bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer
Authors: Halford Sarah , Veal Gareth J. , Wedge Stephen R. , Payne Geoffrey S. , Bacon Chris M. , Sloan Philip , Dragoni Ilaria , Heinzmann Kathrin , Potter Sarah , Salisbury Becky M. , Chénard-Poirier Maxime , Greystoke Alastair , Howell Elizabeth C. , Innes William A. , Morris Karen , Plummer Chris , Rata Mihaela , Petrides George , Keun Hector C. , Banerji Udai , Plummer Ruth 
Published: January 2023

AbstractPurpose:Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.Patients and Methods:This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.Results:During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.Conclusions:AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).
Abstract A003: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility
Authors: Miyano Masaru , Sayaman Rosalyn W. , Senapati Parijat , Hinz Stefan , Seewaldt Victoria E. , Schones Dustin , LaBarge Mark A. 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR006) of the Conference Proceedings.
Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A003.
Abstract A004: Identification and characterization of the cancer permissive environment in companion dogs
Authors: Modiano Jaime F. , Schulte Ashley J. , DaPauw Taylor A. , Khammanivong Ali , Kim Jong H. , Sarver Aaron L. , Cutter Gary R. , Lindquist Eric , Makielski Kelly M. 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR008) of the Conference Proceedings.
Citation Format: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski. Identification and characterization of the cancer permissive environment in companion dogs [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A004.
Abstract A014: Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals
Authors: Chen Guangbo , Zheng Hong , Rosenberg-Hasson Yael , Araya Saron , Padilla Cindy , Sarin Kavita , Dekker Cornelia L. , Grant Philip , Maecker Holden T. , Furman David , Shen-Orr Shai , Khatri Purvesh , Davis Mark M. 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR002) of the Conference Proceedings.
Citation Format: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis. Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A014.
Abstract A026: History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R]
Authors: Ebied Amr , Salemi Jason , Bakour Chighaf , Gillis Nancy 
Published: January 2023

Abstract
Blood transfusion has long been regarded as a determinant of cancer, plausibly because it influences inflammatory and immunological changes in the recipient's body. Recently, there has been evidence of a role of donor-derived malignancy in donors of autologous stem cell transplants, supporting the possible cancer-driving role of age-related clonal hematopoiesis. Given that routine blood transfusion is more ubiquitous than stem cell transplantation, we hypothesize an association between blood transfusion and the occurrence of hematologic malignancies. We conducted a secondary analysis using data from the 2017-2018 survey of the National Health and Nutrition Examination Survey (NHANES). A total of 4,917 participants were included in our final analytic sample, of whom 587 (11.9%) had ever received a blood transfusion. Out of the participants receiving a blood transfusion, six (1.1%) were diagnosed with hematologic cancer versus 9 (0.21%) from the non-transfusion group. Specifically, three (0.51%) participants from the transfusion group were diagnosed with leukemia versus 2 (0.046%) from the non-transfusion group. Using multivariable logistic regression, we have found that, after adjustment of other predictors, people with a history of blood transfusion were 4.08 (95%CI= 1.18-14.05), 2.09 (95%CI= 0.47-9.27), and 6.76 (95%CI= 1.13-40.44) times more likely to report a history of hematologic cancers, Hodgkin lymphoma, and leukemia, respectively than those who were never transfused. In conclusion, we found a possible significant association between blood transfusion and the risk of developing hematological cancers (particularly leukemia) in the United States. Prospective studies are needed to confirm the temporal sequence of blood transfusion and hematologic cancers in that regard.
Citation Format: Amr Ebied, Jason Salemi, Chighaf Bakour, Nancy Gillis. History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A026.
Abstract B004: Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort
Authors: Lan Tuo , Wang Mei , Williams AnnaLynn M. , Ehrhardt Matthew J. , Finch Emily R. , Lanctot Jennifer Q. , Jiang Shu , Krull Kevin R. , Armstrong Gregory T. , Hudson Melissa M. , Colditz Graham A. , Robison Leslie , Ness Kirsten K. , Park Yikyung 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR014) of the Conference Proceedings.
Citation Format: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park. Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B004.
Abstract B015: Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors
Authors: Hsu Ping-Ching , Bauer Michael , Chiang Tung-Chin , Rogers Lora J. , Aydin A. Murat , Su L. Joseph , Koss Brian 
Published: January 2023

