bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2720: The CD47-blocking innate immune checkpoint inhibitor, TTI-621, triggers CD47-mediated tumor cell apoptosis
Authors: Izrailit Julia Bershadsky , Viller Natasja Nielsen , Pang Xinli , Petrova Penka S. , Uger Robert A. , Winston Jeff , Linderoth Emma 
Published: August 2018

Abstract
CD47 is a cell surface glycoprotein of the immunoglobulin superfamily that is utilized by tumor cells to avoid immune destruction. Overexpression of the CD47 ligand on tumor cells provides a “do-not-eat” signal when bound to its receptor, signal regulatory protein α (SIRPα), on macrophages, resulting in inhibition of phagocytosis and tumor survival. TTI-621 is a soluble SIRPα recombinant fusion protein with an IgG1 Fc tail that triggers macrophage phagocytosis of tumor cells in vitro, and potently inhibits tumor growth in vivo. It is currently being evaluated in two clinical studies in patients with hematologic and solid cancers (NCT02663518 and NCT02890368). TTI-621's pro-phagocytic effect has been shown to be a result of blockade of the CD47-SIRPα pathway as well as activation of Fc gamma receptors (FcγR) on macrophages. However, engagement of CD47 has also been shown to directly induce apoptosis in tumor cells. Therefore, the objective of this study was to further examine the pro-apoptotic potential of TTI-621.
The induction of apoptosis in tumor cells by TTI-621 was evaluated using flow cytometry and protein expression assays. Ligating CD47 with immobilized TTI-621 efficiently induced apoptosis in malignant T-ALL and DLBCL cells but had no effect on apoptosis in normal peripheral blood mononuclear cells. Immobilized TTI-621 or anti-CD47 mAb promoted caspase-independent but PLCγ-1-dependent apoptosis. Under conditions of cellular stress, both soluble and immobilized TTI-621 induced apoptosis in T-ALL cells. In contrast to immobilized TTI-621, treatment of stressed tumor cells with soluble TTI-621 triggered caspase-dependent but PLCγ-1-independent apoptosis. In addition, anchoring the IgG1 Fc tail of TTI-621 to FcγR-expressing cells enhanced tumor cell apoptosis in a dose-dependent and CD47-dependent manner.
These results suggest that in addition to blocking the anti-phagocytic “do-not-eat” signal on tumor cells and activating FcγR on macrophages, binding of TTI-621 to FcγRs on tumor-infiltrating immune cells may provide a cross-linking scaffold to enhance TTI-621-mediated apoptosis via CD47 on cancer cells. Additionally, under conditions of cellular stress, TTI-621 may induce tumor cell death directly via binding to CD47 on malignant cells, in a cell-autonomous, cytotoxic mechanism. Thus, TTI-621 may employ multiple mechanisms to elicit its anti-tumor effects.
Citation Format: Julia Bershadsky Izrailit, Natasja Nielsen Viller, Xinli Pang, Penka S. Petrova, Robert A. Uger, Jeff Winston, Emma Linderoth. The CD47-blocking innate immune checkpoint inhibitor, TTI-621, triggers CD47-mediated tumor cell apoptosis [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 2720.
Abstract 2784: Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation
Authors: Hedvat Michael , Bonzon Christine , Bernett Matthew J. , Moore Gregory L. , Avery Kendra , Rashid Rumana , Nisthal Alex , Schubert Suzanne , Varma Rajat , Lee Sung-Hyung , Bogaert Liz , Leung Irene W.L. , Chu Seung , Muchhal Umesh , Desjarlais John 
Published: August 2018

Abstract
Combination checkpoint blockade promotes productive anti-tumor clinical responses often associated with an increase in immune-related adverse events. We developed optimized bispecific antibody candidates that simultaneously engage PD1 and CTLA4 (XmAb20717), CTLA4 and LAG3 (XmAb22841), and PD1 and ICOS (XmAb23104), that preferentially bind to cells co-expressing the targeted receptors. Because tumor infiltrating lymphocytes (TILs) typically express multiple immune checkpoints and costimulatory receptors, we hypothesized that these bispecific antibodies will enable selective targeting of tumor-reactive TILs, leading to safer and more cost-effective combination checkpoint blockade. The PD1 x CTLA4 bispecific antibody XmAb20717 and the PD1 x ICOS bispecific antibody XmAb23104 promoted superior in vitro T cell activation when compared to an anti-PD1 bivalent antibody. The CTLA4 x LAG3 bispecific antibody XmAb22841 combines productively with an anti-PD1 bivalent antibody achieving additive T cell activation through triple checkpoint blockade. Treatment with bispecific antibodies caused superior engraftment and activation of human T cells in NSG mice compared to an anti-PD1 bivalent antibody. Bispecific antibodies also potentiate allogeneic anti-tumor activity against human cancer cells in vivo. Each bispecific antibody promoted a unique RNA gene signature suggesting distinct mechanisms of action. These bispecific antibodies demonstrate compelling immune modulatory activity suggesting clinical development is warranted for the treatment of human malignancies.
