bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 314: Highly polymeric grape seed proanthocyanidins: A call for establishing the safe dose
Authors: Thilakarathna Wasitha , Rupasinghe H.P. Vasantha 
Published: July 2021

Abstract
Introduction: Proanthocyanidins (PC) are the oligomers and polymers of flavan-3-ols, especially catechin and epicatechin. PC in general are proven to be beneficial against cancers and widely available as over the counter (OTC) supplements. However, role of highly polymeric PC (HP-PC) on human cancer prevention remain unknown. Therefore, the effects of HP-PC supplementation on hepatic pathology in the context of hepatocellular carcinoma (HCC) were evaluated. HP-PC supplementation on mice gut microbiota was also evaluated considering the association of dysbiosis-mediated inflammation with HCC.
Methodology: Crude PC was extracted from grape seeds (GS) using 70% acetone (in water) as the extraction solvent. PC mixture was purified and fractionated by flash chromatography. Monomeric and oligomeric PC was eluted with 100% ethanol and the HP-PC was collected by eluting with 70% acetone. C57BL/6 mice (49 - 56 days old) were supplemented with HP-PC (200 mg/kg body weight per day) for 14 days and sacrificed to collect livers and blood serum. Feces samples were collected from mice colon to evaluate the composition of gut microbiota using the 16S rRNA sequencing technology. Mice liver histopathology was examined by staining with hematoxylin and eosin. The level of alanine aminotransferase (ALT) in mice blood serum was measured as a marker of liver damage.
Results: Evaluation of liver histopathology revealed signs of steatosis in the mice supplemented with HP-PC. Interestingly, rare foci of monocytic lobular inflammation was visible in the hepatic tissues of the mice supplemented with HP-PC. The alpha diversity of the mice gut microbiome was evaluated in terms of Shannon Index, Pielou's evenness, Faith's phylogenic diversity, and observed operational taxonomic units. A significant difference was not observed for the alpha diversity between the HP-PC supplemented and control group mice gut microbiota. The levels of ALT in the mice blood serum were not significantly different between HP-PC supplemented and control group mice.
Conclusions: The preliminary experimental data suggests the potential of HP-PC to promote steatosis and hepatic inflammation. However, further studies must be conducted to understand potential harmful effect of HP-PC (if any) in hepatic toxicity and safer dose to use for potential health benefits. Furthermore, the results of this study emphasize the critical importance of establishing the safe dose of HP-PC or any OTC supplements.
Citation Format: Wasitha Thilakarathna, H.P. Vasantha Rupasinghe. Highly polymeric grape seed proanthocyanidins: A call for establishing the safe dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 314.
Abstract 3144: Intratumor heterogeneity quantification using 3D segmentation of organoids co-culture systems
Authors: Mukashyaka Patience , Noorbakhsh Javad , Kumar Pooja , Courtois Elise , Anczukow Olga , Robson Paul , Liu Edson , Chuang Jeffrey 
Published: July 2021

Abstract
Intratumoral heterogeneity is an essential aspect of cancer biology, as the diversity of cancer cells can increase challenges of designing effective treatment. Cancer cells within the same tumor evolve and compete for shared resources and may also respond differently to drug treatments. In previous work, by closely analyzing triple negative breast cancer xenografts, we have identified a system of closely-related subclonal populations within a tumor that respond differentially to chemotherapy. To explore the dynamics of competition and cooperation between these subclones, we derived cell lines from each and tagged them with fluorescent markers. We then co-cultured these cell lines in 3D organoids and tracked them using Opera Phenix high content screening system (3D confocal fluorescence microscopy). To determine the number of cells and the location of each subclones within organoids, we developed a 3D cell segmentation pipeline. Our pipeline relies on a two-step process where organoids are segmented first and then individual cells are detected within each organoid. Preliminary analysis of hundreds of organoids suggests that the two cell types preserve their relative ratio and sensitivity to treatment regardless of organoid size, suggesting that the system is in a state of ecological coexistence. We will present results on cellular mixing during growth and treatment and the implications for adaptive therapy ecologies in tumors.
Citation Format: Patience Mukashyaka, Javad Noorbakhsh, Pooja Kumar, Elise Courtois, Olga Anczukow, Paul Robson, Edson Liu, Jeffrey Chuang. Intratumor heterogeneity quantification using 3D segmentation of organoids co-culture systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3144.
Abstract 3149: Investigation of the potential therapeutic value of CAF-derived milk fat globule-EGF factor 8 protein (MFG-E8) in esophageal squamous cell carcinoma
Authors: Liu Beilei 
Published: July 2021

