bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplemental Figure 8 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 8. Association of mobile phone use status (users vs. non-users) with incident site-specific cancers in women, excluding the cases identified before Oct 1, 2012.
Supplemental Figure S3 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

Measurement model for latent variable service quality at pharmacy.
Supplemental Figure 1 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 1. Flowchart of study participants.
Supplementary Table S42 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 S42 shows intra-class correlation coefficients resulting from the full mixed model analysis for all analytes and from the mixed model analysis when no covariates were included in the model.
Data 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

AbstractBackground:
Previous studies have suggested anthocyanidins or anthocyanidin-rich foods and extracts exhibit protective effects against various cancers. However, the relationship between dietary anthocyanidins and the risk of biliary cancer remains uncertain.
Methods:
This study used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to investigate the relationship between total anthocyanidins intake and biliary cancer incidence. Cox regression analysis was conducted to estimate HRs and corresponding 95% confidence intervals (CI) for the incidence of biliary cancer, with adjustments made for confounding factors. A restricted cubic spline model was employed to examine the dose–response relationship. In addition, subgroup and sensitivity analyses were conducted to evaluate potential interactions and test the model's robustness.
Results:
During 8.9 years and 872,645.3 person-years of follow-up, 95 cases of biliary cancer were observed. The incidence rate of biliary cancer in this study was 11 cases per 100,000 person-years. Using the fully adjusted Cox regression model, the inverse association was observed between total anthocyanidins intake and the risk of biliary cancer (HR Q4 vs..Q1: 0.52; 95% CI: 0.29–0.91; Ptrend = 0.043). This association remained significant in sensitivity analyses. A linear dose–response relationship (Pnonlinearity = 0.118) and potential interaction with drinking status (Pinteraction = 0.033) were identified.
Conclusions:
This study provides evidence of an inverse association between total anthocyanidins intake and biliary cancer incidence.
Impact:
Our study found a total anthocyanidin-rich diet was associated with a reduced risk of biliary cancer in Americans ages 55 to 74 years.
Data 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

AbstractBackground:
We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk.
Methods:
A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 (“baseline”), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders.
Results:
During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile (“most adherent”) of the standardized lifestyle score, compared with lowest (“least adherent”), a HR of 0.82 [95% confidence interval (CI): 0.74–0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67–0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk.
Conclusions:
Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk.
Impact:
With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits.
Abstract A008: Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
Authors: Saatci Ozge , Cetin Mein , Uner Meral , Tokat Unal Metin , Chatzistamou Ioulia , Ersan Pelin Gulizar , Montaudon Elodie , Akyol Aytekin , Aksoy Sercan , Uner Aysegul , Marangoni Elisabetta , Sajish Mathew , Sahin Ozgur
Published: January 2024

Estrogen receptor (ER)-positive (ER+) breast cancer has the highest incidence rate and accounts for around 75% of all cases. Endocrine therapy and CDK4/6 inhibitors are the standard of care (SOC) in ER+ breast cancer; however, resistance is common, and it greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun-mediated transcription. Importantly, we demonstrated that high PDE4D mRNA and protein expression is associated with dramatically worse disease-free survival and overall survival in endocrine therapy-treated ER+ breast cancer. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status in multiple acquired SOC resistant cell line models, primary cultures and organoids of endocrine resistant ER+ PDXs in vitro and in vivo, providing actionable targets for restoring SOC efficacy. Considering the availability of potent and non-toxic PDE4D inhibitors, clinically approved EGFR and PARP1 inhibitors, our findings have great translational potential.

Citation Format: Ozge Saatci, Mein Cetin, Meral Uner, Unal Metin Tokat, Ioulia Chatzistamou, Pelin Gulizar Ersan, Elodie Montaudon, Aytekin Akyol, Sercan Aksoy, Aysegul Uner, Elisabetta Marangoni, Mathew Sajish, Ozgur Sahin. Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A008.
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

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

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

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

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

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

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

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.
Supplementary Figure 8 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

The comparison of the relative expression of CD24 across paired neuroblastoma cells and tumors in Kaplan-Meier survival study.
Improved outcomes in the treatment of post-myocardial infarction ventricular septal defect with percutaneous TandemHeart left ventricular mechanical circulatory support
Authors: Loyalka Pranav , Nascimbene Angelo , Nathan Sriram , Radovancevic Rajko , Raman Ajay , Patel Manish , Rajagopal Keshava , Kar Biswajit , Gregoric Igor
Published: January 2024

