bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3021: Understanding the effects of a ketogenic diet against pancreatic cancer
Authors: Hajihassani Omid , Vaziri-Gohar Ali , Zarei Mehrdad , Hue Jonathan , Cheng Helen , Mudigonda Anusha , Katayama Erryk , Graor Hallie , Winter Jordan 
Published: June 2022

Abstract
With an overall survival of less than 3%, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the U.S. at its advanced stages. With the most promising therapeutics, the overall survival after a stage IV PDAC diagnosis is only at 11.1 months. The marginal effects of current therapeutics emphasize the importance of developing new approaches to treat PDAC. In a wide range of cancer subtypes, a ketogenic diet has shown encouraging effects as combination therapy. However, the underlying anti-tumorigenic pathways involved in this diet alone are still not well understood. The ketogenic diet’s core elements and direct physiologic effects (ketone bodies, fatty acids, low glucose, low insulin levels) potentially alter PDAC biology that span from redox homeostasis to mitochondrial metabolism, and epigenetic modifications. We hypothesized that in carefully controlled in vitro and in vivo experiments, KD components delay growth of PDAC. Additionally, we hypothesize that understanding the underlying drivers of the anti-tumor effects of a ketogenic diet could be leveraged into the rational design of combination therapies that augment these anti-tumor effects. We show that in the subcutaneous mouse model of PDAC, tumor growth is markedly delayed under ketogenic diet restrictions Furthermore, in PDAC cell culture models, we observed anti-cancer effects when the ketogenic diet core elements are isolated. Specifically, fatty acids and ketone bodies inhibit PDAC cell growth, particularly under high glucose conditions. These effects are somewhat attenuated under low glucose, suggesting that these elements result in competing effects on PDAC cells (i.e., support some pro-survival pathways while inhibiting others). Future studies seek to better delineate the mechanistic impact of the principal ketogenic diet elements on metabolic pathways with a focus on mitochondrial metabolism, as well effects on epigenetic signaling.
Citation Format: Omid Hajihassani, Ali Vaziri-Gohar, Mehrdad Zarei, Jonathan Hue, Helen Cheng, Anusha Mudigonda, Erryk Katayama, Hallie Graor, Jordan Winter. Understanding the effects of a ketogenic diet against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3021.
Abstract 3241: IC50-Seeding Density Slope (ISDS)-measurement as a standardized methodology for assessing anti-cancer therapeutic activity in vitro
Authors: Punyamurtula Ujwal , Zhang Shengliang , Brown Thomas , De La Cruz Arielle , Raufi Alexander , Strandberg Jillian , Carlsen Lindsey , Zhou Lanlan , El-Deiry Wafik 
Published: June 2022

Abstract
The 50% inhibitory concentration (IC50) is a widely used measure of how effective a given anti-cancer therapeutic is at reducing cancer cell viability in vitro. It is known that IC50 of a given therapeutic agent is dependent on the seeding density of the treated cells (in that more densely-seeded cells tend to be more resistant to therapeutic agents). We performed experiments using the CellTiter Glo cell viability assay to assess the cytotoxicity of various chemotherapeutic drugs towards various cancer cell lines. To elucidate the role the extracellular environment of densely-seeded cells plays in cancer cell chemoresistance, we tested conditioned media from cells cultured at high density on cells seeded at low densities. The resulting impact on the IC50 of the low-density cells was determined. The IC50 of the various therapeutic agents tested was cell density-dependent in each cancer cell line examined. Based on this analysis, we propose the IC50-seeding density slope (ISDS), which relates seeding density to the effectiveness of a drug and that we believe could be a standardized quantitative measurement of how a given cancer cell line responds to a given therapeutic treatment. Our results from the conditioned media experiments consistently indicated that the environment of densely-seeded tumor cells conferred chemoresistance to sparsely-seeded cells, suggesting that extracellular cytokines and growth factors may be involved in density-dependent chemoresistance mechanisms. We are currently exploring the effect of serum deprivation on in vitro chemoresistance, in order to further understand how the presence of extracellular nutrients impacts observed IC50 trends. In addition, we are examining the role that cell-cell contact, integrin and FGF signaling pathways play in giving rise to density-dependent chemoresistance. Moreover, to analyze the manner in which conditioned media gives rise to chemoresistance and how this effect relates to intracellular survival pathways, we are performing cytokine profiling experiments. Overall, we describe density-dependent IC50 variations as a hallmark of cancer cells and propose that ISDS may serve as a standardized method of assessing chemosensitivity.
