bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A029: DDR pathway genes in CRT resistance: Insights from longitudinal whole exome sequencing in cervical cancer
Authors: Ehsan Shafqat F. , Wang Rui , Wu Xiaogang , Karpinets Tatiana V. , Bronk Julianna K. , Kapadia Chiraag , Song Xingzhi , Futreal Andrew M. , Klopp Ann H. , Harris Tim , Zhang Jianhua , Colbert Lauren E. 
Published: January 2024

Abstract
Background: Cervical cancer patients undergoing CRT face a 40% mortality rate, and the genetic underpinnings of radiation response variability remain under-explored. Our laboratory has developed a noninvasive cervical swab biopsy method, complemented by a custom computational pipeline that facilitates longitudinal whole-exome sequencing (WES) from samples with minimal tumor purity. This investigation used the pipeline for the identification of persistent or clonally expanded genes during CRT. The aim is to identify genes and pathways associated with radiation resistance. Methods: Tumor swabs from 30 cervical cancer patients were collected at baseline (week 1) and CRT completion (week 5) paired with corresponding buccal samples. We performed whole exome sequencing, adjusting for calculated tumor purity with strict mutation calling using several tools. Results: Our analysis revealed genes in known DNA damage and repair (DDR) pathways, in addition to unique genes not previously associated with DDR and radiation response, including BAGE3, CGREF1, XRCC5, ATM, LINP1, etc. Future work will include validation of these identified genes in vitro radiation sensitivity screening and validation in large-scale datasets, such as The Cancer Genome Atlas, and network and pathway analysis. Discussion: This exploratory analysis suggests that serial sequencing during chemoradiation to identify novel radiation sensitization targets is feasible and further study is needed. Their recurring involvement in DDR pathways underscores their pivotal role in CRT resistance mechanisms. Conclusions: Through longitudinal WES, we've deepened the understanding of CRT resistance and flagged potential targets for improved radiosensitization strategies in cervical cancer. Future Directions: We are moving towards experimental validation of these genes in patient-derived organoids using CRISPR/Cas9 and CyTOF. Additionally, we'll be screening FDA-approved drugs to pinpoint effective radiosensitizers. A major upcoming effort is the development of a CRT resistance map, enhanced by machine learning, promising a transformative impact on cervical cancer treatment.
Citation Format: Shafqat F. Ehsan, Rui Wang, Xiaogang Wu, Tatiana V. Karpinets, Julianna K. Bronk, Chiraag Kapadia, Xingzhi Song, Andrew M. Futreal, Ann H. Klopp, Tim Harris, Jianhua Zhang, Lauren E. Colbert. DDR pathway genes in CRT resistance: Insights from longitudinal whole exome sequencing in cervical 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 A029.
Abstract B010: DNA-PKcs-dependent phosphorylation of RECQL4 promotes NHEJ by stabilizing the NHEJ machinery at DNA double-strand breaks
Authors: Davis Anthony J. 
Published: January 2024

