , Zeng Chudai , Hu Qian
Published: January 2024

Causal Effects Estimated via Seven Methods in Subgroup Analysis
Supplementary Figure 3 from Abbreviated Score to Assess Adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer in the UK Biobank
Authors: Malcomson Fiona C. , Parra-Soto Solange , Ho Frederick K. , Celis-Morales Carlos , Sharp Linda , Mathers John C.
Published: January 2024

Bland-Altman plot for agreement between total score and abbreviated score
Supplemental Table 4 from Mobile Phone Use and Risks of Overall and 25 Site-Specific Cancers: A Prospective Study from the UK Biobank Study
Authors: Zhang Yanjun , Zhang Yuanyuan , Ye Ziliang , Yang Sisi , Liu Mengyi , Wu Qimeng , Zhou Chun , He Panpan , Gan Xiaoqin , Qin Xianhui
Published: January 2024

Supplemental Table 4. Associations of mobile phone use status (users vs. non-users) with incident site-specific cancers in men.
Supplemental Table 3 from Mobile Phone Use and Risks of Overall and 25 Site-Specific Cancers: A Prospective Study from the UK Biobank Study
Authors: Zhang Yanjun , Zhang Yuanyuan , Ye Ziliang , Yang Sisi , Liu Mengyi , Wu Qimeng , Zhou Chun , He Panpan , Gan Xiaoqin , Qin Xianhui
Published: January 2024

Supplemental Table 3. Proportion of mobile phone use in cancer and non-cancer cases among different age groups.
Supplementary Table 4 from Association between Dietary Anthocyanidins and Biliary Cancer Risk in 98,458 Participants: Results from a Prospective Study
Authors: Xiang Ling , Wu Dabin , Xu Zhiquan , Tang Yunhao , He Hongmei , Wang Yaxu , Gu Haitao , Peng Linglong
Published: January 2024

Supplementary Table 4. Association between subclasses flavonones and biliary cancer risk.
Supplementary Table 3 from Association between Dietary Anthocyanidins and Biliary Cancer Risk in 98,458 Participants: Results from a Prospective Study
Authors: Xiang Ling , Wu Dabin , Xu Zhiquan , Tang Yunhao , He Hongmei , Wang Yaxu , Gu Haitao , Peng Linglong
Published: January 2024

Supplementary Table 3. Association between subclasses anthocyanidins and biliary cancer risk.
Supplemental Table 10 from Mobile Phone Use and Risks of Overall and 25 Site-Specific Cancers: A Prospective Study from the UK Biobank Study
Authors: Zhang Yanjun , Zhang Yuanyuan , Ye Ziliang , Yang Sisi , Liu Mengyi , Wu Qimeng , Zhou Chun , He Panpan , Gan Xiaoqin , Qin Xianhui
Published: January 2024

Supplemental Table 10. Association of length of mobile phone use as a time-dependent variable with incident overall cancer, nonmelanoma skin cancer in men and women, prostate cancer and urinary tract cancer in men, and vulva cancer in women, among mobile phone users.
Supplemental Figure 6 from Mobile Phone Use and Risks of Overall and 25 Site-Specific Cancers: A Prospective Study from the UK Biobank Study
Authors: Zhang Yanjun , Zhang Yuanyuan , Ye Ziliang , Yang Sisi , Liu Mengyi , Wu Qimeng , Zhou Chun , He Panpan , Gan Xiaoqin , Qin Xianhui
Published: January 2024

Supplemental Figure 6. Association of mobile phone use status (users vs. non-users) with incident site-specific cancers in women, excluding the cases identified during the first 2 years of follow-up.
Supplementary Table S6 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S6 shows the results of weighted multiple linear regression analysis of log-transformed urinary trans-3’-hydroxycotinine with study covariates
Table S4. from Adherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study
Authors: Peng Yang , Bassett Julie K. , Hodge Allison M. , Melaku Yohannes Adama , Afshar Nina , Hopper John L. , MacInnis Robert J. , Lynch Brigid M. , Smith-Warner Stephanie A. , Giles Graham G. , Milne Roger L. , Jayasekara Harindra
Published: January 2024

Hazard ratiosa for WCRF/AICR diet and lifestyle scores and total, alcohol-, obesity- and smoking-related, and digestive tract cancer risk for women in the Melbourne Collaborative Cohort Study
Table S3. from Adherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study
Authors: Peng Yang , Bassett Julie K. , Hodge Allison M. , Melaku Yohannes Adama , Afshar Nina , Hopper John L. , MacInnis Robert J. , Lynch Brigid M. , Smith-Warner Stephanie A. , Giles Graham G. , Milne Roger L. , Jayasekara Harindra
Published: January 2024