Citation Format: Ujwal Punyamurtula, Shengliang Zhang, Thomas Brown, Arielle De La Cruz, Alexander Raufi, Jillian Strandberg, Lindsey Carlsen, Lanlan Zhou, Wafik El-Deiry. IC50-Seeding Density Slope (ISDS)-measurement as a standardized methodology for assessing anti-cancer therapeutic activity in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3241.
Abstract 3304: Gene expression profiling of full-thickness skin after FLASH proton radiotherapy
Authors: Velalopoulou Anastasia , Karagounis Ilias V. , Skoufos Giorgos , Verginadis Ioannis I. , Kim Michele , Shoniyozov Khayrullo , Hatzigeorgiou Artemis G. , Diffenderfer Eric , Dong Lei , Metz James , Koumenis Constantinos , Cengel Keith A. , Maity Amit , Busch Theresa M. 
Published: June 2022

Abstract
Purpose: To investigate the transcriptomic changes induced by FLASH proton radiotherapy (F-PRT) that could be responsible for the protection of normal epithelial tissues by radiation-induced toxicities as have been previously shown by us and others.
Methods: C57BL/6J mice received 30 Gy of F-PRT or S-PRT to the hind leg at respective dose rates of 69-124 Gy/sec or 0.39-0.65 Gy/sec. RNA sequencing was performed using full-thickness leg skin at 5 days after radiation revealing major pathways regulated by F-PRT and S-PRT. In an endeavor to identify the full repertoire of cells and gene expression profiles that are involved in the sparing effects of FLASH PRT, we expanded our studies to include single-cell RNA sequencing (sc-RNA seq) and examined additional time points such as Day 2 and Day 10 after radiation. Single-cell transcriptome libraries were generated on a 10X Genomics Chromium system. Datasets were acquired from cell samples derived and sequenced from pooled skin samples of three mice per group. Skin from the sequenced mice was also embedded for spatial analysis of gene expression.
Results: RNA sequencing revealed that F-PRT uniquely upregulates almost four times more genes compared to S-PRT (F-PRT-uniquely upregulated 489 genes vs S-PRT-uniquely upregulated 129 genes). Also, F-PRT uniquely downregulated 178 genes, compared to the 125 genes uniquely downregulated by S-PRT. GO analysis demonstrates that the keratinization and apoptosis pathways are uniquely upregulated by S-PRT, whereas F-PRT uniquely upregulates genes involved in vascular development pathway. During submission of the abstract, analysis of sc-RNA seq samples was pending.
Conclusion: Our comprehensive studies inform on the transcriptomic profiling of skin cell populations that are affected by F-PRT vs S-PRT; this insight will further spur discoveries on the biology of FLASH radiotherapy effects.
Citation Format: Anastasia Velalopoulou, Ilias V. Karagounis, Giorgos Skoufos, Ioannis I. Verginadis, Michele Kim, Khayrullo Shoniyozov, Artemis G. Hatzigeorgiou, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch. Gene expression profiling of full-thickness skin after FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3304.
Abstract 3319: Purified poloxamer 188 mitigates radiation-induced lung toxicity
Authors: Dennis-Little Sarah G. , Ngwa Wilfred , Laiho Marikki , Warren Graham , Yost Michael J. 