Abstract
RECQL4, one of the five RecQ helicases in mammalian cells, guards the genome by promoting DNA replication, DNA repair, and telomere maintenance. Mutations in human RECQL4 are associated with three genetic disorders, Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome, which display accelerated aging, developmental abnormalities, and a predisposition to cancer. It is believed that accumulation of DNA damage contributes to the clinical features observed in patients with RECQL4 mutations. Previously, RECQL4 was implicated in promoting the DNA double strand break repair pathway non-homologous end joining (NHEJ), but its role in the pathway remains unresolved. In this study, we report that RECQL4 stabilizes the NHEJ machinery at DSBs to promote repair. Specifically, we find that RECQL4 interacts with the NHEJ core factor DNA-PKcs and the interaction is increased following IR. RECQL4 promotes DNA end bridging mediated by DNA-PKcs and Ku70/80 in vitro and the accumulation/retention of NHEJ factors at DSBs in vivo. Moreover, interaction between DNA-PKcs and the other core NHEJ proteins following IR treatment is attenuated in the absence of RECQL4. These data indicate that RECQL4 promotes the stabilization of the NHEJ factors at DSBs to support formation of the NHEJ long-range synaptic complex. In addition, we observed that the kinase activity of DNA-PKcs is required for accumulation of RECQL4 to DSBs and that DNA-PKcs phosphorylates RECQL4 at six serine/threonine residues. Blocking phosphorylation at these sites reduced the recruitment of RECQL4 to DSBs, attenuated the interaction between RECQL4 and NHEJ factors, destabilized interactions between the NHEJ machinery, and resulted in decreased NHEJ. Collectively, these data illustrate reciprocal regulation between RECQL4 and DNA-PKcs in NHEJ and the potential that dysfunctional NHEJ may play a role in RECQL4-associated genetic disorders and tumorigenesis.
Citation Format: Anthony J. Davis. DNA-PKcs-dependent phosphorylation of RECQL4 promotes NHEJ by stabilizing the NHEJ machinery at DNA double-strand breaks [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 B010.
Abstract B013: A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS)
Authors: Niedmann Cole , Sainz Judit Jimenez 
Published: January 2024

Abstract
Deleterious mutations in homology-directed repair pathway genes impact both future cancer risk and therapeutic intervention options for cancer diagnosis and prognosis. Homology-directed repair pathway is a high-fidelity DNA repair pathway for resolving double-strand breaks (DSBs) throughout the human genome. BRCA2, as a homology-directed repair factor, is essential to ensure genome integrity through an error-free process. Deleterious BRCA2 mutations increase the lifetime risk of breast, ovarian, melanoma, prostate, and pancreatic cancers. Deleterious BRCA2 mutations cover only 25% of the total BRCA2 mutations identified in the population by genetic testing whereas 60% are mutations with unknown connection to the disease called Variants of Uncertain Significance (VUS). The majority of BRCA2 VUS are missense mutations with one point mutation which could potentially alter BRCA2 cellular localization and/or nuclear functions. Thus, evaluating BRCA2 cellular localization and function in BRCA2 missense carriers and tumors is urgently needed to provide clinical guidance regarding cancer risk and treatment options. We have identified a paradoxical relationship between BRCA2 nuclear import and treatment. Deleterious missense mutations in the DNA binding domain of BRCA2 direct the protein to the cytosol which increase sensitivity to PARP inhibitors (PARPi) and platinum drugs. Therefore, although BRCA2 mislocalization might be a cause of cancer, keeping it out of the nucleus allows for much better treatment outcomes. Here, we present how BRCA2 cancer-driver missense mutations lead to cytosolic mislocalization and how BRCA2 localization can be used as a diagnostic tool to stratify patients. Our robust multi-step molecular approach will guide future clinical decision rules surrounding BRCA2 VUS. By providing reliable and accurate functional assays to correctly evaluate the pathogenicity of BRCA2 VUS, our goal is to improve personalized medicine by providing actionable information to patients and their physicians.
Citation Format: Cole Niedmann, Judit Jimenez Sainz. A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS) [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 B013.
Abstract B023: SMARCAL1 is a novel candidate therapeutic target for ALT-positive osteosarcoma
Authors: Taglialatela Angelo , Chen Xiao , Khan Zahra Fatema , Dela Cruz Filemon , Shivi Dua , Oswald Dillon , Benura Azeroglu , Denchi Eros Lazzerini , Jaewon Min , Kung Andrew L. , Ciccia Alberto 
Published: January 2024

