bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5122: Comprehensive detection of germline and somatic structural mutation in cancer genomes by Bionano Genomics optical mapping
Authors: Pang Andy 
Published: August 2019

Abstract
In cancer genetics, the ability to identify constitutive and low-allelic fraction structural variants (SVs) is crucial. Conventional karyotype and cytogenetics approaches are manually intensive. Microarrays and short-read sequencing cannot detect calls in segmental duplications and repeats, often miss balanced variants, and have trouble finding low-frequency mutations.
We describe the use of Bionano Genomics’s Saphyr platform to comprehensively identify SVs for studying cancer genomes. DNA &gt;100 kbp is extracted, labelled at specific motifs, and linearized through NanoChannel arrays for visualization. Molecule images are digitized and de novo assembled, creating chromosomal arm scale genome maps. Somatic mutations can be identified by running the variant annotation pipeline that compares the cancer sample’s assembly SVs against &gt;600,000 SVs in Bionano’s control sample SV database, and against a matched control sample’s SVs, if avaliable. Also, two new Bionano pipelines leverage these long molecules to identify additional somatic SVs: the copy number variation (CNV) and the molecule mapping pipelines. By examining the coverage-depth of molecules alignment to the public reference, the pipeline can identify megabases long CNVs. Similarly, clusters of split-molecule alignments can reliably find translocations and other rearrangements.
We applied this suite of discovery tools to identify SVs in a well-studied melanoma cell line COLO829. We collected data from the tumor and the matched blood cell line, constructed contiguous assemblies (N50 &gt;50 Mbp), and called &gt;6,000 SVs in each genome. Then, we classified 51 as somatic by comparing the tumor and the blood control. The two new pipelines further increased sensitivity to rearrangements, for example they captured a BRAF duplication, and other chromosome-arm CNVs. We apply these thorough approaches to multiple well-studied cancer lines to identify novel SVs missed by previous studies. In conclusion, with one comprehensive platform, Saphyr can discover a broad range of traditionally refractory but relevant SVs, and further improves our understanding of cancer.
Citation Format: Andy Pang. Comprehensive detection of germline and somatic structural mutation in cancer genomes by Bionano Genomics optical mapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5122.
Abstract 5127: Association of inactivating calcium sensing receptor exon 7 SNPs with hypercalcemia-related disease phenotypes
Authors: Actkins Ky'Era , Beasley Heather , Faucon Annika , Davis Lea , Sakwe Amos 
Published: August 2019

Abstract
The calcium sensing receptor (CaSR) is a ubiquitously expressed G-protein coupled receptor known to be a major calcium sensor in most tissues and organ systems. It is known to regulate systemic calcium homeostasis by sensing slight increases in systemic calcium and by influencing the secretion of parathyroid hormone by parathyroid chief cells. Unfortunately, the CaSR is known to be invariably mutated and inactivating mutations in particular, are associated with the development of cancer-induced hypercalcemia (CIH). Among the several inactivating CASR polymorphisms described thus far, the rs1801725 (A986S SNP) is common among Caucasian subjects while the rs1801726 (Q1011E SNP) is common among African American subjects. However, whether these mutations contribute to other hypercalcemia-related disease phenotypes remains unclear. In this study, we carried out a phenome-wide association study (PheWAS) using the Synthetic Derivative (SD), a database at VUMC containing de-identified electronic health records (EHRs) linked to patient DNA samples in the BioVU biorepository. Using 39,893 genotyped individuals in the Multi-Ethnic Genotyping Array (MEGA), we observed that SNP rs1801725 was significantly associated with disorders of bone and cartilage (p = 5.93e-6, OR = 1.28) as well as with secondary malignancy of bone (p = 1.46e-5, OR = 1.21); whereas SNP rs1801726 was significantly associated with osteoporosis related phenotypes (p = 5.93e-6, OR = 1.28). Given that breast cancer and other solid tumors frequently metastasize to skeletal tissues, these data suggests that the inactivating rs1801725 and rs1801726 CaSR variants differentially influence hypercalcemia-related comorbidities and cancer metastasis to bone. We will further verify these effects using the associated clinical data and perform genetic risk analyses for the expression of these SNPs and the associated disease phenotypes.
Citation Format: Ky'Era Actkins, Heather Beasley, Annika Faucon, Lea Davis, Amos Sakwe. Association of inactivating calcium sensing receptor exon 7 SNPs with hypercalcemia-related disease phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5127.
Abstract 5144: The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer
Authors: Lu Xuman , Ji Zhe , Zhao Jing , Zhang Yuzi , Huang Mengli , Cai Shangli , Huang Jun 
Published: August 2019