Published: June 2022

Abstract
The dose-limiting factor in radiation therapy (RT) is damage to healthy tissues, which presents as radiation-induced lung toxicity (RILT). Acute RILT, pneumonitis, is an early inflammatory-driven toxicity that develops within weeks to months following RT. Purified poloxamer 188 (PP188) is a triblock copolymer that associates with and protects cell membranes from oxidative insult, minimizing secondary inflammatory damage. This study aimed to investigate the effects of PP188 to mitigate the onset of acute radiation pneumonitis in a rat model of RILT, and to test the effect of PP188 on the efficacy of RT on tumor growth of a syngeneic CT26.WT murine colon carcinoma in Balb/c mice. To evaluate the efficacy of PP188 to mitigate RILT in healthy tissues, Sprague Dawley rats were given 200mg/kg PP188 or vehicle via IV 1hr prior to a single dose of partial volume (6mm) 20Gy X-irradiation to the right lung, and then were followed for 6 weeks. To validate PP188 treatment does not interfere with RT efficacy to reduce tumor volume, Balb/c mice were implanted with CT26.WT murine colon adenocarcinoma in the high axilla space, given 5Gy SARRP irradiation, and tumor volume was monitored. Rats were evaluated for histopathological changes indicative of acute RILT, including leakage of proteins into alveolar space, thickening of alveolar septa, and alteration of bronchial epithelium and capillaries; for presence of inflammatory infiltrate (Hanker-Yates Peroxidase Leukocyte kit); and for immunohistochemical expression of alpha-smooth muscle actin (SMA). Without PP188, significant inflammatory infiltrate was observed in all lungs bilaterally (p&lt;0.001) contributing to significant bronchiole epithelium thickening (p&lt;0.001) and alveolar septa thickening (p&lt;0.001). Within the thickened alveoli there was significant SMA expression (p&lt;0.001) indicative of cells undergoing a myofibroblast transition that was not observed in the PP188+RT animals or controls. Morphological assessment demonstrated that PP188 significantly attenuated pathological changes in the functional subunits of the lung, alveoli, as well as the vasculature including bronchiole epithelium and small capillaries, with no significant differences from control animals. Finally, it was shown that PP188 does not abrogate radiation-induced tumor volume reduction. The unique mechanism of PP188 provides radioprotection to healthy tissue without interfering with tumor control, and has the potential to mitigate radiation-induced toxicities in the majority of cancers treated with RT.
Citation Format: Sarah G. Dennis-Little, Wilfred Ngwa, Marikki Laiho, Graham Warren, Michael J. Yost. Purified poloxamer 188 mitigates radiation-induced lung toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3319.
Abstract 3323: Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation
Authors: Kim Dongsu , Son Woo Seung , Jang Anna , Lee Yeri , Kim Donggeon , Choi Changyu , Min Kyung Hoon , Choi Sung Pil , Lim Sang Kyun 
Published: June 2022

Abstract
EGFR is a transmembrane protein that functions as a receptor tyrosine kinase (RTK). Upon ligand binding or by activating mutations (Exon19 deletion, L858R mutation, and others), EGFR turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations and amplifications are frequently found in various human cancers and, in non-small cell lung cancer (NSCLC), the EGFR gene is mutated with 10-15% frequency (about 50% in Asian patients). While the 1st and 2nd generation EGFR inhibitors are effective in targeting EGFR mutants with Exon19 deletion and L858R mutation, additional T790M mutation in the EGFR gene causes resistance. The 3rd generation EGFR inhibitor (Osimertinib) works against EGFR mutants with T790M mutation; however, another EGFR mutation occurs at the amino acid 797 position (C797S), which makes Osimertinib ineffective. This is one of the major resistance mechanisms in Osimertinib-treated patients, and the 4th generation EGFR inhibitor that can target the C797S mutant is needed. We developed a compound that effectively disables various EGFR mutations, including Del19/T790M/C797S, L858R/T790/C797S, Del19/C797S, and L858R/C797S. In vitro kinase assay and cellular assays showed high potency and selectivity. In vivo PK/PD and efficacy tests confirmed the great therapeutic potential of this inhibitor for patients with EGFR mutations.