Hazard ratiosa for WCRF/AICR diet, standardized lifestyle and expanded lifestyle scores and total, alcohol-, obesity- and smoking-related, and digestive tract cancer risk in the Melbourne Collaborative Cohort Study, adjusted for smoking intensity instead of smoking status
Supplementary Table S37 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S37 shows the results of weighted multiple linear regression analysis of log-transformed urinary phenylmercapturic acid (PhMA) with study covariates
Table S1. from Adherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study
Authors: Peng Yang , Bassett Julie K. , Hodge Allison M. , Melaku Yohannes Adama , Afshar Nina , Hopper John L. , MacInnis Robert J. , Lynch Brigid M. , Smith-Warner Stephanie A. , Giles Graham G. , Milne Roger L. , Jayasekara Harindra
Published: January 2024

Construction of components used in World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet and lifestyle scores
Supplementary Table S33 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S33 shows the results of weighted multiple linear regression analysis of log-transformed urinary N‐acetyl‐S‐(2‐hydroxyethyl)‐L‐cysteine (2HEMA) with study covariates
Supplementary Table S4 from Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum
Authors: Grabski Isabella N. , Heymach John V. , Kehl Kenneth L. , Kopetz Scott , Lau Ken S. , Riely Gregory J. , Schrag Deborah , Yaeger Rona , Irizarry Rafael A. , Haigis Kevin M.
Published: January 2024

Supplementary Table S4: B-PCA loadings for NSCLC, CRC, and PDAC.
Supplemental Figure 2 from Pre- and Postnatal Exposures to Tobacco Smoking and Survival of Childhood Acute Lymphoblastic and Myeloid Leukemias in California, United States
Authors: Metayer Catherine , Morimoto Libby M. , Kang Alice Y. , Sanchez Alvarez Jacklyn , Winestone Lena E.
Published: January 2024

Supplemental Figure 2 shows the Pearson correlation coefficients between sources/windows of child’s exposure to tobacco smoking pre- and postnatally; blue indicates a positive correlation and red indicates a negative correlation, with the magnitude of the correlation represented in the bottom scale.
Supplementary Table S2 from Racial and Ethnic Disparities in the Use of Robot-Assisted Surgery and Minimally Invasive Surgery in Pelvic Cancer Treatment: A Systematic Review
Authors: Mao Jialin , Genkinger Jeanine M. , Rundle Andrew G. , Wright Jason D. , Aryal Suvekshya , Liebeskind Alexander Y. , Tehranifar Parisa
Published: January 2024

Other relevant information for studies included in the systematic review.
Supplementary Table S18 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S18 shows the results of weighted multiple linear regression analysis of log-transformed urinary 2-hydroxyfluorene with study covariates
Supplementary Table S14 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S14 shows the results of weighted multiple linear regression analysis of log-transformed urinary N’-nitrosoanabasine with study covariates
Supplementary Table S13 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S13 shows the results of weighted multiple linear regression analysis of log-transformed urinary N’-nitrosonornicotine (NNN) with study covariates
Supplementary Table S1 from Influence of Half-life and Smoking/Nonsmoking Ratio on Biomarker Consistency between Waves 1 and 2 of the Population Assessment of Tobacco and Health Study
Authors: Ashley David L. , Zhu Wanzhe , Bhandari Deepak , Wang Lanqing , Feng Jun , Wang Yuesong , Meng Lei , Xia Baoyun , Jarrett Jeffery M. , Chang Cindy M. , Kimmel Heather L. , Blount Benjamin C.
Published: January 2024

Supplementary Table S1 shows the number of observations for each biomarker evaluated in this study
Supplementary Figure 5 from A Population-Based Family Case–Control Study of Sun Exposure and Follicular Lymphoma Risk
Authors: Odutola Michael K. , van Leeuwen Marina T. , Bruinsma Fiona , Turner Jennifer , Hertzberg Mark , Seymour John F. , Prince H. Miles , Trotman Judith , Verner Emma , Roncolato Fernando , Opat Stephen , Lindeman Robert , Tiley Campbell , Milliken Samuel T. , Underhill Craig R. , Benke Geza , Giles Graham G. , Vajdic Claire M.
Published: January 2024

Supplementary Figure 4 shows the estimated trajectories of outdoor hours by control type for warmer months (A and B), cooler months (C and D) and total (E and F)
Data from Abbreviated Score to Assess Adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer in the UK Biobank
Authors: Malcomson Fiona C. , Parra-Soto Solange , Ho Frederick K. , Celis-Morales Carlos , Sharp Linda , Mathers John C.
Published: January 2024