Background Post-myocardial infarction (MI) ventricular septal defect (VSD) is associated with 40% - 50% of peri-procedural mortalities; however, it is amenable to catheter-based therapies. We retrospectively investigated the impact of state-of-the-art bridging percutaneous left ventricular mechanical circulatory support (MCS) using the TandemHeart® (TH) ventricular assist device (VAD) on a patient with post-MI VSD. Results From July 2008 to March 2014, 23 patients were referred for treatment of post-MI VSD. Initially, 18/23 patients required MCS; 12 received an intra-aortic balloon pump (IABP), while 6 received initial TH support. Seven of the IABP patients later required TH support. Catheter-based device VSD closure was performed in 18 of the patients; however, three patients required conversion to conventional open cardiac surgical repair via VSD patch closure due to failure of the catheter-based approach. Five patients with TH underwent planned open cardiac surgical repair due to an anticipated lack of suitability for catheter-based treatment. Results revealed that delayed closure after MI correlated with improved survival. Overall, 30-day and 6-month survival rates were 83% (19/23) and 70% (16/23), respectively. Conclusions Further, Qp/Qs ratios of
Predicting Bleeding and Thrombosis Complications in Patients with Continuous Flow Left Ventricular Assist Devices
Authors: Zacholski Kyle , Huan William , McCann Justin , Schadler Aric , Cook Aaron , Parli Sara , Sieg Adam
Published: January 2024

Background: Left ventricular assist device (LVAD) therapy has been proven to relieve heart failure symptoms and improve survival, but is not devoid of bleeding and/or thrombotic complications. Risk stratification tools have been utilized in other cardiovascular disease populations to estimate the risk of bleeding and thrombosis with and without anticoagulation, including the HAS-BLED, HEMORR2HAGES, CHADS2 and CHA2DS2-VASc models. The study objective was to evaluate the predictive value of available risk models for bleeding and thrombotic complications in patients with an LVAD within one year of implantation. Methods: This was a retrospective, single-center analysis of patients implanted with the HeartMate II continuous-flow LVAD from July 2011 to June 2016. All patients who received an LVAD within the study period were eligible for inclusion. The primary endpoint was the first occurrence of bleeding or thrombosis within one year from implantation. Baseline risk model scores were calculated at the time of LVAD implantation. Chi-square and student’s t-test were used to measure baseline differences and compare mean risk model scores between patients who had an event. A receiver operator characteristic (ROC) curve analysis was performed to evaluate the accuracy of the risk models to predict an event. Results: A total of 129 patients underwent LVAD implantation within the study time period. Mean CHADS2, CHA2DS2-VASc, and HAS-BLED scores were not significantly different in patients with and without an event. The mean HEMORR2HAGES score was 3.09 and 2.51 in those with and without a bleeding event, respectively (p = 0.008). The ROC curve area for the HEMORR2HAGES model was the highest at 0.620. Conclusion: The HAS-BLED, HEMORR2HAGES, CHADS2and CHA2DS2-VASc risk stratification models did not accurately predict bleeding or thrombosis events in our population. The mean HEMORR2HAGES model score was higher in patients who experienced a bleeding event. However, this model did not have strong positive predictive value. Better risk models are needed to predict bleeding and thrombotic events in this patient population.
Modeling Hospital-Wide Extracorporeal Cardiopulmonary Resuscitation: Pros and Cons
Authors: Joshi Shiksha , Shringi Sandipan , Sira Manpreet , Guglin Maya
Published: January 2024

Background: We aimed to analyze the potential benefits of implementing a hospital-wide extracorporeal cardiopulmonary resuscitation (ECPR) protocol. Methods: We analyzed in-hospital cardiac arrests in a large, academic hospital for two consecutive years. For this model, we assumed that ECPR would be started in all adults, with no upper age limit, who have a full code status. We excluded codes lastingminutes, arrests with asystole as an initial rhythm, and patients with hemorrhagic shock or who coded due to new stroke (contraindications for anticoagulation). We calculated how many extra lives could be saved per year if ECPR was initiated during each code meeting these criteria. Results: During two consecutive years, a total of 710 in-hospital cardiac arrests occurred. We excluded 91 codes due to bleeding or new stroke, 96 cases with asystole as an initial rhythm, and 206 codes lasting less than 15 minutes. In the remaining 317 codes, ECPR could have been used. In 229 cases out of 317, patients survived conventional CPR, so ECPR would be futile. Out of remaining 88 codes, only 38 (3.5%) were due to reversible cardiac or non-cardiac emergencies and resulted in death. They could have favorable outcomes if ECPR was used. Using the Extracorporeal Life Support Organization data, survival to discharge after ECPR is about 30%. So, we estimate that 13 patients (1.2%) could have been saved in 2 years, or ~7 patients per year. Considering 317 veno-arterial extracorporeal membrane oxygenation (VA ECMO) initiations, the ratio would be 24.4 VA ECMO initiations per one life saved. Conclusion: An implementation of a hospital-wide ECPR could change outcomes from unfavorable to favorable in 1.2% of patients, at the cost of initiation of 24.4 VA ECMO initiations per one life saved.
Cutting the Cord: A Case of Late Presenting Driveline Infection
Authors: Laughey Brian , Eyadiel Lauren , Pisani Barbara
Published: January 2024