Citation Format: Dongsu Kim, Woo Seung Son, Anna Jang, Yeri Lee, Donggeon Kim, Changyu Choi, Kyung Hoon Min, Sung Pil Choi, Sang Kyun Lim. Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3323.
Abstract 3337: Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer
Authors: Tangpeerachaikul Anupong , Bigot Ludovic , Friboulet Luc , Pelish Henry E. 
Published: June 2022

Abstract
The ALK receptor tyrosine kinase can be aberrantly activated by gene fusions, point mutations, or amplification to promote cancer. ALK fusions are detected in approximately 5% of advanced non-small cell lung cancers (NSCLC), 50% of inflammatory myofibroblastic tumors, 50% of adult and 90% of childhood anaplastic large cell lymphomas, and rare cases of cholangiocarcinomas. Over 90 fusion partners of ALK have been identified, each exerting a different influence on the biochemical properties of the fusion protein and its preclinical sensitivity to ALK inhibitors. Besides fusions, ALK point mutations and amplification account for up to 14% and 2% of sporadic neuroblastomas, respectively, with most activating mutations occurring at residues F1174, F1245, or R1275. Some activating mutations, such as those occurring at F1174 and I1171, also confer resistance to FDA-approved ALK inhibitors. Because ALK plays an oncogenic role in diverse cancer types, it is an important therapeutic target for other indications beyond NSCLC.
NVL-655 is a novel, brain-penetrant ALK-selective inhibitor that exhibits preclinical activity against ALK alterations, including resistance mutations, while also sparing inhibition of TRKB. TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved ALK inhibitor lorlatinib. We previously reported the preclinical activity of NVL-655 in several NSCLC models bearing ALK-fusions, including human cell lines, a human cell-line derived xenograft, and a patient-derived xenograft. Here we report a broader characterization of NVL-655 in ALK-driven cancer models beyond NSCLC, alongside other ALK inhibitors that are either FDA-approved or in development.
In biochemical assays, NVL-655 showed potent inhibition (IC50 &lt; 10 nM) of ALK with mutations at residues 1151, 1174, or 1275, all of which have been identified in neuroblastoma. In cell-based assays, NVL-655 was observed to inhibit proliferation of a human anaplastic large cell lymphoma cell line harboring NPM1-ALK fusion and human neuroblastoma cell lines harboring ALK activating mutations or amplification. In conclusion, the preclinical profile of NVL-655 supports its potential to address a medical need for patients with ALK-driven disease in both NSCLC and other cancers such as anaplastic large cell lymphoma and neuroblastoma.
Citation Format: Anupong Tangpeerachaikul, Ludovic Bigot, Luc Friboulet, Henry E. Pelish. Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3337.
Abstract 3379: Multi-cohort study shows HCC is associated with a relative regional reduction in TGFBR2 in liver biopsies from patients with cirrhosis
Authors: Bhowmick Krishanu , Amdur Richard , Xiang Xiyan , Yu Herbert , Wong Linda L. , Rao Shuyun , He Aiwu R. , Amin Karan , Zaheer Daewa , Narayan Raj K. , Satapathy Sanjaya K. , Guha Chandan , Latham Patricia S. , Shetty Kirti , Gough Nancy R. , Mishra Lopa 
Published: June 2022

Abstract
Background: Early detection of hepatocellular carcinoma (HCC) is challenging partly because most patients also have cirrhosis. Furthermore, patients with cirrhosis are at high risk of developing HCC. Loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. The goal of this study was to determine if a reduction in TGF-β receptors (TGFBR1, TGFBR2) was able to reliably and reproducibly predict HCC in cirrhotic tissue.
Methods: We performed quantitative immunohistochemical (IHC) analysis of biopsy tissue from patients with cirrhosis with or without HCC using 3 separate sets of samples. We developed an automated image analysis pipeline to quantify IHC of TGFBR1 and TGFRB2 in liver biopsies. Using logistic regression modeling, we evaluated the predictive power of staining intensity of TGFBR1, TGFBR2, or the combination in differentiating HCC from cirrhosis.
