bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5717: Mass spectrometry as a tool for MHC class I and II neoantigen discovery
Authors: Ford Michael J. , Jones Richard , Allen David , Amunugama Ravi , Pisano Michael , Mobley James , Domanski Paul , Ho Bill , Bochar Daniel , Holt Melissa 
Published: August 2018

Abstract
A neoantigen is a patient-specific tumor antigen resulting from mutations during oncogenesis (1). Advances in genome sequencing of cancer tumor tissues combined with bioinformatics have enabled the identification of tumor specific mutations and the prediction of the peptides that will be presented by the MHC complex. The presented peptides are recognized as foreign by the immune system and can be used to discriminate cancerous from normal cells. Neoantigen prediction by gene sequencing and in silico approaches can be strengthened and further supported by mass spectrometry. The molecular level characterization of peptides associated with molecules of the major histocompatibility complex requires a targeted protein complex enrichment, an unbiased peptide elution, and finally a peptide analysis method. We use immunoaffinity to isolate the target complex, elute the peptides under conditions minimizing protein contamination and finally analyze the peptides by mass spectrometry. Here we present a case studies of our recent work applying workflows for the analysis of peptides associated with both Class I and Class II MHC molecules. Combining state-of-the-art mass spectrometry and bioinformatics, we demonstrate the utility of this approach for neoantigen identification and quantitation.
Reference: 1. Sun et al. Cancer Lett 2017;392:17-25.
Citation Format: Michael J. Ford, Richard Jones, David Allen, Ravi Amunugama, Michael Pisano, James Mobley, Paul Domanski, Bill Ho, Daniel Bochar, Melissa Holt. Mass spectrometry as a tool for MHC class I and II neoantigen discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5717.
Abstract 5732: Zinc transporter, ZIP14, as a mediator of systemic muscle wasting in metastatic cancers
Authors: Biswas Anup , Wang Gang , Ma Wanchao , Coker Courtney , Tanji Kurenai , Kandpal Manoj , Davuluri Ramana , Acharyya Swarnali 
Published: August 2018

Abstract
Metastasis contributes to the vast majority of cancer-related mortalities. Metastatic tumors secrete factors that systemically affect various organs leading to dysfunction and accelerated death. More than 80% of metastatic cancer patients experience a progressive and debilitating loss of muscle mass and function by a process known as cachexia. Cachectic patients suffer deterioration of diaphragm and cardiac muscles and often die prematurely due to respiratory and cardiac failure. The prognosis for these patients is further diminished by the fact that they are often too weak to tolerate standard doses of anti-cancer treatments. Cachexia is therefore an important determinant of therapeutic response, outcome and patient survival in advanced cancer patients. Although systemic metabolic derangements and chronic inflammation predominate in cachexia, the underlying molecular mechanisms driving its development are not well understood. Therefore, insights into the specific interventions that could either reverse or prevent cachexia are expected to improve treatment outcome, survival and quality of life in cancer patients. In this study, we identified a metal ion transporter, ZIP14 that was upregulated in cachectic muscles from five independent metastatic models, as well as in metastatic cancer patients. We find that TNF-alpha and TGF-beta cytokines upregulate ZIP14 in muscles, which in turn results in the accumulation of intracellular zinc. Increased zinc influx in muscle cells is associated with the degradation of myofibrillar proteins that contributes to muscle atrophy and muscle mass loss. Importantly, germline ablation or muscle-specific depletion of Zip14 markedly inhibits cancer-induced muscle wasting. Our study demonstrates a novel function of ZIP14 in muscles as a mediator of cachexia in advanced cancers. Insights from this study can be used to develop therapeutic strategies to prevent cachexia, and improve the survival and quality of life in metastatic cancer patients.
Citation Format: Anup Biswas, Gang Wang, Wanchao Ma, Courtney Coker, Kurenai Tanji, Manoj Kandpal, Ramana Davuluri, Swarnali Acharyya. Zinc transporter, ZIP14, as a mediator of systemic muscle wasting in metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5732.
Abstract 5745: Effect of activator of G-protein signaling 3 (AGS3) on prostate tumorigenesis
Authors: Adekoya Timothy O. , Smith Nikia , Mowatt Tonelia , Aladeniyi Temilade , Richardson Ricardo M. 
Published: August 2018