AbstractBackground:
The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are lifestyle-based guidelines which aim to reduce cancer risk. This study investigated, in the UK Biobank, associations between an abbreviated score to assess adherence to these Recommendations and the risk of all cancers combined and of 14 cancers for which there is strong evidence for links with diet, adiposity, and physical activity.
Methods:
We used data from 288,802 UK Biobank participants (mean age 56.2 years), cancer-free at baseline. An abbreviated version of the 2018 WCRF/AICR Score was calculated to assess adherence to five Recommendations on (i) body weight, (ii) physical activity, (iii) fruits, vegetables, and dietary fiber, (iv) red and processed meat, and (v) alcohol. Multivariable Cox proportional hazards models were used to analyze associations between the abbreviated score (range, 0–5 points) and cancer incidence, adjusting for confounders.
Results:
During a median follow-up of 8.2 years (interquartile range, 7.4–8.9), 23,448 participants were diagnosed with cancer. The abbreviated score was inversely associated with risk of cancer overall [HR: 0.93; 95% confidence interval (CI): 0.92–0.95 per 1-point increment], and breast (HR: 0.90; 95% CI: 0.87–0.94), colorectal (HR: 0.86; 95% CI: 0.83–0.90), lung (HR: 0.89; 95% CI: 0.84–0.94), kidney (HR: 0.83; 95% CI: 0.76–0.90), pancreatic (HR: 0.86; 95% CI: 0.79–0.94), uterine (HR: 0.79; 95% CI: 0.73–0.86), esophageal (HR: 0.82; 95% CI: 0.75–0.90), stomach (HR: 0.89; 95% CI: 0.79–0.99), and liver (HR: 0.80; 95% CI: 0.72–0.90) cancers.
Conclusions:
Greater adherence to the Cancer Prevention Recommendations, assessed using an abbreviated score, was associated with reduced risk of all cancers combined and of nine site-specific cancers.
Impact:
Our findings support compliance to these Recommendations for cancer prevention.
Data from Patient Willingness to Use a Pharmacy-Based Colorectal Cancer Screening Service: A National Survey of U.S. Adults
Authors: Shah Parth D. , Wangen Mary , Rohweder Catherine L. , Waters Austin R. , Odebunmi Olufeyisayo O. , Marciniak Macary W. , Ferrari Renée M. , Wheeler Stephanie B. , Brenner Alison T.
Published: January 2024

AbstractBackground:
We aimed to understand U.S. adults’ willingness to use a pharmacy-based fecal immunochemical test (FIT) distribution service for routine colorectal cancer screening called PharmFIT using Diffusion of Innovation Theory, evaluating patient's appraisals of the program's relative advantage, compatibility, and complexity.
Methods:
From March to April 2021, we conducted a national online survey of 1,045 U.S. adults ages 45 to 75. We identified correlates of patient willingness to use PharmFIT using structural equation modeling.
Results:
Most respondents (72%) were willing to get a FIT from their pharmacy for their regular colorectal cancer screening. Respondents were more willing to participate in PharmFIT if they perceived higher relative advantage ($\hat{\beta}$= 0.184; confidence interval, CI95%: 0.055–0.325) and perceived higher compatibility ($\hat{\beta}$ = 0.422; CI95%: 0.253–0.599) to get screened in a pharmacy, had longer travel times to their primary health care provider ($\hat{\beta}$ = 0.007; CI95%: 0.004–0.010). Respondents were less willing to participate in PharmFIT if they were 65 years or older ($\hat{\beta}$ = −0.220; CI95%: −0.362 to −0.070).
Conclusions:
Most U.S. adults would be willing to participate in PharmFIT for their routine colorectal cancer screening. Patient perceptions of the relative advantage and compatibility of PharmFIT were strongly associated with their willingness to use PharmFIT. Pharmacies should account for patient preferences for these two traits of PharmFIT to increase adoption and use.
Impact:
Pharmacy-based colorectal cancer screening may be a viable public health strategy to significantly increase equitable access to screening for U.S. residents.
Abstract A006: Targeting SETD2 in combination with radiotherapy in rectal cancer
Authors: Akana Lokesh , Rodrigues Henrique , Zuniga Oscar , Wolfe Adam R.
Published: January 2024