Abstract
The physiological state of the tumor microenvironment (TME) is closely linked with tumorigenesis. RNA sequencing data from our lab showed a broad range of dysregulated genes between ESCC isolated CAFs and paired peripheral blood isolated Fbcs. Among the 2347 up-regulated genes, we found the GO analysis is many focused in extracellular matrix and the top 4 GO terms enriched in cell development and adhesion. Due to this, enriched CAF-secreted extarcellular proteins attracts our attention. MFG-E8 is highly expressed secreted protein in CAFs but low expressed in tumor cells. TCGA database revealed high expression of MFG-E8 is associated with poor overall survival and disease-free survival. In addition, ESCC cell line k410 and K180 with MFG-E8 protein showed a strong ability in cell migration, cell invasion and apoptosis inhibition compared with the PBS group. The further western blot demonstrated MFG-E8 promoted ESCC cell migration and invasion by triggering EMT, and activated an altered akt/stat3 signaling pathway. Moreover, Anti-MFG-E8 antibody effectively reduced tumor size, especially combined with cisplatin. Therefore, MFG-E8 may act as a potential target effective therapeutic strategies.
Citation Format: Beilei Liu. Investigation of the potential therapeutic value of CAF-derived milk fat globule-EGF factor 8 protein (MFG-E8) in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3149.
Abstract 3188: β-catenin in metastatic ovarian cancer cells mediates polyploidy induced by tumor-associated macrophages
Authors: To Sally Kit Yan , Shi Jue , Wong Alice Sze Tsai 
Published: July 2021

Abstract
Tumor-associated macrophages (TAMs) closely associate with tumor progression and could promote metastatic spread. However, how TAMs interact with individual cancer cell in the heterogeneous cancer cell population is unknown. Here, using an isogenic cell line pair with different metastatic potentials, we showed that highly metastatic (HM) cells, but not non-metastatic (NM) cells, could skew the co-cultured macrophages to TAM-like phenotypes. Single-cell tracking by time lapse imaging revealed that during co-culture, macrophages could induce failed cytokinesis in a subset of HM cells. Subsequent analyses suggested that this induction could be facilitated by direct cell-cell contact. We further identified that the cell-surface metadherin expression induced by β-catenin in HM cells is involved in this induction, while surface CEACAM1 expressed on macrophages could be responsible for the interaction with metadherin. HM-macrophage interaction promotes macrophage secretion of the cytokine CCL3, a strong chemoattractant for monocytes, which may further amplify the interaction. In an orthotopic humanized mice model, knockdown of β-catenin in HM cells reduced tumor burden as well as the number of tumor-infiltrating CD163+ TAMs. These findings demonstrate a positive feedback loop between macrophages and a subpopulation of cancer cells mediated by β-catenin to enhance the metastatic cascade (This work is supported by RGC GRF grant 17141216).
Citation Format: Sally Kit Yan To, Jue Shi, Alice Sze Tsai Wong. β-catenin in metastatic ovarian cancer cells mediates polyploidy induced by tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3188.
Abstract 383: Efficacy of immune checkpoint inhibitors in lung cancer patients with EGFR P719A mutation: A case report
Authors: Gong Fuyu , Zheng Kai 
Published: July 2021

Abstract
Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the efficacy of inhibitors of programmed cell death protein-1in lung cancer patients with driver oncogene EGFR P719A mutations and strong positive PD-L1 expression in one special case.
Methods: Tissue samples were subjected to NGS in our College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression.
Results: A 52-year-old male never-smoker who complained of a persistent cough was examined by computed tomography (CT), which revealed a 39 mm wide tumor in the upper region of the right lobe of the lung in May 2019. Tumor biopsy pathology revealed that the patient had a stage IIIB (T2N3M0) adenocarcinoma. NGS performed on a formalin-fixed, paraffin-embedded tumor specimen to identify genomic aberrations. The tumor was positive for EGFR, EGFR P719A mutation. The PD-L1 expression have been tested by FDA-approved 22C3 antibodies, and PD-L1 expression level of 95%. The patients received anti-PD-1 combination treatment. He has reached partial response (PR) after 4 cycle treatment. After ten months, he has the opportunity to receive the operation. The following anti-PD-1/L1 monotherapy is still ongoing until now.
Conclusion: Our real-world study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression.
Citation Format: Fuyu Gong, Kai Zheng. Efficacy of immune checkpoint inhibitors in lung cancer patients with EGFR P719A mutation: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 383.
Abstract 406: Development of a gene signature assessing ER modulation by SERMs and SERDs as a target engagement biomarker for endocrine therapy in breast cancer
Authors: Lee Joon Sang , Shomali Maysoun , Bouaboula Monsif , Wang Emma , Dos-Santos-Bele Wilson , Dib Colette , Boitier Eric , Pelekanou Vasiliki , Ternes Nils , Gosselin Alice , Cohen Patrick , Celanovic Marina , Soria Christopher , Protopopov Alexei , Pollard Jack 
Published: July 2021