Abstract
Prostate cancer (PCa) is a leading cause of cancer death among men, with greater prevalence of the disease among the African American population in the US. Activator of G-protein Signaling 3 (AGS3/GPSM1), a receptor-independent activator of G-protein signaling has been shown to affect different cellular processes and cell cycle activity as well as tumor growth and development. AGS3 contains seven tetratricopeptide (TPR) repeats in its N-terminal half and four G-protein regulatory (GPR) motifs in its C-terminal half. The aim of this study is to assess the role of AGS3 in prostate cancer development and metastasis as well as to understand the molecular dynamics involved. To that end, the metastatic PCa cell lines LNCaP, PC3, MDA PCa 2b and DU-145 were analysed for AGS3 expression relative to RWPE-1, a non-metastatic Pca cell line. Quantitative RT-PCR and western blot analysis have shown that AGS3 expression varies in the PCa cell lines relative to control RWPE-1. Overexpression of AGS3 in PC3 and LNCaP cells significantly enhanced tumor progression in nude mice xenografts. Interestingly, expression of the TPR, not the GPR, repeats in LNCaP promoted tumor growth as well as the full length AGS3. Preliminary studies with a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice deficient in AGS3 expression (TRAMP+/AGS3-/-) displayed decrease prostate tumorigenesis. Taken together, these results indicate that AGS3 expression promotes prostate tumor growth. The data also suggest that the effect of AGS3 in prostate tumorigenesis is mediated via its TPR, not GPR motif.
Citation Format: Timothy O. Adekoya, Nikia Smith, Tonelia Mowatt, Temilade Aladeniyi, Ricardo M. Richardson. Effect of activator of G-protein signaling 3 (AGS3) on prostate tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5745.
Abstract 5752: Protumoral and pro-metastatic effects of TLR7 in lung cancer
Authors: Dajon Marion , Iribarren Kristina , Alifano Marco , Damotte Diane , Cremer Isabelle 
Published: August 2018

Abstract
TLR7 agonists are currently under investigations for their ability to enhance anti-tumor immune responses. However, in some tumor models, these agonists also stimulate tumor cells, which can express high levels of TLR7, a receptor for single-stranded RNA [1]. We have demonstrated that stimulation of lung tumor cell lines expressing TLR7 with synthetic TLR7 agonists led to upregulation of the antiapoptotic protein Bcl-2, tumor cell survival and chemoresistance [2]. In Non-Small-Cell Lung Carcinoma (NSCLC) cohorts of patients, we have observed high expression of TLR7 on tumor cells of 70% of patients, which conferred poor clinical outcome and was strongly associated with resistance to chemotherapy [3]. This pro-tumoral effect of TLR7 has been validated in murine models in which the injection of TLR7 agonists in NOD/SCID mice, in C57BL/6 wild-type or in TLR7-deficient mice grafted with lung adenocarcinoma tumor cells led to increased tumor progression, increased lung metastasis, and resistance to chemotherapy. On the contrary, we demonstrated that TLR7 antagonist injection led to antitumoral effect. Additionally, TLR7 stimulation resulted in a significant increase of Myeloid-Derived Suppressor Cells (MDSC) in the tumor microenvironment. Depletion experiments of MDSC indicated that these cells are involved in the pro-tumoral effect induced upon TLR7 stimulation. Finally, we have demonstrated that the pro-tumoral effect of TLR7 stimulation, mediated by the MDSC recruitment, was independent of TLR7 stimulation on immune cells. Our results reveal the mechanism by which TLR7 stimulation induce the pro-tumoral effect in mice, and open the way to the development of novel cancer therapeutics including TLR7 inhibitors, for NSCLC patients. This results demonstrate the important role of TLR7 in lung tumor progression. Knowing that natural ligands of TLR7 are ssRNA, we suppose that this effect could be linked to viral infections or RNA released in the tumor microenvironment. [1] Dajon, et al. Immunobiologie. 2016 [2] Cherfils-Vicini J, et al. J Clin Invest. 2010 [3] Chatterjee J, et al. Cancer Res. 2014
Citation Format: Marion Dajon, Kristina Iribarren, Marco Alifano, Diane Damotte, Isabelle Cremer. Protumoral and pro-metastatic effects of TLR7 in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5752.
Abstract 5762: Fast screening of CD40 agonistic antibodies for cancer immunotherapy
Authors: Jin James , Guo Yanan , Shen Yuelei , Yang Benny 
Published: August 2018

