bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient adenoviral N-methylpurine DNA glycosylase overexpression imparts chemotherapeutic sensitivity to human breast cancer cells
Authors: Rinne Mikael , Caldwell David , Kelley Mark R. 
Published: June 2022

Abstract
In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, we have used adenoviral overexpression of N-methylpurine DNA glycosylase (MPG or ANPG/AAG) in breast cancer cells to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results show that MPG-overexpressing cells are significantly more sensitive to the alkylating agents methyl methanesulfonate, N-methyl-N′-nitro-N-nitrosoguanidine, methylnitrosourea, dimethyl sulfate, and the clinical chemotherapeutic temozolomide. Sensitivity is further increased through coadministration of the BER inhibitor methoxyamine, which covalently binds abasic or apurinic/apyrimidinic (AP) sites and makes them refractory to subsequent repair. Methoxyamine reduction of cell survival is significantly greater in cells overexpressing MPG than in control cells, suggesting a heightened production of AP sites that, if made persistent, results in increased cellular toxicity. We further explored the mechanism of MPG-induced sensitivity and found that sensitivity was associated with a significant increase in the number of AP sites and/or single-strand breaks in overexpressing cells, confirming a MPG-driven accumulation of toxic BER intermediates. These data establish transient MPG overexpression as a potential therapeutic approach for increasing cellular sensitivity to alkylating agent chemotherapy.
Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model
Authors: Raben David , Bianco Cataldo , Damiano Vincenzo , Bianco Roberto , Melisi Davide , Mignogna Chiara , D'Armiento Francesco Paolo , Cionini Luca , Bianco A. Raffaele , Tortora Giampaolo , Ciardiello Fortunato , Bunn Paul 
Published: June 2022

Abstract
Objective: Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Methods: Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti–factor VIII–related antigen monoclonal antibody. Results: ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis, substantially increasing the level of necrosis seen when combined with radiation therapy. The combination of radiation therapy, ZD6126, and ZD1839 induced the greatest effects on tumor growth and angiogenesis. Conclusion: This first report shows that a selective vascular-targeting agent (ZD6126) + an anti–epidermal growth factor receptor agent (ZD1839) and radiation have additive in vivo effects in a human cancer model. Targeting the tumor vasculature offers an excellent strategy to enhance radiation cytotoxicity. Polytargeted therapy with agents that interfere with both growth factor and angiogenic signaling warrants further investigation.
Inhibition of constitutively activated nuclear factor-κB radiosensitizes human melanoma cells
Authors: Munshi Anupama , Kurland John F. , Nishikawa Takashi , Chiao Paul J. , Andreeff Michael , Meyn Raymond E. 
Published: June 2022

Abstract
Melanoma tumors and cultured cell lines are relatively resistant to the cytotoxic effects of ionizing radiation, thereby limiting the use of radiotherapy for the clinical treatment of melanoma. New strategies for sensitizing melanoma cells therefore deserve examination. In an attempt to identify and target signaling pathways that contribute to radioresistance, we investigated the role of nuclear factor-κB (NF-κB), a transcription factor known to inhibit apoptosis induced by a variety of stimuli and promote radioresistance. Two human metastatic melanoma cell lines, A375 and MeWo, were used to examine the radiosensitizing effects of inhibitors of the NF-κB pathway. Nuclear extracts from these cell lines were tested for active NF-κB using the electrophoretic mobility shift assay. Both melanoma cell lines had constitutively activated NF-κB as observed by electrophoretic mobility shift assay. In an attempt to reverse NF-κB activity, cells were treated either with vehicle alone (DMSO) or with a proteasome inhibitor Z-Leu-Leu-Leu-H (MG132; 10 μmol/L for 2 hours prior to irradiation) that inhibited both constitutive and radiation-induced NF-κB activity. The clonogenic cell survival assay showed that pretreatment with MG132 enhanced tumor cell radiosensitivity with the survival factor at 2 Gy being reduced from 48 ± 0.8% and 48 ± 1.6% in vehicle-treated cells to 27.7 ± 0.32% and 34.3 ± 0.7% in MG132-treated MeWo and A375 cells, respectively. To test the role of NF-κB in radioresistance more directly, MeWo cells were stably transfected with a dominant-negative mutant IκBα construct, which led to the inhibition of both constitutive and radiation-induced NF-κB activity. A modest restoration of radiosensitivity was also observed in the stably transfected MeWo cells with survival factor at 2 Gy values being reduced from 47 ± 0.8% in parental MeWo cells to 32.9 ± 0.7% in stable transfectants. Because constitutively activated mitogen-activated protein kinase kinase (MEK) pathway has been shown to lead to activated NF-κB, we wanted to determine the relative contribution of activated MEK in the human melanoma cells. To test this, MeWo and A375 melanoma cells were exposed to the MEK inhibitor PD184352. Treatment with PD184352 partially reversed NF-κB activity but did not impart radiation sensitivity to these cells. Our results indicate that activated NF-κB may be one of the pathways responsible for the radioresistance of melanoma cells and that strategies for inhibiting its influence may be useful in restoring the radioresponse of melanomas.
Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets
Authors: Holland Cathrine M. , Saidi Samir A. , Evans Amanda L. , Sharkey Andrew M. , Latimer John A. , Crawford Robin A.F. , Charnock-Jones D. Stephen , Print Cristin G. , Smith Stephen K. 
Published: June 2022