Ventricular assist device (VAD) related infection, specifically driveline infection, is a common complication after VAD implantation. A 45-year old patient with a delayed skin infection at the site of the original driveline nearly one year after VAD inactivation and surgical driveline burial was treated with antibiotics and surgical debridement for approximately six months. Continued discharge at driveline site and growth of methicillin susceptible Staphylococcus aureus resulted in the recommendation of explantation of the VAD. Post-VAD explantation, the patient remains symptom free and without infection 21 months following explant.
Lactate Dehydrogenase Rising: Bleeding or Clotting?
Authors: Long Ashleigh , Yehya Amin , Baran David
Published: January 2024

Modern continuous-flow ventricular assist devices (VADs) have greatly improved the survival of patients with end stage heart failure. However, they are associated with adverse effects, including cerebrovascular accidents (CVA), bleeding, infection, and device thrombosis. Definitive measures to evaluate for pump thrombosis can be challenging; hence, multiple laboratory and imaging modalities have been studied to help guide decision making. Lactate dehydrogenase (LDH) has proven to be a reliable test when used in the appropriate clinical settings to help diagnose pump thrombosis. When a patient presents with both signs of life-threatening cerebral hemorrhage and VAD thrombosis, the clinical picture can be quite challenging. We present a case with intracerebral hemorrhage that was associated with a significant increase in LDH and created a clinical dilemma since anticoagulation had to be completely reversed in the setting of the bleed. The fact that brain injury (in particular hemorrhage) leads to elevation of LDH is highlighted. Importantly, not all that raises LDH in a ventricular assist patient is thrombosis of the device.
Cangrelor: Safe and Effective for Left Ventricular Assist Device Thrombosis
Authors: Rao Roopa , Anderson Eve , Jones Mark , Safiia Muhamed , Guglin Maya
Published: January 2024

Pump thrombosis is a devastating complication of left ventricular assist device implantation as it increases the risk of mortality and morbidity. Early and effective treatment is important to prevent the progression of the clot and to avoid the surgical need for pump exchange or heart transplant. The current strategies of intensifying anticoagulation therapy are not consistently effective and carry significant bleeding risks. Cangrelor is a new pharmacological agent that has been utilized as an antiplatelet agent in several cardiac procedures. In this case series, we describe the use of cangrelor for left ventricular assist device thrombosis in five patients. Cangrelor appears to be a potentially safe and effective alternative strategy.
Pulseless Paradoxus: A Clue to the Presence of Cardiac Tamponade During Continuous-Flow Mechanical Circulatory Support
Authors: Araj Faris
Published: January 2024

This letter to the editor is in response to the published article by by Akhtar et al.
Impact of Atrial Fibrillation on Outcomes after Left Ventricular Assist Device Implantation: Systematic Review and Meta-Analysis
Authors: Buttar Chandan , Lakhdar Sofia , Nassar Mahmood , Nso Nso , Collura Giovina , Munira Most
Published: January 2024

Background: Atrial fibrillation (AF) is a common finding in patients with heart failure and is well-known for its deleterious effects on cardiac function and hemodynamics; however, there are gaps in knowledge regarding the impact of AF on patients with left ventricular assist devices (LVADs). Methods: In this study, we searched PubMed/Medline, Embase, and Cochrane Library databases through September 2021 to find articles that assessed the outcomes of AF in patients with LVADs. Results: A total of 12 studies that underwent systematic review evaluated the outcomes of 7853 adult patients. The meta-analysis analyzed findings from a total of 1003 patients. Pooled findings indicated a 25% higher risk of mortality in patients with AF as compared to those in sinus rhythm (P = .02). No statistically significant differences in mortality were noted between patients with paroxysmal AF or persistent AF (P = .13). No statistically significant differences were noted between the groups in terms of bleeding (P = .70). There was an increased risk of thromboembolism in patients with sinus rhythm compared to those with AF (P < .001). Conclusion: The presence of AF was not found to be associated with an increased risk of bleeding or thromboembolism but may be associated with increased mortality.
A Unique Case of Inflow Cannula Obstruction by a Tissue Membrane
Authors: Rao Roopa , Saleem Kashif , George Bistees , Guglin Maya
Published: January 2024