Citation Format: Michael Hedvat, Christine Bonzon, Matthew J. Bernett, Gregory L. Moore, Kendra Avery, Rumana Rashid, Alex Nisthal, Suzanne Schubert, Rajat Varma, Sung-Hyung Lee, Liz Bogaert, Irene W.L. Leung, Seung Chu, Umesh Muchhal, John Desjarlais. Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation [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 2784.
Abstract 2875: Calycosin is a double-edged sword in the treatment of pancreatic cancer
Authors: Zhang Zhu , Ko Joshua KS 
Published: August 2018

Abstract
Calycosin is known for its suppression of breast cancer cell growth. We are the first group to report the effects of calycosin in pancreatic cancer development. Growth inhibition of the human pancreatic cell line MIA PaCa-2 was evaluated by MTT assay. Cell cycle distribution was determined by flow cytometry. Cell migratory activity was investigated by a wound healing assay. Subcutaneous xenografting of MIA PaCa-2 cells was conducted in Balb/C nude mice, while orthotopic inoculation of the mouse Pan01 pancreatic cancer cells was performed in C57BL/6 mice. Our results have shown that calycosin exhibited modest growth inhibition of MIA PaCa-2 cells, together with induction of S phase arrest and restoration of p53. Besides, promotion of both caspase-dependent apoptosis and autophagy implicate that the anticancer mechanism of calycosin strongly rely on programmed cell death. Alternatively, calycosin also inhibited the migration of MIA PaCa-2 cells in line with downregulation of epithelial–mesenchymal transition (EMT) and pro-metastatic biomarkers. The above in vitro benefits of calycosin was confirmed by a significant reduction of tumor mass in the MIA PaCa-2 xenograft. Nevertheless, when we look closely on the in vivo anticancer effect of calycosin in the Pan01 orthotopic mice model, although both attenuation of tumor growth and proapoptotic action were confirmed by histological findings, the tumor tissue expression of Snail, vimentin and CD31 was all elevated, indicating possible promotion of EMT and pro-angiogenic potential of the drug. These controversial findings suggest that calycosin could be an effective anticancer agent by promoting programmed cell death and inhibition of cell proliferation of pancreatic cancer cells, while it may also facilitate metastatic development of tumor, particular at the advanced stages. It would be essential to further dissect the conditions and factors that differentiate the dual actions of calycosin in pancreatic cancer therapy.
Citation Format: Zhu Zhang, Joshua KS Ko. Calycosin is a double-edged sword in the treatment of pancreatic 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 2875.
Abstract 3012: Urban neighborhood and residential factors associated with breast cancer in African American women: A systematic review
Authors: Smith Brandi P. , Madak-Erdogan Zeynep 
Published: August 2018

Abstract
Residential characteristics in urban neighborhoods impacts health and might be an important factor contributing to health disparities, especially in the African American population. The purpose of this systematic review is to understand the relationship between urban neighborhood and residential factors and breast cancer incidence and prognosis in African American women. Using PubMed and Web of Science, the existing literature was reviewed. Observational, cross-sectional, cohort, and prospective studies until February 2017 were examined. Studies including populations of African American women, setting in “urban” areas, and a measure of a neighborhood or residential factor were reviewed. Four parameters related to neighborhood or residential factors were extracted including: neighborhood socioeconomic status (nSES), residential segregation, spatial access to mammography, and residential pollution. Our analysis showed that African American women living in low nSES have greater odds of late stage diagnosis and mortality. Furthermore, African American women living in segregated areas (higher percentage of Blacks) have higher odds of late stage diagnosis and mortality compared to White and Hispanic women living in less segregated areas (lower percentage of Blacks). Late stage diagnosis was also shown to be significantly higher in areas with poor mammography access and areas with higher Black residential segregation. Lastly, residential pollution did not affect breast cancer risk in African American women. Overall, this systematic review provides a qualitative synthesis of major neighborhood and residential factors on breast cancer outcomes in African American women.