Abstract
CD40, Cluster of Differentiation 40, is a member of the TNF-receptor superfamily. CD40 is a co-stimulatory protein found primarily on antigen presenting cells, including B cells, macrophages and dendritic cells. Its ligand, CD40L (CD154) is predominantly expressed on T helper cells, whose engagement activates antigen presenting cells and induces a variety of downstream effects. Whereas most immune checkpoint receptors are expressed on the surface of T cells, CD40 stands out as it is expressed by antigen presenting cells and controls the proper activation of these cells. In turn, CD40 activation exerts a significant impact on T cell-mediated activity against cancer cells. Several pharmaceutical companies are pursuinganti-CD40 therapiesfor treating hematological and solid cancers. Having an access to Biocytogen's antibody discovery and in vivo efficacy screening platform for immune checkpoints, we asked whether we could find suitable anti-CD40 reagents which can successfullycombat developed tumors in preclinical settings. We designed a powerful screening strategy using Biocytogen's humanized CD40 mouse (B-hCD40). Candidate antibodies were generated by immunizing wild-type mice with recombinant hCD40 protein. Then the hybridomas were screened by high-throughput flow cytometry. Instead of examining the immune modulating activity in cell culture, we applied these antibodies to B-hCD40 mice bearing MC38 tumors. Through this straightforwardscreening, several clones stood out by their unparallelingbenefits. These clones were further selected for humanization. Again, the cohort of recombinant humanized CD40 antibodies was screened in B-hCD40 mice. In the end, we discovered the leads with the most potent anti-tumor activity. In conclusion, our work successfully identified several CD40 antibodies that are highly effective for cancer treatment in the preclinical setting.
Citation Format: James Jin, Yanan Guo, Yuelei Shen, Benny Yang. Fast screening of CD40 agonistic antibodies for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5762.
Abstract 5774: Novel cell-based high-throughput hybridoma screening method using the Celigo image cytometer for antibody discovery
Authors: Chan Leo L. , Zhang Haohai , Rice William , Kassam Nasim , Longhi Maria S. , Zhao Haitao , Robson Simon C. , Gao Wenda , Wu Yan 
Published: August 2018

Abstract
Hybridoma screening is a highly important process for antibody discovery, which can identify potential clones from hundreds to thousands of hybridoma cultures against the desired target antigen. Traditional screening methods using ELISA and flow cytometry presented technical issues such as limited accuracy, reduced high-throughput capability, increased time and cost. Conventional ELISA screening with coated antigen can also be impractical for difficult to express hydrophobic membrane antigens or multi-chain protein complexes. Here, we demonstrate novel cell-based high-throughput screening methodology using plate-based Celigo Image Cytometer, which avoids nonspecific signals by contrasting antibody binding signals directly on living cells, with and without recombinant antigen expression. The image cytometry-based high-throughput screening method was optimized by detecting the binding of hybridoma supernatants to the recombinant antigen CD39 expressed on Chinese hamster ovary (CHO) cells. Both target CHO and CFSE-stained wild type were co-cultured to simultaneously detect target antibodies (Alexa Fluor 594) and nonspecific binding, which can eliminate the need to produce a separate control sample for each hybridoma supernatant. Next, the image cytometer was used to screen 672 unique hybridoma supernatants to develop the high-throughput screening workflow. The Celigo was used to quickly image and analyze antibody binding of 672 samples, using Hoechst, Alexa Fluor 594 and CFSE fluorescence to identify high, medium, and low binding hits. Finally, the sensitivity of the image cytometer was demonstrated by serial dilution of purified CD39 antibody. Celigo was used to measure antibody affinities of commercial and in-house antibodies to membrane-bound CD39. This cell-based screening procedure can be completely accomplished within one day, significantly improving throughput and efficiency of hybridoma screening. Furthermore, measuring direct antibody binding to living cells eliminated both false positive and false negative hits. The image cytometry method was highly sensitive and versatile, and could detect positive antibody in supernatants at concentrations as low as ~5 ng/mL, with concurrent Kd binding affinity coefficient determination. We propose that this screening method will greatly improve screening technologies and facilitate more efficient antibody discovery.
Citation Format: Leo L. Chan, Haohai Zhang, William Rice, Nasim Kassam, Maria S. Longhi, Haitao Zhao, Simon C. Robson, Wenda Gao, Yan Wu. Novel cell-based high-throughput hybridoma screening method using the Celigo image cytometer for antibody discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5774.
Abstract 5776: Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft models
Authors: Wang Yaolin , Shi Zhe , Jiang Yueheng , Dai Xing 
Published: August 2018

Abstract
Breast cancer is the most common form of cancer in women in the developed world, with estrogen receptor-positive (ER+) breast cancer accounting for 70-80% of all breast cancers. Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of ER+ breast cancer patients, either alone or in combination with CDK4/6 inhibitor (palbociclib or abemaciclib). However, due to poor pharmacokinetic property, fulvestrant has to be given via intramuscular injection. In addition, patients relapsed after prolonged endocrine therapy with aromatase inhibitors such as letrozole and anastrozole due to emergence of ER mutations. Here, we report the discovery of D-0502, an orally bioavailable SERD with potent activity in various ER+ breast cancer cell lines and xenograft models. In addition, combination of our SERD candidates and palbociclib in both MCF-7 xenograft model and ESR-1 mutated (Y537S) patient-derived breast cancer xenograft model resulted in further tumor growth inhibition or regression. Comparison of various SERD molecules showed our candidate has more potent antitumor activity in MCF-7 xenograft model than GDC-0810, AZD9496 and fulvestrant. More importantly, drug metabolism and pharmacokinetic (PK) studies both in vitro and in vivo demonstrated that our SERD molecule D-0502 exhibits superior PK profiles suitable for clinical development.
Citation Format: Yaolin Wang, Zhe Shi, Yueheng Jiang, Xing Dai. Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5776.
Abstract 5800: Vorinostat and indole-3-carbinol modulate microRNAs and histone deacetylase activity in subtypes of triple-negative breast cancer
Authors: Lyn-Cook Beverly , NouriEmamzaden Fatemeh , Hawkins Anfernee , Hammons George , Word Beverly 
Published: August 2018