AbstractEndometrial cancer is the most common gynecologic malignancy, frequently arising in association with obesity and diabetes mellitus. To identify gene pathways contributing to endometrial cancer development, we studied the transcriptome of 20 endometrial cancers and 11 benign endometrial tissues using cDNA microarrays. Among the transcript changes identified in endometrial cancer were up-regulation of the nuclear hormone receptors peroxisome proliferator-activated receptors (PPAR) α and γ, whereas retinoid X receptor β was down-regulated. To clarify the contribution of PPARα to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPARα, significantly reduced proliferation and increased cell death, suggesting that altered expression of nuclear hormone receptors involved with fatty acid metabolism leads to deregulated cellular proliferation and apoptosis. These results support further investigation of members of the PPAR/retinoid X receptor pathway as novel therapeutic targets in endometrial cancer.
Abstract A13: Papillary thyroid cancer clusters in North Carolina 1997-2017
Authors: Hoffman Kate , Stapleton Heather M. 
Published: June 2022

Abstract
Thyroid cancer is the fastest-increasing cancer in the U.S., and papillary thyroid cancer (PTC) accounts for &gt;80% of incident cases. Data also indicate that the incidence of PTC varies geographically. We investigated associations between residential location and PTC incidence using data from the North Carolina Central Cancer Registry to generate hypotheses about social and environmental factors related to etiology or diagnosis. Analyses included data on 961,111 individuals diagnosed with cancer between 1997 and 2017 (16,468 with PTC). We explored relationships between PTC and residential location at the time of diagnosis. Generalized additive models were used to predict PTC odds across North Carolina while adjusting for individual-level covariates. Cancer patients living in several regions of North Carolina (e.g., areas of the Western Piedmont and the Southern Coast) were up to 200% more likely to be diagnosed with PTC compared with individuals living elsewhere in the state. Patterns were not explained by geographic variation in individual age, sex, or race. We also examined temporal patterns in PTC incidence; these analyses suggest that geographic patterns vary over time and have diminished in recent years. To evaluate whether diagnostic factors explained observed patterns, we evaluated the average tumor size and disease stage in communities identified as having excess odds of PTC. Results of these analyses do not indicate that diagnostic factors are driving spatial patterns; tumor sizes and disease stage in these communities were similar to those in the state as a whole, which would not be expected if diagnostic bias explained variation. Cumulatively, our data suggest that localized environmental factors are influencing geographic distributions of PTC in North Carolina and provide exposure hypotheses for a future large-scale epidemiologic investigation.
Citation Format: Kate Hoffman, Heather M. Stapleton. Papillary thyroid cancer clusters in North Carolina 1997-2017 [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A13.
Abstract A49: Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides
Authors: Leeman-Neill Rebecca J. , Basu Uttiya 
Published: June 2022