Abstract
Introduction: Accelerated aging is associated with lifetime stress and frailty, and has been reported in aging-related disease and mortality, including lung cancer, postmenopausal breast cancer, childhood cancer, and coronary heart disease. However, current knowledge on the impact of epigenetic aging in anti-tumor immunity remains limited. Pre-existing immune status heavily contributes to cancer diagnosis and the success of immunotherapy treatment, therefore, the relationship between epigenetic aging and immune function, and how it may lead to racial health disparity needs to be further explored. Methods: Genome-wide DNA methylation analysis were conducted in a feasibility test of 16 participants with equal number of African Americans (AAs) and European Americans (EAs), and epigenetic age (mAge) were calculated using R package methylclock for the established multi-tissue epigenetic clock algorithms which consists of 353 CpGs by Horvath. Correlation analysis was performed between mAge and in vitro T cell activation tests. Results: As expected, high correlation of calculated mAge versus chronological age was observed from 16 participants using the Horvath calculator, with higher mAge in AAs than EAs. Significant separation in DNA methylation profiles between AAs and EAs existed based on the top 1,000 CpG sites from the principal component analysis. To understand the effects of aging on T cell function, a series of functional assays were performed from different age groups, and significant (P&lt;0.05) negative correlations of Age and mAge to flow cytometry defined naïve lymphocyte subsets were detected. Significant positive correlations between mAge and the expression of T-cell inhibitory receptors CTLA4 and TIGIT were observed in activated T cells from this sample population. Conclusion: The human immune system undergoes dramatic aging-related changes, which continuously progress and contribute to the decline in immune-mediated protection against infections and cancer. Our study serves as a proof-of-principle to highlight the degree of accelerated epigenetic aging and its impact on T cells function among different racial and age groups), which warrants further research that may shed more light into therapeutic cellular immune responses and mechanisms of immune-related adverse events in patients treated with immunotherapy for cancer.
Citation Format: Ping-Ching Hsu, Michael Bauer, Tung-Chin Chiang, Lora J. Rogers, A. Murat Aydin, L. Joseph Su, Brian Koss. Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B015.
Abstract IA001: DNA damage repair: Impact on aging and cancer and applications of nutritional interventions
Authors: Hoeijmakers Jan H 
Published: January 2023

Abstract
Rare DNA repair syndromes display strong cancer predisposition and/or premature aging, indicating that DNA damage underlies both, consistent with the notion that age is the most important risk factor for cancer. We have generated a series of DNA-repair-deficient mouse mutants, and discovered that defects in transcription-coupled repair cause accelerated, segmental aging and overprotect from cancer, whereas global genome repair defects are predominantly associated with cancer. When combined aging is dramatically accelerated, indicating a dose-dependent causal relationship. We also found that premature aging triggers a potent anti-aging ‘survival response’, which suppresses growth (IGF1) and enhances resilience and defenses, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting progeroid mutants to actual DR tripled lifespan, and drastically retarded accelerated aging, most notably neurodegeneration. We also found that DR lowered DNA damage, explaining how DR counteracts aging and cancer and why DNA repair mutants overrespond to DR. Interestingly, expression profiles of progeroid mutants showed gradual decline of expression in a genelength-dependent manner, due to genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. This transcription stress is also prominent in normal aging of many (post-mitotic) tissues and explains protein aggregation in dementias. DR largely alleviated transcription stress and hence prolongs genome function. I will present phenotypes of conditional DNA repair models targeting aging to selected organs, striking parallels with Alzheimer’s disease and the first remarkable results translating these concepts from mice to repair-deficient children. Our findings identify DNA damage as main cause of aging, establish repair-deficient mice as models for interventions to promote healthy aging, explain the molecular anti-aging, anti-cancer mechanism of DR and the aging component of proteinopathies based on transcription stress and promote counterintuitive DR-like interventions for progeroid syndromes, for preventing neurodegenerative diseases and ischemia reperfusion damage in surgery and for improving chemotherapy outcome and reducing side effects.
Citation Format: Jan H Hoeijmakers. DNA damage repair: Impact on aging and cancer and applications of nutritional interventions [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA001.
Abstract IA016: Epigenetics mechanisms of tissue aging
Authors: Sen Payel 
Published: January 2023

Abstract
Epigenetic alterations are one of the key hallmarks of aging. How epigenetic changes broadly affect euchromatin-heterochromatin balance, three-dimensional chromatin conformation, histone composition and global transcriptome in aging have been limitedly addressed. These outstanding questions are key to understanding the susceptibility of aged tissue to develop cancers, the incidence of which exponentially increases with age. Using murine liver as a model organ and an integrated multi-omics approach, we find that aged cells assume a repressed chromatin state characterized by condensed chromatin, broad heterochromatinization, and global suppression of the transcriptome. At the local level, there are site-specific chromatin openings with simultaneous derepression of genes. Our findings reveal a unique chromatin state in aging with opposing changes at the global and local levels.
Citation Format: Payel Sen. Epigenetics mechanisms of tissue aging [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA016.
Abstract IA022: Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis
Authors: Gomes Ana P. 
Published: January 2023