Abstract
Triple-negative breast cancer is a highly heterogeneous and aggressive subtype of breast cancer. Epigenetic drugs are continuing to emerge as promising therapies for triple-negative breast cancer (TNBC). These drugs, including the one used in this study, vorinostat, a histone deacetylase inhibitor (HDAC), are capable of multiple actions and are considered multifunctional drugs. Epigenetic mechanisms have been shown to play a role in the etiology of this cancer, through modulation of DNA methylation, histone modification or microRNAs. We have shown in this study that vorinostat and indole-3-carbinol (I3C) modulated the expression of microRNAs 221 and 222 differently in basal-like-2 (BL2), MSL, basal-like1 (BL1) and M subtypes of TNBC cells. Additional studies demonstrated that combination of tamoxifen and vorinostat significantly decreased expression of miRNA 221 in TNBC cell lines. MiRNAs are short noncoding RNAs that regulate the function of target genes post-transcriptionally. In addition, breast cancer microarrays further showed modulation of a number of other miRNAs that play a role in cell proliferation, drug resistance, cell invasion and metastasis. MicroRNAs are epigenetic targets for drug development. Using a global HDAC activity assay, it was also shown that subtypes of TNBC cells respond differently to vorinostat and I3C treatment, depending on their HDAC activity. HCC70, an African American cell line and a BL2 subtype, had the highest HDAC activity and its activity was significantly decreased by vorinostat treatment compared to BT549 (M), HCC 1806 (BL2), MCF7 (ER positive) and a basal nonmalignant cell line, MCF10A. Both vorinostat and I3C show great promise alone and in combination as effective agents in triple-negative breast cancer. Histone deacetylase inhibitors and dietary agents are emerging as therapy for triple-negative breast cancer and are currently in clinical trials.
Citation Format: Beverly Lyn-Cook, Fatemeh NouriEmamzaden, Anfernee Hawkins, George Hammons, Beverly Word. Vorinostat and indole-3-carbinol modulate microRNAs and histone deacetylase activity in subtypes of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5800.
Abstract 5822: Secretory acetylated APE1/Ref-1 requirement for suppression of tumor growth in triple-negative breast cancer in vivo: Extracellular apoptotic initiator
Authors: Lee Yu Ran , Park Myoung Soo , Joo Hee Kyoung , Kim Ki Mo , Kim Jeryong , Jeon Byeong Hwa , Choi Sung 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a relatively large proportion of BC-related death. Thus more effective therapeutic strategies are needed for the management of TNBC. We previously demonstrated that the stimulation of apoptosis by the binding of secreted acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) to the receptor for advanced glycation end products (RAGE) was essential for the TNBC cell death in response to hyperacetylation. The aim of the present study was to assess the potential therapeutic efficacy of secretory Ac-APE1/Ref-1 in orthotopic TNBC xenografts in vivo. We found that hyperacetylation in xenografts caused secretion of Ac-APE1/Ref-1 into the blood, where the factor bound directly to RAGE in hyperacetylated tumor tissues. Hyperacetylation in the TNBC xenografts induced strong inhibition of tumor growth and development. Hyperacetylation also caused cell death in tumors, accompanied by increased RAGE expression and generation of reactive oxygen species, which induced apoptosis. Tissues exhibited markedly higher counts of apoptotic bodies, a reduced proliferation index, and reduced neovascularization compared with control tumors. Ac-APE1/Ref-1-stimulated apoptosis was markedly reduced in RAGE-knockdown tumors compared with RAGE-overexpressing tumors, even in the presence of hyperacetylation. The function of secreted Ac-APE1/Ref-1 was confirmed in other hyperacetylated TNBCs xenografts using BT-459 and MDA-MB-468 cells, demonstrating its relevance as an anticancer molecule. Our findings suggest that the Ac-APE1/Ref-1 possesses potent chemotherapeutic efficacy against hyperacetylated TNBCs based on stimulation of cell death by RAGE-dependent triggering of Ac-APE1/Ref-1.
Citation Format: Yu Ran Lee, Myoung Soo Park, Hee Kyoung Joo, Ki Mo Kim, Jeryong Kim, Byeong Hwa Jeon, Sung Choi. Secretory acetylated APE1/Ref-1 requirement for suppression of tumor growth in triple-negative breast cancer in vivo: Extracellular apoptotic initiator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5822.