Purpose: Tri-methyl-histone H3 (Lys36) is a modification of histone H3 involved in gene regulation and chromatin organization. It plays a crucial role in cell response to ionizing radiation and affects DNA damage repair, with altered levels linked to decreased radiation sensitivity. We hypothesize that targeting SETD2, the histone methyltransferase responsible for adding the tri-methyl group to Lys36 of histone H3, may enhance radiosensitivity in rectal cancer cells. Methods: To understand the role of Tri-Methyl-Histone H3 (Lys36) in response to ionizing radiation (IR), clonogenic assays, γH2aX foci staining, and western blot analysis of DNA damage response proteins and histones were performed on two established human rectal cancer cell lines following either RNA inhibition (RNAi) or drug targeting of SETD2, EPZ-719. Results: After treating two colorectal cancer cell lines (LS123 and LoVo) with IR (5 Gy) in vitro, Tri-Methyl-Histone H3 (Lys36) levels increased. When combined with IR, SETD2 RNAi reduced Tri-Methyl-Histone H3 (Lys36) and decreased clonogenic survival and cell proliferation. In vitro treatment with a novel SETD2 inhibitor, EPZ-719, increased DNA damage following IR (5 Gy) as measured by γH2aX foci staining. The treatment with EPZ-719 showed an enhancement in radiosensitization with a 0.37 improvement in the dose enhancement ratio. Conclusion: Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys36) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.

Citation Format: Lokesh Akana, Henrique Rodrigues, Oscar Zuniga, Adam R. Wolfe. Targeting SETD2 in combination with radiotherapy in rectal 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 A006.
Abstract A018: GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination
Authors: Tainer John A. , Schlacher Katharina , Wang Bin , Peng Guang , Ahmed Zamal
Published: January 2024

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adaptor for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover, in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.

Citation Format: John A. Tainer, Katharina Schlacher, Bin Wang, Guang Peng, Zamal Ahmed. GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination [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 A018.
Abstract A027: Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer
Authors: Turchi John J. , Mendoza-Munoz Pamela L. , VanderVere-Carozza Pamela S. , Gavande Navnath S. , Dynlacht Joseph R. , Garrett Joy E. , Chauhan Dineshsinha , Pawelczak Katherine S.
Published: January 2024

DNA-PK, the DNA-dependent protein kinase is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role in the non-homologous end joining (NHEJ) DNA repair pathway. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs drives clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat cancer. Modulating the DSB repair pathways is an effective mechanism to increase clinical efficacy of IR and certain chemotherapeutic regimens. We have taken the novel approach to inhibit target the DDR and NHEJ by developing small molecule inhibitors of the DSB sensor Ku, and its interaction with DNA. The Ku heterodimer serves as initiator of the NHEJ pathway following DSB induction and is the key DNA-binding component of the DNA-PK. We have created an extensive library of Ku DNA binding inhibitors (Ku-DBis) and demonstrate a direct interaction with the Ku heterodimer and potent inhibition of Ku-DNA binding and DNA-PK catalytic activity. In vitro analysis of a series of Ku truncation mutants defines the necessary domains for Ku-DBi activity. Ku-DBi’s show potent inhibition of in vitro and cellular NHEJ and, as a result, potentiate cellular sensitivity to DSB-inducing agents. Enhancement of sensitivity is a function of inhibiting DNA-PKcs autophosphorylation and dysregulation of signaling to the DDR. Recent chemical optimization has identified independent pharmacophores that drive off-target cytotoxicity, direct Ku inhibitory potency, and enhance cellular uptake activity. These data served as the basis for creation of a novel series of Ku-DBi’s towards interrogating NHEJ and DDR signaling in vivo, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer.

Citation Format: John J. Turchi, Pamela L. Mendoza-Munoz, Pamela S. VanderVere-Carozza, Navnath S. Gavande, Joseph R. Dynlacht, Joy E. Garrett, Dineshsinha Chauhan, Katherine S. Pawelczak. Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of 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 A027.
Abstract A033: The ING5 epigenetic reader regulates a subset of DNA repair genes to maintain genomic integrity
Authors: Dantas Arthur E , Al-Shueili Buthaina , Djamshidi Mahbod , Riabowol Karl
Published: January 2024

The ING family of epigenetic histone code readers (ING1-5) recognize the H3K4Me3 epigenetic mark to target histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to regulate local acetylation levels and affect transcription. We and others have shown that ING5 promotes stem cell character in normal and in cancer stem cells and that loss of ING5 promotes stem cell differentiation. Examination of an ING5 knockout (KO) mouse model showed increased levels of DNA damage in different tissues, and particularly in the male germ line. ING5 mouse embryo fibroblasts (MEFs) also show a >2-fold increase in cells containing gH2AX foci in the absence of exogenous DNA damaging agents. Examining the transcriptomes of ING5 KO and wild-type littermate MEFs indicates that several genes encoding key DNA repair proteins such as those acting in homologous recombination (BRCA1 and BRCA2) and base excision repair (PARP1) are repressed several-fold and ING5 KO MEFs show increased sensitivity to the PARP inhibitor olaparib. Given that ING5 functions to help maintain stem cell character in normal and in cancer stem cells, we propose that ING5 serves a role in maintaining a high level of DNA repair capability in stem cell populations to preserve genomic integrity.