Abstract
The DNA translocase SMARCAL1 has been characterized by our laboratory and others as a DNA replication-associated factor that promotes the remodeling of stalled replication forks to facilitate the repair of DNA damage and the restart of DNA synthesis. Recent genome-wide analyses of CRISPR-Cas9 loss-of-function screens in pediatric cancer cell lines have suggested an essential function for SMARCAL1 in a subset of pediatric tumors (Dharia NV et al., Nature Genetics, 2021). In agreement with these observations, pan-cancer analysis of dependency scores in over 1,000 cell lines from the DepMap project revealed an important role for SMARCAL1 in tumors of mesenchymal origin and especially in osteosarcoma. We found that SMARCAL1 dependency in osteosarcoma is selectively associated with lack of telomerase expression. In the absence of telomerase, cancer cells mostly rely on a recombination-based mechanism, known as ALT (Alternative Lengthening of Telomeres), for the maintenance of their telomere length. Surprisingly, by comparing genome-wide CRISPR screening data of known ALT-positive vs ALT-negative osteosarcoma cell lines, we found that SMARCAL1 is among the genes that are most selectively essential in ALT-positive tumors. We validated in multiple cellular models a strict correlation and functional relationship between ALT status and SMARCAL1 dependency. In line with previous findings (Cox KE et al., Cell Reports, 2016), we observed that SMARCAL1 localizes to a subset of telomeres in ALT-positive cells and loss of SMARCAL1 induces accumulation of telomere damage. SMARCAL1 enzymatic activity and its RPA-binding function contribute to suppress DNA damage in ALT-positive cells. Furthermore, our studies suggest that SMARCAL1 protects telomere stability in ALT-positive cancer cells by limiting PRIMPOL-mediated restart of stalled replication forks. In addition, SMARCAL1 deficiency enhances cell-intrinsic immune response and anti-tumor immunity. Collectively, our studies have uncovered SMARCAL1 as a novel candidate therapeutic target for the treatment of ALT-positive cancer patients. In these patients, SMARCAL1 inhibition may have a dual beneficial effect by promoting selective cancer cell toxicity combined with stimulation of anti-tumor immunity and enhancement of immunotherapy response.
Citation Format: Angelo Taglialatela, Xiao Chen, Zahra Fatema Khan, Filemon Dela Cruz, Dua Shivi, Dillon Oswald, Azeroglu Benura, Eros Lazzerini Denchi, Min Jaewon, Andrew L. Kung, Alberto Ciccia. SMARCAL1 is a novel candidate therapeutic target for ALT-positive osteosarcoma [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 B023.
Abstract IA001: Single strand DNA GAP accumulation as a functional biomarker for USP1 inhibitor sensitivity
Authors: D'Andrea Alan D. 
Published: January 2024

Abstract
Recent studies suggest that PARP inhibitors and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA gaps (ssDNA gaps) at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetic lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Here, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells. USP1 inhibition increased monoubiquitinated PCNA at replication forks and resulted in accumulation of ssDNA gaps in BRCA1-deficient cancer cells. Knockdown of RAD18, the E3 ubiquitin ligase known to ubiquitinate PCNA, caused USP1 inhibitor resistance and suppression of ssDNA gaps. ssDNA gap accumulation induced by USP1 inhibition correlates with drug sensitivity of BRCA1-mutated cancer cells and overcomes PARP inhibitor resistance in cell line and xenograft models. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. A set of patient-derived ovarian cancer organoids (PDOs) were used to confirm the sensitivity of BRCA1-deficient cells to USP1 inhibition. Five PDOs were derived from patients with high grade-serous ovarian cancer (HGSOC). Among the five PDOs, two of them were from tumors harboring germline BRCA1 pathogenic mutations. BRCA1-mutant PDOs, but not BRCA1-WT PDOs, were sensitive to a USP1 inhibitor and to PARP inhibitor monotherapies. The accumulation of ssDNA gaps after treatment with a USP1 inhibitor or PARP inhibitor correlated with the sensitivity to these drugs in all the models tested. Moreover, the combination of a PARP inhibitor and USP1 inhibitor showed synergy in a BRCA1-WT model, which was resistant to both monotherapies. Interestingly, ssDNA gaps accumulated with the combination treatment and not with monotherapy in this model. Ovarian cancer PDOs therefore provide a powerful tool for rapid in vitro sensitivity testing. The detection of ssDNA gap accumulation may be a useful predictive biomarker for response to USP1 inhibition as monotherapy or in combination in ongoing clinical trials.
Citation Format: Alan D. D'Andrea. Single strand DNA GAP accumulation as a functional biomarker for USP1 inhibitor sensitivity [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 IA001.
Abstract PR001: DNA damage-induced senescence as a driver of glioblastoma recurrence
Authors: Burma Sandeep , Tomimatsu Nozomi , Cristofaro Luis , Kanji Suman , Jordan Benjamin , Mukherjee Bipasha 
Published: January 2024