Citation Format: Brandi P. Smith, Zeynep Madak-Erdogan. Urban neighborhood and residential factors associated with breast cancer in African American women: A systematic review [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 3012.
Abstract 3055: A model of CSC converted from iPSC in the conditioned medium of HCC paving the way to establish HCC CSC
Authors: Afify Said M , Calle Anna Sanchez , Kumon Kazuki , Nawara Hend M , Khairani Apriliana C , Mahmud Hafizah , Oo Aung Ko Ko , Juan Du , Zahara Maram H , Seno Akimasa , Kasai Tomonari , Iwasaki Yoshiaki , Seno Masaharu 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) represents the major histological subtype, accounting for 70%–85% of cases of primary liver cancer. Liver CSCs sustain their self-renewal remains largely unknown. The self-renewal and pluripotency of liver CSC are maintained by several signaling cascades. However, the mechanism of regulating these signaling is unknown.
In this study, we tried to convert mouse iPSCs into CSCs with the conditioned medium (CM) from human HCC cell line Huh7 cells without any genetic manipulation aiming at establishing liver CSCs.
First of all, CM was collected from confluent culture of Huh7 cells. Then, mouse iPSCs cells without MEF feeder cells were cultured in the presence of 50% CM for 4 weeks. The medium was changed every day with fresh medium containing 50% of CM. Mouse iPSCs cultured in the complete medium with LIF were used as a control.The survived cells (5x105 cells) were suspended in HBSS and injected into the liver of BALB/c nude mice. After 25 days malignant tumor was formed in the liver while benign teratoma was formed by the injection of iPSCs. Tumors were then excised and partly fixed in 10% neutral formalin buffer solution for HE staining and immunohistochemical analysis. The rest of tumors were subjected to rt-qPCR anaylsis and primary culture. Immunohistochemical analysis with GFP antibody showed that malignant tumor sustained GFP expression while teratoma from miPSCs did not. Immunocytochemistry of the primary cells from malignant tumor showed high expression of both glypican-3 (GPC3) and cytokeratin19 (CK19) when compared to that in miPSCs. Expression of stem cell markers (Nanog, Oct3/4, Sox2, Klf4) and CSC markers (CD44, EpCAM) were also confirmed by rt-qPCR in both the CSCs converted from iPSCs (miPS-Huh7cm cells) and the primary culture cells. These results indicate that the primary cells from the malignant tumor are rich in CSCs with high expression of GPC3 and CK19, which paves the way to establish a model of HCC CSC. This model should be very important and useful to assess the significant molecular mechanisms necessary to maintain HCC CSC, which will help develop effective therapy of liver cancer.
Citation Format: Said M Afify, Anna Sanchez Calle, Kazuki Kumon, Hend M Nawara, Apriliana C Khairani, Hafizah Mahmud, Aung Ko Ko Oo, Du Juan, Maram H Zahara, Akimasa Seno, Tomonari Kasai, Yoshiaki Iwasaki, Masaharu Seno. A model of CSC converted from iPSC in the conditioned medium of HCC paving the way to establish HCC CSC [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 3055.