Abstract
Hormone or endocrine therapy is the primary treatment for estrogen receptor-positive (ER+) breast cancer. Selective Estrogen Receptor Modulators (SERMs) have been used for women with ER+ invasive cancer in the adjuvant setting. However, they do not fully inhibit ER transcriptional activity. Therefore, selective estrogen receptor degraders (SERDs) such as fulvestrant have been developed to overcome the partial modulation of ER transcriptional activity by SERMs. However, the clinical benefit of fulvestrant is limited by its pharmaceutical properties, and burden of intramuscular administration. We developed amcenestrant (SAR439859), a novel, orally bioavailable SERD to improve drug properties and is under clinical investigation.To assess the relative ER modulating activity, we developed a gene signature by transcriptional profiling of multiple ER+ cell lines. We identified 87 genes that were either up- or down-regulated by estradiol and reversed by SERM and SERD compounds or differentially expressed between a SERM/SERD compound and estradiol. We assessed ER activity scores by applying Gene Set Variation Analysis (GSVA) method to the ER gene signature and evaluated the effect of 6 SERD compounds. Amcenestrant and fulvestrant illuminated a deeper inhibition of ER activity compared to the other compounds. In addition, these ER activity scores could potentially be utilized in clinics as pharmacodynamic (PD) biomarker to assess target engagement. We applied this ER signature to RNA-seq data from paired pre- and post-treatment tumor biopsies from patients of NCT03284957 study (AMEERA-1), an open-label, phase 1/2 study of amcenestrant in postmenopausal women with ER+/HER2- metastatic breast cancer. The results of our analysis showed that ER activity is down-regulated by amcenestrant (oral SERD) for 3 out of 5 patients, in parallel with clinical benefit. Validation in a larger patient cohort is needed.
Citation Format: Joon Sang Lee, Maysoun Shomali, Monsif Bouaboula, Emma Wang, Wilson Dos-Santos-Bele, Colette Dib, Eric Boitier, Vasiliki Pelekanou, Nils Ternes, Alice Gosselin, Patrick Cohen, Marina Celanovic, Christopher Soria, Alexei Protopopov, Jack Pollard. Development of a gene signature assessing ER modulation by SERMs and SERDs as a target engagement biomarker for endocrine therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 406.
Abstract 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer
Authors: Snyder Lawrence B. , Flanagan John J. , Qian Yimin , Gough Sheryl M. , Andreoli Monica , Bookbinder Mark , Cadelina Gregory , Bradley John , Rousseau Emma , Chandler Julian , Willard Ryan , Pizzano Jennifer , Crews Craig M. , Crew Andrew P. , Houston John , Moore Marcia Dougan , Peck Ron , Taylor Ian 
Published: July 2021

Abstract
ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of &gt;90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented.
Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.
Abstract 443: Bintrafusp alfa enhances the antitumor efficacy of anti-VEGF and VEGF receptor kinase inhibitors in preclinical solid tumor models
Authors: Yeung Tsz-Lun , Lazorchak Adam , Yu Huakui , Qi Jin , Qin Guozhong , Marelli Bo , Fu Kai , Lan Yan 
Published: July 2021