Abstract
Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR), yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. An understanding of mechanisms driving GBM recurrence is critical for improving therapy. During GBM therapy, both the tumor and the normal brain tissue surrounding the tumor are treated with up to 60 Gy of IR. IR is a potent inducer of senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting proteases, cytokines and growth factors that create a senescence-associated secretory phenotype (SASP). We have shown previously that IR-induced senescence of astrocytes in the brain leads to the secretion of SASP factors that promote the growth and invasiveness of tumor cells in mouse models of GBM (Fletcher-Sananikone, et al, Cancer Research, 2021). Following up on this study, we irradiated a panel of GBM cell lines and found that a significant fraction of these cells senesced rapidly in a p21-dependent manner. Senescent glioma cells upregulated SASP genes in a NF-kB-dependent manner, prominently, the interleukin IL6, which is an activator of the JAK-STAT pathway. Conditioned media from senescent GBM cells activated the JAK-STAT pathway in non-senescent GBM cells and promoted tumor cell proliferation and radiation resistance. Interestingly, conditioned media from senescent GBM cells could also activate the NF-kB pathway and induce SASP in non-senescent cells. These results indicate that senescent GBM cells can activate pro-tumorigenic pathways in their non-senescent counterparts and SASP can spread from senescent to non-senescent cells. Bioinformatic analyses of the transcriptomic profiles of irradiated GBM cells and the TCGA database revealed that the inhibitor of apoptosis protein cIAP2 is a critical survival factor for senescent glioma cells. We find that targeting cIAP2 using Smac mimetics triggers apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells like astrocytes. Upregulation of cIAP2 in irradiated tumor cells was also seen in multiple PDX models of GBM. Using these PDX lines, we demonstrate that adjuvant senolytic treatment can delay or even prevent recurrence in pre-clinical mouse models of GBM. In sum, our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence after radiotherapy.
Citation Format: Sandeep Burma, Nozomi Tomimatsu, Luis Cristofaro, Suman Kanji, Benjamin Jordan, Bipasha Mukherjee. DNA damage-induced senescence as a driver of glioblastoma recurrence [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 PR001.
Abstract PR009: SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion
Authors: Leuzzi Giuseppe , Vasciaveo Alessandro , Taglialatela Angelo , Chen Xiao , Firestone Tessa M. , Hickman Allison R. , Mao Wendy , Thakar Tanay , Vaitsiankova Alina , Huang Jen-Wei , Cuella-Martin Raquel , Hayward Samuel B. , Kesner Jordan S. , Ghasemzadeh Ali , Nambiar Tarun S. , Ho Patricia , Rialdi Alexander , Hebrard Maxime , Li Yinglu , Gao Jinmei , Gopinath Saarang , Adeleke Oluwatobi A. , Venters Bryan , Drake Charles G. , Baer Richard , Izar Benjamin , Guccione Ernesto , Keogh Michael-Christopher , Guerois Raphael , Sun Lu , Lu Chao , Califano Andrea , Ciccia Alberto 
Published: January 2024

Abstract
Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy.
Citation Format: Giuseppe Leuzzi, Alessandro Vasciaveo, Angelo Taglialatela, Xiao Chen, Tessa M. Firestone, Allison R. Hickman, Wendy Mao, Tanay Thakar, Alina Vaitsiankova, Jen-Wei Huang, Raquel Cuella-Martin, Samuel B. Hayward, Jordan S. Kesner, Ali Ghasemzadeh, Tarun S. Nambiar, Patricia Ho, Alexander Rialdi, Maxime Hebrard, Yinglu Li, Jinmei Gao, Saarang Gopinath, Oluwatobi A. Adeleke, Bryan Venters, Charles G. Drake, Richard Baer, Benjamin Izar, Ernesto Guccione, Michael-Christopher Keogh, Raphael Guerois, Lu Sun, Chao Lu, Andrea Califano, Alberto Ciccia. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion [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 PR009.
SULFATE AMMONIUM FERTILIZER ON THE OFF-SEASON PRODUCTION OF SNAKE FRUIT (Salacca sumatrana Becc.)
Authors: Adelina Rasmita - , Suliansyah Irfan , Syarif Auzar , - Warnita - 
Published: January 2024