The use of a left ventricular assist device has increased and is a primary surgical treatment for heart failure. However, one major complication of left ventricular assist device support is an obstruction in the blood flow pathway. Pump thrombosis and outflow graft occlusion are some of the common causes of such obstructions. Here, we describe a unique case of HeartMate II (Abbott Laboratories) inflow cannula obstruction from a membranous structure without evidence of thrombus. The histology showed evidence of fibrous tissue and heart muscle tissue in the membrane. The patient underwent a successful device exchange with a HeartMate 3 (Abbott Laboratories) and is doing well.
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.
INCREASING RISK OF HEAVY METAL CONTAMINATION IN SILVOFISHERY PONDS
Authors: Hastuti Endah Dwi
Published: January 2024

This research aims to observe the concentration of organic matter, Pb and Cd in a silvofishery pond, to study the toxicity level status, to analyze changes in their concentration within a yearâ€™s period, and to analyze the correlation between the concentration and changes. The research was conducted through field observation and laboratory analysis from May 2016 to July 2017, which included five observation activities. Statistical analysis was conducted by using ANOVA and correlation tests. The results show that the concentration of organic matter, Pb and Cd, was increasing in all five observations. Throughout the research, the ranges of organic matter, Pb and Cd, were recorded at 1.60â€“3.30 mg/kg, 3.130â€“8.230 mg/kg, and 1.089â€“2.820 mg/kg, respectively. In all observations, toxicity level showed that Cd concentration in the sediment had exceeded the standards recommended by US EPA (â‰¤1.0 mg/kg) and ANZECC & ARMCANZ (â‰¤1.5 mg/kg), while Pb was within the safe range (â‰¤21 mg/kg and â‰¤50 mg/kg). The correlation analysis showed that the concentration and accumulation of Pb and Cd were highly related, which indicated the possibility of the same pollutant sources. Recommendations for a better management plan to avoid heavy metal accumulation in silvofishery ponds would include the arrangement of mangrove plants in inlet canals and periodic pruning to hinder heavy metal from returning to the environment through litter fall.
Janusz Korczak: rei Mateusinho primeiro e a revolução das crianças: uma vida analisada pela obra
Authors: Holtman Cecília Szenkowicz
Published: January 2024

Poucos educadores conheceram tão a fundo a alma da criança e do adolescente como Janusz Korczak, um polonês de raízes judaicas, médico, pediatra, pedagogista, escritor, autor infantil, publicista, ativista social e oficial do Exército Polaco, que desde muito jovem interessou-se por assuntos relacionados com a educação das crianças. Sua dedicação aos pequenos foi tamanha que com um grupo deles fez a viagem final, em meio ao extermínio da Segunda Guerra Mundial. O romance infantil Rei Mateusinho Primeiro, de Korczak, está recheado de emoções e lições, tanto para as crianças, como para os adultos. Através da análise deste romance que em 2023 comemora o centenário de sua publicação apresentamos a trajetória de vida do Bom Doutor, seus dispositivos pedagógicos e a importância de sua obra na luta pelos Direitos das Crianças.
História concisa da dança Israeli
Authors: Davidovitsch Fernando
Published: January 2024

Quando se fala em dança israeli, não se está se referindo a um tipo de dança milenar como é a religião judaica. Diferentemente disto, é uma forma de expressão cultural historicamente quase tão recente quanto o Estado de Israel, fundado em 1948. O início da evolução da dança israeli pode ser localizado no final do séc. XIX d. C. e primeira metade do séc. XX d. C., um pouco após começarem as primeiras imigrações massivas de judeus em Israel, mobilizadas pelo movimento sionista, o qual trazia como ideia central a necessidade de retorno desse povo à sua terra de origem. O que se denomina como dança israeli são as formas de dança que se constituíram dentro da região de Israel, tanto as derivadas dos vários lugares de onde os imigrantes judeus vieram, quanto aquelas referentes aos grupos étnicos não judeus, que também habitam aquele território. Ela é um grande conjunto que engloba uma pluralidade de tipos de dança. O reconhecimento de que existe uma forma de expressão de dança própria de Israel (ainda que resultante da mistura de informações de outros lugares) é fruto do empenho de uma turma de coreógrafos, que buscavam consolidar uma identidade cultural para este novo Estado. Fizeram isto investindo na estruturação e disseminação da harkadá (bailes de danças circulares israeli) e organizando festivais que reuniam os diversos tipos de dança próprios de cada grupo étnico que habitava Israel e as novas formas nacionais de dança que estavam emergindo naquele território,
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

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.