Citation Format: Arthur E Dantas, Buthaina Al-Shueili, Mahbod Djamshidi, Karl Riabowol. The ING5 epigenetic reader regulates a subset of DNA repair genes to maintain genomic integrity [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 A033.
Abstract B014: KDM4B mutations in human cancers
Authors: Bush Wesley A. , Petreaca Ruben C.
Published: January 2024

Homology-dependent-repair (HDR) is an essential process for the error-free correction of double-strand-breaks (DSBs). The histone demethylase KDM4B plays a role in the HDR repair process, wherein its H3K9 demethylase activity aids recruitment of repair factors such as the ATM checkpoint activator and KAT5 histone acetyltransferase and remodeler to the break site. Inhibition of KDM4B has been shown to disrupt the recruitment of ATM, and KAT5, affecting other downstream HDR factors and leading to widespread unrepaired DNA damage. Both over- and under-expression of KDM4B have implications for cancer severity, and changes in KDM4B expression have been shown to affect the expression of other oncogenes outside of the HDR pathway. We performed a pan-cancer analysis of the effects of KDM4B alterations in human cancers using data from the Catalogue of Somatic Mutations in Cancers (COSMIC). We find that KDM4B mutations occur in nearly every cancer. Further, there is a tendency of co-occurring mutations between KDM4B and several HDR genes the most significant being BRCA2. Machine learning tools did not predict any of the observed KDM4B mutations to be drivers. Our data suggests that although KDM4B does not display a driver phenotype it contributes to the destabilization of DNA damage repair machinery that causes cellular transformation and immortalization.

Citation Format: Wesley A. Bush, Ruben C. Petreaca. KDM4B mutations in human cancers [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 B014.
Abstract IA010: Molecular archeology of cancer
Authors: Van Loo Peter
Published: January 2024

Tumor development is driven by changes to the genome leading to fitness advantages underlying successive clonal expansions. As somatic changes occur across most or all cell cycles, the cancer genome carries an archeological record of its past. Over the past years, we have developed several approaches to mine that archeological record from the cancer genome, which we collectively call 'molecular archeology of cancer'. Using these approaches, we are able to infer the subclonal architecture of tumors and gain key insights into the order and timing of the genomic changes that occurred over their evolutionary history. We have applied these approaches in a large-scale pan-cancer setting, showing that intra-tumor heterogeneity is pervasive across cancers and that the timelines of tumor evolution span multiple years to decades. Key driver events in tumor evolution typically occur early, and copy number gains often accumulate as punctuated bursts, commonly after genome doubling. Late genome doubling is frequent in cancer evolution and is typically followed by an increase in the rate of copy number gains. Genome duplications affect the selection landscape of copy number losses, while only minimally impacting copy number gains. Extending our timing framework to time mutational signatures, we find that, as expected, environmentally associated mutations are associated with early tumor development. We also find evidence of episodic APOBEC mutagenesis across many tumors and clear timing patterns in many mutational processes that have unknown origins. Our approaches increase the evolutionary information that can be obtained from tumor genome sequences and, therefore, improve our understanding of the developmental history of cancer.

Citation Format: Peter Van Loo. Molecular archeology of 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 IA010.
Abstract IA011: Polymerase-based bypass of atypical UV photoproducts
Authors: Roberts Steven A.
Published: January 2024

UV light is a ubiquitous environmental mutagen that is an etiological cause of skin cancers like melanoma. While the genomes of human cutaneous melanomas have high mutation burdens primarily consisting of C to T substitutions in TC and CC dinucleotides (consistent with cyclobutane pyrimidine dimer formation), many of the driver mutations contributing to disease progression involve other types of substitutions at non-dipyrimidine sequences. Our whole genome sequencing of UVB or UVC irradiated yeast has revealed non-canonical UV induced substitution types. These mutations included TA to TT and AC to TT substitutions that commonly occur as activating BRAF mutations in human melanomas. UV treatment and sequencing of deletion mutants of DNA polymerase eta, the protein mutated in human XPV patients, indicated that this polymerase does not impact TA to TT mutagenesis, but contributes to the formation of AC to TT substitutions. Surprisingly, loss of pol eta revealed additional CA to AA substitutions, highlighting another UV-induced mutation class possibly created by a non-canonical photoproduct. All novel mutation classes in pol eta deficient yeast displayed transcriptional asymmetry, consistent with the repair of the cognate lesion by transcription-coupled nucleotide excision repair. However, UV-induced mutations lacked replication asymmetry in both wild type and rad30Δ yeast, suggesting TLS occurs nearly equally on leading and lagging strands. Both TA to TT and AC to TT substitutions were dependent on DNA polymerase zeta, and altered by a mutant of DNA polymerase epsilon, suggesting the involvement of both TLS and replicative polymerases in UV-induced mutagenesis. These results emphasize the importance of non-canonical UV lesions in driving melanomagenesis, provide mechanisms of how these lesions result in mutations, and suggest the variable accuracy of TLS polymerases across from atypical UV photoproducts may alter the trajectory of skin cancer evolution in XPV patients.