Sidimpuan snake fruit is one of the local specialties of Padangsidimpuan City in Sumatra. The fruit is known for its sweet, sour and astringent taste which differentiates it from Pondoh and Balinese snake fruit. However, snake fruit farmers have been experiencing an increasing failure rate of fruit-set during the off-season which has led to a decrease in production. Â Â Use fertilization and drip irrigation in the off-season has been suggested as a solution. This research investigates the use of these to overcome the failure of fruit set to optimize production of Sidimpuan snake fruit throughout the year by determining the optimal dosage of ammonium sulfate fertilizer and drip irrigation for fruit set and production in the off-season. This research used a split-plot design with the main plot for drip irrigation and the subplot for ammonium sulfate. Observation parameters include the number of flower and fruit bunches, fruit set percentage and a nutrient analysis of the leaves. The results revealed that drip irrigation had a significant effect on the observed variables of fruit set and number of harvested fruit bunches.Â Drip irrigation had a significant effect on the fruit set percentage and the number of harvested fruit bunches. The best combination of treatments was also discovered to be 400 g ammonium sulfate fertilizer per plant and drip irrigation 3000 ml/plant. The fertilization period of July-Sept gave an off season harvest that was able to match the fruit set percentage (10.76% difference) and number of fruit bunches that were formed (25.65% difference ) by the April-June fertilization for the on-season harvest demonstrating that drip irrigation and ammonium sulfate can overcome fruit set failure in Sidimpuan snake fruit during the off-season.
The First U.S.-Based Soviet Nuclear Spy: The Saga of Clarence Hiskey and Arthur Adams
Authors: Klehr Harvey , Haynes John Earl 
Published: January 2024

Abstract
Years before anything was publicly disclosed about the nuclear espionage of Julius and Ethel Rosenberg, Klaus Fuchs, and Theodore Hall, the U.S. Federal Bureau of Investigation (FBI) and U.S. Army Intelligence identified Clarence Hiskey, a Manhattan Project scientist, as a Soviet spy helping to provide highly sensitive nuclear weapons information. The two agencies kept watch on a Soviet intelligence officer, Arthur Adams, who was living illegally in the United States and serving as Hiskey's control officer. Despite an extensive investigation, neither Hiskey nor Adams was ever arrested. Although Adams was named in a sensational tabloid newspaper article shortly after the end of World War II and closely shadowed by the FBI, he was able to flee to the Soviet Union. Hiskey was never indicted for espionage. Based on material released from declassified Russian archives and FBI files made available under the Freedom of Information Act, the article tells the story of the first U.S.-based nuclear spy and how he got away with it.
The Committee for the Free World and the Defense of Democracy
Authors: Søndergaard Rasmus Sinding 
Published: January 2024

Abstract
The Committee for the Free World (CFW), a U.S.-based advocacy group, constituted a key foreign policy branch of the neoconservative movement in the late Cold War. This article offers the first comprehensive examination of the CFW, tracing the motivations for its establishment, the scope of its activities, its position within the neoconservative movement, and its relations with the Reagan administration. The group sought to ensure that the defense of democracy would be a core component of U.S. foreign policy, but in the 1980s this mainly encompassed the defense of existing Western democracies against Communism rather than an attempt to spread democracy to non-democratic authoritarian states. By tracing the CFW's vision for democracy promotion, the article unearths a key intellectual lineage for the more active democracy promotion agenda in U.S. foreign policy that emerged in the post–Cold War world.