Abstract 3278: Performance assessment of de novo assembly-based structural variation detection in the human genome
Authors: Xiao Chunlin ,   SEQC2 Working Group #3
Published: August 2018

Abstract
Structural variations (SVs) contribute to genetic diversity of human populations, affect biologic functions, and cause various human disorders. However, accurately identifying SVs with correct sizes and locations in the human genome remains challenging due to the complexity of the human genome, limitations of sequencing technologies, and drawbacks of analysis methods. The advancement of next-generation sequencing technologies has dramatically decreased the sequencing cost, while substantially increased the lengths of the sequencing reads. Thus, using de novo assembly-based approaches for discovering a full spectrum of SVs in human genome becomes appealing. While various assembly methods have been developed and proposed for general use by the community, the relative efficiency and predictive accuracy of SVs calling based on these assembly methods have not been fully evaluated. In this study, we applied several popular de novo assembly tools to the sequencing read data that were generated using multiple sequencing technologies with technical replicates for NA12878/HG001, a well-studied individual from NIST-led Genome-in-a-Bottle (GIAB) project: a HapMap Caucasian trio and a Chinese Quartet from FDA-led Sequencing Quality Control Phase II (SEQC2) project. Assemblies and SVs callsets were generated for each of the eight samples, and repeatability in the SVs of the technical replicates and reproducibility across sequencing sites were evaluated. The assembly-based SVs callsets have been compared with alignment-based SVs callsets. These results allow better understanding of the impacts of de novo assembly methods on SVs calling, thus providing a better insight to precision medicine.
Citation Format: Chunlin Xiao, SEQC2 Working Group #3. Performance assessment of de novo assembly-based structural variation detection in the human genome [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 3278.
Abstract 3432: Evolving genomes of breast cancer aromatase inhibitor resistance models
Authors: Hoppe Reiner , Kandabarau Siarhei , Fan Ping , Jordan V Craig , Brauch Hiltrud B. 
Published: August 2018

Abstract
Acquired endocrine resistance is a severe barrier in the anti-hormonal treatment of breast cancer and is responsible for its failure in about half of the treated patients. In vitro models of long-term estrogen deprived breast cancer cells serve as laboratory tools to explore new therapeutic strategies. The models MCF-7:5C and MCF-7:2A mimic clinical AI resistance but regress with E2 due to the reconfiguration of survival signaling known as E2-inducible apoptosis (5C rapid, 2A delayed reaction). Alterations of stress related pathways including the accumulation of endoplasmic reticulum stress, oxidative stress, and inflammatory stress that occur prior to E2-induced apoptosis (Ariazi et al. 2011; Fan et al. 2013, 2015; Sweeney et al. 2014) and specific miRNA expression profiles (Hoppe et al Oncotarget 2016) have been linked with these resistance and E2-inducible apoptosis phenotypes. Little is known on their underlying genetic variability. Here we compare the mutational profiles of 5C and 2A clones with those of the estradiol stimulated growth sensitive MCF-7:WS8 and standard MCF-7 (ATCC) cells. Whole genome libraries were sequenced on the Illumina HiSeq platform (2x150bp reads). Alignments were manually inspected (bcftools mpileup) to avoid false negative variant calling in poorly (&lt;20x) covered regions. Loci with at least 10x coverage and absence of any variant reads were classified as wildtype. The coding genome positions defined as mutant or wildtype in all four cell types served as a basis to select candidate mutations for the verification of MCF-7 variants via comparison to the COSMIC database (http://cancer.sanger.ac.uk/cosmic) and identification of novel mutations by variant calling (GATK HaplotypeCaller). Putative protein effects of variants were predicted by the SnpEff tool. We verified 421 point mutations in MCF-7 (COSMIC) of which 203 mutations were lost in our models, with additional specific losses of 4, 4, and 18 mutations in WS8, 2A and 5C, respectively. In 5C cells new mutations affected 261 genes with 31 high impact mutations based on splice site alterations in 7 genes (i.e. CERS2, SEMA3A, TDRD7, ATP5H) and gain of stop codons in 24 genes (i.e. CACNA1S, NOTCH4, SUN1, JPH3, SERPINB2). Similarly, in 2A cells there were 12 high impact mutations among 122 affected genes (e.g. ARHGEF5, ARHGAP35, ARAP2). We will report on the integrative genomic analysis including larger structural variants (short indels and CNVs) towards the evolution of these models for a comprehensive understanding of the biology of E2-inducible apoptosis.
Citation Format: Reiner Hoppe, Siarhei Kandabarau, Ping Fan, V Craig Jordan, Hiltrud B. Brauch. Evolving genomes of breast cancer aromatase inhibitor resistance 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 3432.