Abstract
Many studies have drawn associations between pesticide exposures and lymphomagenesis, both in occupational settings and in the general population. The specific compounds responsible for an increased risk of non-Hodgkin lymphoma in pesticide-exposed individuals have not been entirely established. Furthermore, the biologic mechanisms by which pesticides act as lymphomagens are unknown. One mechanism of B-cell genomic instability that plays a role in lymphomas derived from germinal center (GC)-type B cells, including follicular lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma, is the off-target/aberrant activity of activation-induced cytidine deaminase (AID). AID damages DNA through deamination of cytidine. This occurs on a physiologic basis within GC B cells and is responsible for both class switch recombination (CSR) and somatic hypermutation (SHM). AID can also target nonimmunoglobulin loci, including several proto-oncogenes, resulting in both mutations (aberrant somatic hypermutation; aSHM) and chromosomal translocations. Overexpression of AID has previously been found to increase B-cell genomic instability. In this study, GC-type B cell lines (Ramos, Raji, and CL-01) were treated with pesticides, including herbicides and insecticides from various classes, to determine the effect on AID expression. Real-time RT-PCR was used to determine the degree of AID mRNA expression after chemical treatment. Two representative phenylurea herbicides, linuron and diuron, were found to induce AID expression, in a time- and dose-dependent manner, at concentrations ranging from 50-200 micromolar, with maximal induction of 2- to 6-fold depending on the compound and time point. Additional pesticides that were tested but not found to induce AID expression, at concentrations that were minimally toxic in vitro, included representative organochlorine, organophosphate, phenoxy, and phosphanoglycine pesticides. The findings raise the possibility of increased AID-mediated genomic instability in GC type B cells exposed to phenylurea herbicides. Future studies will investigate the possible link between the observed phenylurea herbicide-related induction of AID, B-cell genomic instability, and lymphomagenesis.
Citation Format: Rebecca J. Leeman-Neill, Uttiya Basu. Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A49.
Abstract IA01: The global impact of environmental carcinogenesis and interventions for prevention
Authors: Wild Christopher P. 
Published: June 2022

Abstract
The global burden of cancer is projected to increase markedly over the next two decades, driven by population aging, population growth, and changes in exposure to known risk factors. The greatest percent increases will be in low- and middle-income countries, the majority of which currently do not have the health care infrastructure to meet this challenge. At the same time much is known about the causes of different cancer types worldwide, with the major contribution arising from environmental and behavioral factors. This recognition provides a foundation to counter the projected increases in cancer burden. However, for a number of these risk factors there remains a gap in developing preventive interventions, whereas for others interventions are available but often fail to be implemented in effective programs. In addition, the etiology of a number of common cancer types remains unexplained. Based on the projected cancer burden, the spiraling costs of therapy, and the unavailability of effective treatment in many parts of the world, prevention should be a priority in overall cancer control planning in every country. Similarly, research on cancer prevention (establishing etiology, preventive interventions and their implementation) should be better supported. To progress, cancer prevention must draw upon new knowledge on carcinogenic mechanisms and the associated technology to address knowledge gaps in innovative ways. There is a major opportunity for interdisciplinary prevention research to provide the basis for a reduction in the projected rises in cancer burden worldwide. Translation of knowledge about causes and prevention into observed reductions in cancer rates is a long and hazardous journey. Researchers should become more aware of the inherent hurdles and active opposition that lie in the way of achieving the goals of cancer prevention. Notably, the tactics of vested interests in casting doubt on the scientific evidence base for prevention should be widely disseminated and understood if researchers are to see their efforts bring benefits. Only by combining the evidence base with a well-planned strategy for implementation will the full fruits of cancer prevention research be realized.
Citation Format: Christopher P. Wild. The global impact of environmental carcinogenesis and interventions for prevention [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA01.
Abstract IA21: A systems approach to cancer prevention
Authors: Hoppin Polly J. , Kriebel David , Jacobs Molly 
Published: June 2022