Citation Format: Steven A. Roberts. Polymerase-based bypass of atypical UV photoproducts [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 IA011.
Abstract IA014: BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair
Authors: Lim Pei Xin , Jasin Maria
Published: January 2024

Tumor suppressor BRCA2 functions in multiple pathways. The role of BRCA2 in homologous recombination, also termed homology-directed repair (HDR), is particularly well known. We also showed that it has a key role in the protection of stalled replication forks from the MRE11 nuclease. Moreover, BRCA2 also suppresses the formation of single-stranded gaps during replication. We have attempted to delineate the relative contributions of these three pathways to the maintenance of genome integrity and chemotherapy response using separation of function alleles. First, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for both fork protection and gap suppression but not HDR. In mice, loss of fork protection and gap suppression do not compromise genome instability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection and gap suppression defects are also observed in Brca2 heterozygous cells from mice, likely due to reduced RAD51 stabilization at stalled forks and gaps. Sensitivity to the PARP inhibitor olaparib is greatest for HDR-deficient cells, although fork protection/gap suppression-defective cells show a weak sensitivity. Gaps arise from PRIMPOL activity, which is associated with sensitivity to 5-hydroxymethyl-2’-deoxyuridine (hmdU) and DNPH1 inhibition due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase inhibition. In summary, this work demonstrates that HDR deficiency has the major role in generating sensitivity to chemotherapeutics, although gap suppression deficiency may be targeted by specific agents.

Citation Format: Pei Xin Lim, Maria Jasin. BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair [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 IA014.
Abstract PR010: Understanding extrachromosomal telomere generation in ALT cancers
Authors: Lee Junyeop , Lee Jina , Sohn Eric J. , Taglialatela Angelo , O’Sullivan Roderick J. , Ciccia Alberto , Min Jaewon
Published: January 2024

Introduction: Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication (BIR), evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of Cytosine-rich (CCCTAA) sequences. These C-circles are unique biomarkers of ALT cells and may be generated from extrachromosomal telomeric single-stranded DNAs (ssDNAs), also unique to ALT cells, but the generation process remains undefined. Methods and results: In order to investigate C-rich ssDNA, we developed a highly sensitive method to detect single stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single stranded DNAs that are near 200 to 1500 nucleotides in size. Both telomeric ssDNAs and C-circles are abundant in cytoplasm and nucleoplasm fractions, which supports the hypothesis that telomeric ssDNA accumulation may indeed precede C-circle formation. We also found that telomeric ssDNAs originate during Okazaki fragment processing during C-rich lagging strand DNA synthesis at telomere ends during telomere elongation in ALT cancers. During lagging strand priming and synthesis, the CST-PP complex (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha) primes the telomeric C-rich strand; then, Polymerase delta and BLM helicase facilitate excessive strand displacement, leading to the accumulation of telomeric ssDNAs in the nucleoplasm and cytoplasm which is potential precursor material for C-circles in ALT cancers. Conclusion: Here, we introduce a highly sensitive 4SET method for studying telomeric ssDNA, which we used to propose a new model for the generation of telomeric C-rich ssDNAs and C-circles during ALT-mediated telomere elongation. Our work contributes to a growing body of knowledge pertaining to the idiosyncrasies of the ALT mechanism based on investigation of its unique biomarkers.

Citation Format: Junyeop Lee, Jina Lee, Eric J. Sohn, Angelo Taglialatela, Roderick J. O’Sullivan, Alberto Ciccia, Jaewon Min. Understanding extrachromosomal telomere generation in ALT cancers [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 PR010.
Data from RanBPM Has Proapoptotic Activities That Regulate Cell Death Pathways in Response to DNA Damage
Authors: Atabakhsh Elnaz , Bryce Dawn M. , Lefebvre Karen J. , Schild-Poulter Caroline
Published: January 2024