Abstract 3544: Ras GTPases are modified by SUMOylation
Authors: Choi Byeong Hyeok , Chen Changyan , Philips Mark , Dai Wei 
Published: August 2018

Abstract
RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are post-translationally modified (i.e., SUMOylated) by the SUMO pathway. We observed that all three RAS protein isoforms (HRAS, KRAS, and NRAS) were modified by the SUMO3 protein. SUMOylation of KRAS protein, either endogenous or ectopically expressed, was observed in multiple cell lines. The SUMO3 modification of KRAS proteins could be removed by SUMO1/sentrin-specific peptidase 1 (SENP1) and SENP2, but not by SENP6, indicating that RAS SUMOylation is a reversible process. A conserved residue in RAS, Lys-42, was a site that mediates SUMOylation. Results from biochemical and molecular studies indicated that the SUMO-E3 ligase PIASγ specifically interacts with RAS and promotes its SUMOylation. Moreover, SUMOylation of RAS appeared to be associated with its activation. In summary, our study reveals a new post-translational modification for RAS proteins. Since we found that HRAS, KRAS, and NRAS can all be SUMOylated, we propose that SUMOylation might represent a mechanism by which RAS activities are controlled.
Citation Format: Byeong Hyeok Choi, Changyan Chen, Mark Philips, Wei Dai. Ras GTPases are modified by SUMOylation [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 3544.
Abstract 3560: Targeting the MIF receptor CD74 in bladder cancer tumorigenesis
Authors: Penticuff Justin , Shanmugam Sambantham , Warrick Joshua , Chase Brian , Abbott Erika , Woolbright Benjamin L. , Taylor John A. 
Published: August 2018

Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that can stimulate cellular proliferation in multiple tumors. Our previous data indicates genetic deletion of MIF results in T1 stage arrest in the N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced bladder cancer model. Similarly, pharmacological inhibition of MIF results in lower stage tumors and reduced bladder weights when given therapeutically. CD74 is a human leukocyte antigen class II trafficking and processing protein that also functions as an extracellular receptor for MIF. Additionally, CD74 complexes with CD44 to act as the cognate MIF receptor complex, and upregulation of CD74 has been noted in high grade bladder cancer. We hypothesized CD74 would be upregulated in malignant bladder cancer cell lines, and knockout of CD74 would reduce bladder cancer tumorigenesis in the murine BBN model. The objectives of this study were to determine the effect of CD74 knockout on development and progression of urothelial cell carcinoma; as well as evaluate expression of the putative MIF signaling axis in BCa cell lines. BCa cell lines HTB-9, HTB-5, RT-4, T24 and HT-1376 and benign urothelial UROtsa cells were analyzed for MIF, CD74, and CD44 expression via quantitative PCR or western blot to assess expression of the MIF signaling axis. CD74 and CD44 expression by q-PCR were dramatically elevated in BCa cell lines vs. benign cell lines. Protein levels of CD74 and CD44 were elevated in multiple cell lines as well. MIF expression levels did not change between cell lines. To ascertain differences in BCa tumorigeneis, WT C57Bl/6J mice or CD74-/- mice were given 0.05% BBN in the drinking water for 22 weeks. Bladders were weighed and evaluated for pathologic staging by histology. After exposure to BBN, bladders from CD74-/- mice had a 33% reduction in weight vs. WT bladders (p=.062). Pathological analysis revealed lower stage tumors in bladders of CD74-/- mice (33% incidence; 6.7% pTa, 0% pTis, 6.7% pT1, 20% pT2, 6.7% pT3) as compared to bladders of WT mice (81.3% incidence; 0% pTa, 6.3% pTis, 25% pT1, 12.5% pT2, 37.5% pT3), which was a statistically significant reduction in tumor stage. Lower tumor stage correlated significantly with the CD74-/- genotype (p=0.02, Fisher's Exact Test). These data suggest CD74 likely mediates a portion of the effects of MIF in BCa, raising the possibility of both CD74 dependent, and independent MIF signaling pathways.
Citation Format: Justin Penticuff, Sambantham Shanmugam, Joshua Warrick, Brian Chase, Erika Abbott, Benjamin L. Woolbright, John A. Taylor. Targeting the MIF receptor CD74 in bladder cancer 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 3560.