Abstract
Cancer prevention research and practice largely focus on three overlapping areas: precision prevention (e.g., genetic, social, and other factors specific to an individual patient), genetics, and health behaviors. All three of these envision the individual patient and her provider as the agents of change. A fourth realm of research and practice with potential to contribute to the primary prevention of cancers targets environmental and social factors over which the individual has little control, but governments, businesses, and communities do. These include environmental carcinogens in consumer products, workplaces, and air and water pollution. For example, flame retardants, dry cleaning solvents, formaldehyde, and diesel exhaust are widespread and often pose disproportionately high risks for people in low-income communities. Historically, laws and regulations have been the primary tools for controlling environmental and workplace contaminants, but despite important successes, significant cancer risks from pollution still occur. This presentation explores two questions based on our recent policy and program research: 1) What does systems analysis tell us about actions that impede and hold promise for reducing exposure to environmental carcinogens at the scale needed? 2) How might a systems approach inform the integration of environmental carcinogen reduction into cancer prevention research and practice? Particularly in the current political climate, system-level interventions that shift dominant narratives about cancer, prioritize interdisciplinary research, and harness market forces deserve prioritization.
Citation Format: Polly J. Hoppin, David Kriebel, Molly Jacobs. A systems approach to cancer prevention [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA21.
Abstract IA24: Applying epidemiology to prevention
Authors: Groopman John D. 
Published: June 2022

Abstract
Within the last decade, for the first time in human history, deaths from chronic diseases have exceeded mortality from acute causes worldwide. These chronic diseases encompass a spectrum of cancers, cardiovascular diseases, neurologic diseases, and the emerging consequences of obesity and overnutrition. Further, there are more people today who are cancer survivors as well as people who are afflicted with multiple chronic diseases. This results in an emerging new group of susceptible populations. Since environmental exposures have a profound impact, from the etiology of disease through progression and response to therapeutic and preventive interventions, a new appreciation of the role of environmental health has emerged. This talk will attempt to provide a global perspective on the transitions that have occurred in environmental health over the last 200 years and how these transitions are impacting diverse populations globally. The extraordinary advances in our understanding of the biology of normal development and the molecular progression of disease processes has created unprecedented opportunities for the translation of basic science to therapy and prevention. The need to integrate findings from the biologic, physical, engineering, social, and behavioral sciences, sometimes called convergence, points to an imperative to develop new team science approaches to address the health consequences of environmental exposures. Finally, as it is increasingly recognized that disease outbreaks in one part of the world are no longer isolated from global impacts, there is a need to assure that our next generations of trained scientists have grounding in global collaborations.
Citation Format: John D. Groopman. Applying epidemiology to prevention [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA24.
Abstract PR01: Genomic UV-hypersensitive sites as sentinels for personal UV exposure
Authors: Premi Sanjay , Han Lynn , Mehta Sameet , Knight James , Zhao Dejian , Bacchiocchi Antonella , Halaban Ruth , Palmatier Meg A. , Kornacker Karl , Brash Douglas E. 
Published: June 2022

Abstract
The largest risk factor for skin cancers such as melanoma is past sun exposure, so an objective measurement of traces of an individual’s sun history would allow a general practitioner to identify people who should be monitored for early cancer detection. If the genome contains outlier DNA sequences hypersensitive to environmental agents such as ultraviolet light (UV), these would be genomic dosimeters for monitoring personal carcinogen exposure and would facilitate noninvasive measurements on small skin samples. Such DNA sites might also allow UV to drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, tagged rare UV-induced cyclobutane pyrimidine dimers (CPDs) and provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than UV-induced CPDs. UV exposure revealed hyperhotspots acquiring CPDs up to 200-fold more frequently than the genomic average; these were 20-fold more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within two motifs. One motif occurred at ETS1 transcription factor binding sites, known to be UV targets, and at sites of mTOR/TOP-tract translation regulation; the second occurred at a sequence that developed delayed CPDs after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ~20 cell pathways targeted, rendering CPD hyperhotspots epigenetic marks.
This abstract is also being presented as Poster A28.
Citation Format: Sanjay Premi, Lynn Han, Sameet Mehta, James Knight, Dejian Zhao, Antonella Bacchiocchi, Ruth Halaban, Meg A. Palmatier, Karl Kornacker, Douglas E. Brash. Genomic UV-hypersensitive sites as sentinels for personal UV exposure [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr PR01.