Abstract
Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein previously implicated in various signaling pathways, but whose function remains enigmatic. Here, we provide evidence that RanBPM functions as an activator of apoptotic pathways induced by DNA damage. First, transient expression of RanBPM in HeLa cells induced cell death through caspase activation, and in the long-term, forced expression of RanBPM impaired cell viability. RanBPM COOH-terminal domain stimulated the ability of RanBPM to induce caspase activation, whereas this activity was negatively regulated by the central SPRY domain. Second, small interfering RNA–directed knockdown of RanBPM prevented DNA damage–induced apoptosis, as evidenced by the marked reduction in caspase-3 and caspase-2 activation. This correlated with a magnitude fold increase in the survival of RanBPM-depleted cells. Following ionizing radiation treatment, we observed a progressive relocalization of RanBPM from the nucleus to the cytoplasm, suggesting that the activation of apoptotic pathways by RanBPM in response to ionizing radiation may be regulated by nucleocytoplasmic trafficking. Finally, RanBPM downregulation was associated with a marked decrease of mitochondria-associated Bax, whereas Bcl-2 overall levels were dramatically upregulated. Overall, our results reveal a novel proapoptotic function for RanBPM in DNA damage–induced apoptosis through the regulation of factors involved in the mitochondrial apoptotic pathway. (Mol Cancer Res 2009;7(12):1962–72)
FIGURE 5 from The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner
Authors: Mazar Joseph , Brooks Jeanne K. , Peloquin Matthew , Rosario Rosa , Sutton Emma , Longo Matthew , Drehner Dennis , Westmoreland Tamarah J.
Published: January 2024

Effect of Zika viral treatment on CD24-exogenously expressing SK-N-AS tumors and CD24 stably knocked-down IMR-32 cells. ZIKV was introduced once at a concentration of 2 × 106 pfu for all tumors. A, Evaluation of the application of ZIKV to SK-N-AS/WT, SK-N-AS/VO (Vector Only control), and SK-N-AS/CD24 (stable exogenous expression of CD24) tumors in NCr nude mice, measuring for changes in tumor size (mm3). Data are depicted through day 12 posttreatment. All comparisons utilized an n = 6 for both vehicle- and Zika-treated cohorts. Error bars represent SD. *, P < 0.05 from SK-N-AS/WT or /VO—vehicle, one-way ANOVA for days 2, 7, and 9. B, Comparison of the mean tumor size between viral-treated versus vehicle-treated tumors for SK-N-AS/WT, SK-N-AS/VO, and SK-N-AS/CD24, measured at day 9 posttreatment. Tumor sizes were normalized to vehicle-treated SK-N-AS/WT. Error bars represent SD. *, P < 0.05 from SK-N-AS/WT or /VO—vehicle, one-way ANOVA. C, Relative expression for CD24 was assessed using qRT-PCR comparing cells (in vitro) with tumors (in vivo) for SK-N-AS/WT, SK-N-AS/VO, and SK-N-AS/CD24. Error bars represent SD. *, P < 0.05 from SK-N-AS/WT or /VO—cells; **, P > 0.05 from SK-N-AS/WT or /VO—tumor, one-way ANOVA. D, Relative expression for CD24 was assessed using qRT-PCR comparing IMR-32/WT cells, IMR-32/shRNA con, and IMR-32/CD24 shRNA (stable). All qPCR expression data shown were normalized to GAPDH and are the composite of triplicate wells acquired from triplicate experiments. *, P < 0.05 from IMR-32/WT or /shRNA con, one-way ANOVA. E, Western blot analysis of CD24 expression in the total cell lysates of IMR-32 cells and stable derivatives. GAPDH was used as a load control. F, Bright-field comparison of IMR-32/WT, IMR-32/shRNA con, and IMR-32/CD24 shRNA stable cells on day 3 posttreatment with ZIKV. Cells were treated with either no virus, an MOI = 1, or an MOI = 10 of virus. Images were generated at a 40x magnification with a 10x zoom. G, Time course of cellular toxicity in IMR-32/WT, IMR-32/shRNA con, and IMR-32/CD24 shRNA stable cells. Cells were treated with either no virus or an MOI = 10 of virus. Cultures were treated with CellTox Green and measured every 24 hours for 5 days postinfection. The results were normalized to uninfected controls. Data shown are the composite of sextuplicate wells, performed in triplicate from independent measurements. Error bars represent SD. *, P < 0.05 from IMR-32/WT or /shRNA con, one-way ANOVA for days 2, 3, and 4.
What Did We Learn about VADs in 2019?
Authors: Guglin Maya
Published: January 2024

This is our 6th annual literature review on mechanical circulatory support (MCS) devices. Our previous reports for 2014, 2015, 2016, 2017, 2018 were published as open access articles and were well received by the readers. In this paper, we summarize the most interesting and important, from our standpoint, publications from 2019. As we have done for the past two years, a section on extracorporeal membrane oxygenation (ECMO) is included and primarily addresses new developments in veno-arterial ECMO use.
Unusual Case of Thrombosis in LVAD Patient with COVID-19 — Diagnostic Challenges
Authors: Frick William , Mallory Ryan , Guglin Maya , Anderson Eve , Lushin Erin , Vivo Rey , Saleem Kashif , Rao Roopa
Published: January 2024