Results: We found a consistently significant reduction in TGFBR2 in HCC (p &lt; 0.02) among independent patient cohorts from 3 separate institutions. With the data, we developed an artificial intelligence-based image analysis pipeline that confirmed the significant reduction in TGFBR2 staining intensity in HCC compared to cirrhotic tissue (p &lt; 0.002). Unfortunately, logistic regression modeling of the quantitative data showed that there is not a simple threshold of TGFBR2 staining intensity that is diagnostic of HCC. Instead, in 84% of samples with HCC, HCC was associated with a relative regional reduction in TGFBR2 compared to tumor-adjacent cirrhotic tissue.
Conclusions: The qualitative and quantitative analyses indicate that evaluating biopsy samples for a reduction in TGFBR2 abundance relative to the surrounding cirrhotic tissue could be an early indicator of the development of HCC in high-risk groups undergoing surveillance for HCC. Furthermore, an automated image analysis pipeline for quantitative IHC of TGFBR staining could improve the reliability of image analysis across institutions participating in clinical trials.
Citation Format: Krishanu Bhowmick, Richard Amdur, Xiyan Xiang, Herbert Yu, Linda L. Wong, Shuyun Rao, Aiwu R. He, Karan Amin, Daewa Zaheer, Raj K. Narayan, Sanjaya K. Satapathy, Chandan Guha, Patricia S. Latham, Kirti Shetty, Nancy R. Gough, Lopa Mishra. Multi-cohort study shows HCC is associated with a relative regional reduction in TGFBR2 in liver biopsies from patients with cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3379.
Abstract 3451: Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis
Authors: Tsuji Takahiro , Wake Hiroaki , Shindo Mariko , Kato Daisuke , Ozasa Hiroaki , Hirai Toyohiro 
Published: June 2022

Abstract
Brain metastasis of lung cancer is a crucial problem that causes poor clinical outcomes and alters patient quality of life. Previous evidence showed that lung cancer cells (LUCs) may escape from host immunity to form distant metastases. We previously used an original imaging model of brain metastasis (IBrM) to show a heterogeneous interaction between microglia, the tissue macrophages in the brain, and LUCs in the brain niche. The findings confirmed that microglia can phagocytose metastatic cancer cells. Here, we show that genetic deletion of the “don’t eat me” signals of cancer cells can promote phagocytic activity of microglia against LUCs. We injected an adenocarcinoma lung cancer cell line expressing mCherry (CMT167mC) via the internal carotid artery of the CX3CR1-EGFP mice, whose microglia had been specifically labeled with EGFP. The microglia and LUCs were visualized in vivo simultaneously by two-photon microscopy for 14 days. The tumor fate and microglial response against cancer cells were evaluated at single cell resolution in the IBrM. CD24, CD47, and/or PDL1 were deleted in CMT167mC cells using CRISPR/Cas9 to examine the effect of the “don’t eat me” signals. The dynamic behavior of LUCs and the microglial phagocytosis activity against LUCs were visualized in living mice. Microglial phagocytosis was significantly increased by single deletion of CD47 or CD24 compared with WT cells. Combined deletion of CD47 and CD24 also synergically increased microglial phagocytosis, resulting in reduced IBrM and prolonged mouse survival. By contrast, deletion of PD-L1 did not enhance microglial phagocytosis or prolong survival. The pharmacological or genetic conditional depletion of microglia canceled both the increased phagocytosis and the extended survival time, suggesting that the effect of “don't eat me” signals was microglia-dependent. These results indicate that suppression of both CD24 and CD47 in LUCs enhances microglial phagocytic activity and suppresses the metastatic formation of LUCs. Furthermore, the combined use of CRISPR/Cas9 in LUCs and in vivo imaging allows us to evaluate potential therapeutic targets associated with microglial phagocytosis. We are currently using single cell RNA-seq and cell-to-cell communication analysis of the brain tumor and surrounding niche to explore other signal pathways that regulate tumor phagocytosis by microglia and to identify potential therapeutic targets.
Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3451.