Abstract
Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal metabolic reprogramming that occurs with aging endows cancer cells with pro-aggressive properties favoring progression into metastatic disease through, at least in part, the accumulation in the circulation of methylmalonic acid, a by-product of vitamin B12 deficiency. On the other hand, we also show that this age-induced organismal metabolic reprogramming makes lung tumors intrinsically more resistant to chemotherapies through the chronic upregulation of glucocorticoid hormones. Together, our work demonstrates a role for age-induced systemic metabolic reprogramming in shaping the tumorigenic process toward more aggressive, treatment-resistant disease and offers a rationale for using interventions that ameliorate the metabolic deregulation that occurs with age in the treatment of age-related cancers.
Citation Format: Ana P. Gomes. Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA022.
Abstract A045: Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion
Authors: Morales Julio C. , Dang Tuyen T. 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive brain cancer. The standard course of treatment is a combination of radiation and chemotherapy. Even with the dual treatment, the 5-year survival rate of patients with GBM is between 4-10%. A possible cause of the low survival rate for GBM patients is the presence of motile neoplastic cells with efficient DNA repair abilities. Thus, the two major obstacles to treating GBMs is 1) the tumors inherent invasive nature and 2) the recurrent tumors ability to acquire treatment resistance. As such, gaining a better understanding of the mechanisms mediating GBM recurrence would allow us to design better treatment strategies for patients. We have found that the 5’-3’ exoribonuclease XRN2 is upregulated in GBMs as compared to normal and other brain cancer types. While XRN2 is traditionally associated with the process of transcription termination, our published work has defined a role for XRN2 in the DNA damage response. Our group has shown that loss of XRN2 sensitizes to a variety of DNA damaging agents but in particular ionizing radiation. Previously, we have shown that XRN2 is required for DNA repair, specifically double stranded break (DSB) repair. Loss of XRN2 impairs both the non-homologous end-joining and homologous recombination DSB repair pathways. Loss of XRN2 also results in increased spontaneous DSB formation, chromosomal aberrations and RNA:DNA hybrid (R-loop) formation. In addition to a role in the DNA damage response, we found that loss of XRN2 is required for GBM cell motility, invasion through a matrix and decreased tumor volume in mouse models. Interestingly, R-loop formation can affect gene expression by modulating the access of genes to transcription factors, miRNA transcription, and methylation status of genes. To gain a better understanding of how XRN2 modulates gene expression, we conducted RNA-Seq analyses of GBM cell lines with and without XRN2 expression and found that XRN2 can regulate genes involved in cell movement, cell development and cellular organization programs. Consistent with our findings that XRN2 impairs DNA damage and tumor invasion; XRN2 loss results in R-loop formation in promoters of genes important for tumor invasiveness and DNA repair such as FOXM1 and Cyclin B1. These data suggest that the regulation of R-loop formation is an important determinant in tumor progression.
Citation Format: Julio C. Morales, Tuyen T. Dang. Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A045.
Abstract B010: The effects of tumor cell-secreted factors on endothelial cell junction phenotype
Authors: DeCastro Ariana Joy L. , Griffith Lauren , Stroka Kimberly 
Published: January 2023

Abstract
Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC metastasizes to specific tissues such as brain and bone in a process termed organotropism. In this process, TNBC cells cross the vascular endothelium; transport across endothelial cells is, in part, regulated by cell-cell junctions. The TNBC cell secretome has been shown to contain factors such as vascular growth factor (VEGF) and matrix metalloproteinases (MMPs) that could play a role in altering endothelium permeability. Prior work by us has shown that VEGF in tumor conditioned media can alter endothelial cell junction phenotype in human brain microvascular endothelial cells. Given the various factors present in tumor conditioned media (TCM), we hypothesized that both VEGF and MMPs are present at distinct levels in conditioned media derived from brain- or bone-seeking TNBC cells and that these factors alter junction phenotype in human umbilical vein endothelial cells. We quantified levels of VEGF and MMPs 1 and 9 in tumor conditioned media from parental, brain-seeking, and bone-seeking MDA-MB-231 cells. Our results show that brain-seeking tumor cell conditioned media reduces VE-cadherin continuous junction coverage compared to conditioned media from parental or bone-seeking cells. VE-Cadherin junctions also have decreased junction widths in response to tumor conditioned treatment from brain-seeking MDAs. These results show that secreted factors from TNBC cells have a modest impact on endothelium junction integrity, and future work will quantify changes in endothelium permeability to test barrier function. This work will contribute to a further understanding of TNBC organotropic metastasis and more effective targeted therapeutics to prevent disease progression.
Citation Format: Ariana Joy L. DeCastro, Lauren Griffith, Kimberly Stroka. The effects of tumor cell-secreted factors on endothelial cell junction phenotype [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B010.