We present the first reported case of left ventricular assist device (LVAD) pump thrombosis in the setting of the coronavirus pandemic. We describe the clinical features of the case which helped to differentiate coronavirus disease 19 (COVID-19) from LVAD pump thrombosis. The patient is 56-year-old female supported by destination LVAD therapy. She was originally implanted with a HeartMate II device in 2015 and underwent two pump exchanges in 2017 and 2019 for pump thrombosis, despite medication adherence. Shortly after routine lab work revealed near doubling of her lactate dehydrogenase (LDH) levels, she tested positive for COVID-19. She then developed power spikes and symptomatic heart failure, which prompted hospital admission. An initial computed tomography (CT) scan showed bilateral ground glass opacities, but repeat testing was negative for COVID-19. Her LVAD pump thrombosis was treated with aspirin, unfractionated heparin, and cangrelor, which was guided by thromboelastogram. Over several weeks, her LDH returned to baseline, and she was transitioned from cangrelor to ticagrelor and from heparin to warfarin. A repeat CT scan after several days of IV diuresis showed resolution of the ground glass opacities.
Extended Cable for Left Ventricular Assist Devices for Monitoring Isolated Patients during the COVID-19 Pandemic
Authors: Waxali Neal , Kenward James , Varona Yasser , Loza Laurie , Bhimaraj Arvind
Published: January 2024

We present a method to create an extended cable for patients who are supported by left ventricular assist devices (LVADs) while infected with SARS-CoV-2. The arrangement described facilitates the LVAD monitor console’s positioning outside of the patient’s room to minimize exposure of the mechanical circulatory support team to the novel coronavirus.
Evaluation of Outpatient Anticoagulation Bridging After Left Ventricular Assist Device Implantation
Authors: Rainess Rebecca , Alderman Laren , Cicci Teresa , Yoder Monty , Pisani Barbara , O’Neill Thomas , Malaver Diego
Published: January 2024

Objective: The aim of this study is to evaluate the safety of outpatient anticoagulation bridging following left ventricular assist device (LVAD) implantation. Methods: This study is a retrospective, single-center cohort of adult patients who underwent LVAD implantation (HeartMate II™ or HeartMate 3™) and received warfarin and at least one dose of therapeutic enoxaparin or fondaparinux for outpatient anticoagulation bridging. The primary endpoint was the incidence of bleeding complications within one week of completing the bridging episode. Secondary endpoints included the incidence of new hemolysis or thrombosis within 30 days, INR at the time of bridge initiation, duration of anticoagulation bridge, and management of bleeding events associated with the bridging episode. Results: Data from 155 bridging episodes in 44 patients were analyzed. The primary endpoint occurred 30 times during 26 encounters. Of these events, 14 systemic bleeding episodes (9.03%) occurred. Localized bleeding complications consisted of injection site adverse reactions, including bruising (7.74%), bleeding (1.94%), and hematomas (0.65%). The majority of bleeding episodes were successfully self-managed by the patient and required monitoring only (83.33%). Only one new hemolysis event occurred (0.65%) and no new thrombotic events occurred within 30 days of any bridging episode. Conclusion: Results of this study suggest that outpatient anticoagulation bridging in the LVAD patient population is associated with a moderate risk of localized bleeding and warrants careful follow-up monitoring.
A "Blinking" Left Ventricular Assist Device
Authors: Guglin Maya , Rao Roopa
Published: January 2024

A 61-year-old male with history of coronary artery disease and end stage ischemic cardiomyopathy underwent a successful implantation of a HeartMate 3 device with an uneventful recovery. However, after 6 months, he complained of increased fatigue, intermittent dizziness, and weakness after minor exertion. The pulsatility index was increased to 8, but the left ventricular assist device (LVAD) was otherwise functioning properly. No major changes in either medications or laboratory results were noted. The patient started getting low flow alarms seven months after the procedure and the dizziness increased. On the controller, a continuously changing (“blinking”) speed was noted (Supplemental Video 1). There was a palpable peripheral pulse and a measurable systolic and diastolic systemic pressure of 105/70 mmHg. There were no signs of hemolysis. The patient was admitted for observation, and a transesophageal echocardiogram was obtained (Supplemental Video 2). The main findings included: 1. Partially recovered left ventricle with ejection fraction 40-45% 2. Small left ventricular cavity with the inflow cannula touching the septum on every other beat 3. Hypokinetic and moderately enlarged right ventricle. After decreasing the speed of the LVAD to from 5200 revolutions per minute to 4800 and giving oral and intravenous fluids, the situation improved. Unfortunately, the symptoms did not completely resolve, and the patient remains admitted to await a cardiac transplantation. This case demonstrates an unusual pattern of a “blinking” LVAD speed due to left ventricular recovery with a small cavity and frequent suctions.