Abstract
The targeting of pathways that regulate tumor angiogenesis is an effective strategy for the treatment of solid tumors. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) are master regulators of tumor angiogenesis that limit the efficacy of cancer therapies and suppress the anti-tumor immune response. Combination therapies consisting of immune checkpoint inhibitors and tumor angiogenesis inhibitors are emerging as effective treatments for solid cancers. Bintrafusp alfa (M7824) is a bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 antibody blocking PD-L1. Here, we tested the antitumor efficacy of a combination therapy consisting of bintrafusp alfa plus a VEGF receptor kinase inhibitor (pazopanib, lenvatinib, regorafenib, axitinib, or nintedanib), or a VEGF neutralizing antibody (B20) in multiple preclinical tumor models. The combination of bintrafusp alfa with lenvatinib, regorafenib, axitinib, or nintedanib showed significantly greater antitumor efficacy than the respective monotherapies in the CT26 mouse syngeneic colon carcinoma model. In the 4T1 mouse breast carcinoma model, the combination of bintrafusp alfa with anti-VEGF, lenvatinib, or regorafenib was significantly more efficacious than the respective monotherapies. Additionally, the combination of bintrafusp alfa with pazopanib also showed superior antitumor efficacy in an orthotopic Renca mouse tumor model. These data indicate that bintrafusp alfa may be a viable combination partner with multiple angiogenesis inhibitors and provide a rational for the continued development of these combination therapies to treat solid cancers.
Citation Format: Tsz-Lun Yeung, Adam Lazorchak, Huakui Yu, Jin Qi, Guozhong Qin, Bo Marelli, Kai Fu, Yan Lan. Bintrafusp alfa enhances the antitumor efficacy of anti-VEGF and VEGF receptor kinase inhibitors in preclinical solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 443.
Abstract 454: The landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations
Authors: Liu Ningbo , Gong Fuyu 
Published: July 2021

Abstract
Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations.
Methods: Tissue samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression.
Results: A total of 22143 lung cancer patients were selected, there are 2120 patients have the driver oncogene mutation, including 1115 (5.04%) ALK positive cases,498 (2.25%) MET positive cases,239(1.08%) RET positive cases,182(0.82%) BRAF positive cases, 72 (0.33%) ROS1 positive cases and 14 (0.03%) NTRK positive cases. Among all the driver oncogene mutation patients, 481 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved 22C3 antibodies. Among all the driver oncogene mutation cases assessed PD-L1 expression (n=481), low PD-L1 expression levels (&lt;1%) were 33.3% (n=160), PD-L1 expression level of 1%-49% accounted for 38.3% (n=184), PD-L1 expression level of 50%-79% accounted for 19.5% (n=94), PD-L1 expression level of 80%-89% accounted for 4.2% (n=20), and PD-L1 expression level higher than 90% accounted for 4.8% (n=23).
Conclusion: Our study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression.
Citation Format: Ningbo Liu, Fuyu Gong. The landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 454.
Abstract 471: Reference materials for tumor mutational burden transcriptome profiling
Authors: Butler Matthew G. , Konigshofer Yves , Dickens Jessica , Anekella Bharathi 
Published: July 2021

Abstract
Immune Checkpoint Inhibitor (ICI) therapies continue to revolutionize treatment of advanced malignancies. However, identification of individuals who respond to ICI treatment remains challenging. Along with programmed death ligand 1(PD-L1 aka CD274) expression and microsatellite instability, tumor mutational burden (TMB), defined as the number of nonsynonymous mutations per megabase of genome, has emerged as a promising biomarker for differentiating responders from non-responders, especially in non-small cell lung cancer. Although promising, TMB is not a perfect biomarker for ICI efficacy with some individuals responding conversely to expectations. The imperfection of TMB as a prognostic biomarker may result from it being a proxy measurement of potential neoantigens. Indeed, all mutations that contribute to TMB will not be expressed as neoantigens and not all neoantigens will illicit immune responses. In refining ICI response prediction, tumor abundance of nonsynonymous mutations has aided in neoantigen prediction. In order to begin development of quality reference materials for neoantigen prediction, we have characterized the transcriptomes of four tumor cell lines that were previously used to formulate TMB reference materials. Sequencing libraries were prepared with the TruSeq Stranded Total RNA with Illumina Ribo-Zero Plus rRNA Depletion Kit and Invitrogen Collibri Stranded RNA Library Prep Kit from Illumina with Collibri H/M/R rRNA Depletion Kit. The resultant transcriptome libraries were sequenced on an Illumina NextSeq2000 platform and relative transcript counts were determined. Broad ranges of expression were observed among transcripts containing nonsynonymous mutations in each of the tumor cell lines tested. These datasets will serve as benchmarks for others attempting to combine TMB and tumor abundance in predicting neoantigen potential.
Citation Format: Matthew G. Butler, Yves Konigshofer, Jessica Dickens, Bharathi Anekella. Reference materials for tumor mutational burden transcriptome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 471.