Abstract
Purpose Immune checkpoint blockades (ICBs) have been reported to be used in early stage colorectal cancer (CRC) as neoadjuvant therapy. However, it seems that microsatellite stable (MSS) CRC patients obtained no significant clinical benefit in studies with small sample size. We aimed to explore the potential biomarkers and rational immunotherapy to optimize response to ICBs in MSS CRC.
Procedures Whole exome sequencing and RNAseq of 612 CRC patients from The Cancer Genome Atlas were analyzed. T cell dysfunction/exclusion signatures and Tumor infiltrating lymphocytes were calculated from TIDE model and TIMER algorithm, respectively. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. P value was adjusted by BH method for multiple comparisons.
Results There were 109 stage I, 228 stage II, 184 stage III and 91 stage IV in 612 CRC patients. The MSI-H prevalence, tumor mutation burden, PD-L1 mRNA and CD8 T cell infiltration decreased with the increase in pathologic stage (all P &lt; 0.01). In MSS CRC, mRNA expression of immune checkpoint related genes including PD-L1, CTLA4 and LAG3 were significantly higher in stage I-III than stage IV (adjusted P &lt; 0.01, &lt; 0.01 and 0.04, respectively). For immune activation genes (CD8A, CXCL9, CXCL10, GBP1, GZMB, GZMA, IFNG, FAS, STAT1, TAP1), their mRNA expression levels increased with the decrease of stage (All adjusted P &lt; 0.01). Besides, stage I-III MSS CRC had lower T cell exclusion signature score than stage IV (adjusted P = 0.02). No similar results were observed in MSI-H. Compared with MSI-H, MSS had higher M2 macrophage signature score (P &lt; 0.001), but no association were observed between M2 macrophage signature and stage.
Conclusions Early stage CRC with MSS had higher levels of positive predictive features for ICBs treatment, which suggested stronger immune responsiveness. Combination of M2 macrophage inhibitor and ICBs has the potential to turn “cold tumor” into “hot tumor” and acts as a promising therapeutic regimen, especially for early stage CRC. More clinical trials are needed to confirm this hypothesis.
Note: This abstract was not presented at the meeting.
Citation Format: Xuman Lu, Zhe Ji, Jing Zhao, Yuzi Zhang, Mengli Huang, Shangli Cai, Jun Huang. The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5144.
Abstract 5152: EMT cells increase the metastatic potential of neighboring carcinoma cells via non-canonical activation of GLI signaling through secretion of VEGF-C
Authors: Kong Deguang , Neelakantan Deepika , Zhou Hengbo , Lewis Michael T. , Ford Heide L. 
Published: August 2019

Abstract
Breast cancer is a devastating disease that claims around 50 million lives per year worldwide, and almost all of these deaths result from metastatic disease rather than from primary tumor burden. Recent studies clearly demonstrate that there is significant intratumor heterogeneity in breast cancer, and that this heterogeneity contributes to malignant progression. Our laboratories previously demonstrated that breast cancer cells that had undergone an oncogenic epithelial-to-mesenchymal transition (EMT) could increase metastasis of neighboring cells via activation of non-canonical GLI transcription factor activity in a paracrine manner that is dependent on Six1 expression in the EMT cells. However, the mechanism by which these Six1-expressing EMT cells activate GLI signaling thereby imparting aggressive properties on neighboring cells remained unknown. Herein we describe the novel discovery that VEGF-C, which is transcriptionally upregulated by Six1, mediates paracrine non-canonical activation of GLI and resultant enhancement of metastatic properties in cells that do not express Six1. Our data demonstrate that VEGF-C is upregulated in HMLER-Snail1 cells, MCF7-Six1 cells and in Met-1 cells endogenously expressing Six1, in a manner that depends on Six1 expression, and that VEGF-C is secreted into the conditioned media (CM) of these cells. Inhibition of VEGF-C in the HMLER-Snail1, MCF7-Six1, and the Met-1 models abrogates paracrine GLI activation and attenuates non-cell autonomous induction of proliferation, migration, and invasion in vitro. In vivo, we show that cells expressing Six1 can enhance the growth and metastasis of those not expressing Six1, and studies will be discussed that examine whether VEGF-C inhibition in Six1 expressing cells disrupts the crosstalk and inhibits non-cell autonomous induction of metastasis by Six1. Finally, by interrogating the TCGA dataset we find that VEGF-C and GLI1 expression significantly positively correlate in human breast cancer encompassing all molecular subtypes. Taken together, these data suggest that VEGF-C secretion may be a novel and conserved paracrine means by which EMT cells activate GLI in neighboring tumor cells that do not express these EMT-inducing transcription factors (TF), ultimately enhancing overall metastasis of heterogenous breast tumors.
Citation Format: Deguang Kong, Deepika Neelakantan, Hengbo Zhou, Michael T. Lewis, Heide L. Ford. EMT cells increase the metastatic potential of neighboring carcinoma cells via non-canonical activation of GLI signaling through secretion of VEGF-C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5152.
Abstract 5153: Measuring T-cell avidity and enrichment using an acoustic force based technology
Authors: Raja Ali , Scheper Wouter , Merino Elena , Braster Rens , Sitter Gerrit , Oswald Felix , Schumacher Ton , Candelli Andrea , Anderson Leif 
Published: August 2019

Abstract
The key driver for effective immunotherapies is the overall strength binding of the immune cell and the target cell (e.g. tumor cells). The overall strength is known as ‘avidity’, a parameter reflecting interaction efficiency. One of the main obstacles has been the generation of immunotherapies promoting effective and long-lasting immune responses, due to the lack of tools measuring this parameter. Here, we have made used of acoustic forces as a novel method to isolate immune cells based on their avidity to specific targets, such as (tumor) cells. The force that cell-target need to experience to be separated is called ‘rupture force’. In this study, we were able to identify the rupture forces of tumor specific and non-specific T cells and separate these different populations applying controllable acoustic forces. T cells engineered with a melanoma antigen recognizing T-cell receptor needed 6 times more relative force than the control, non-specific T cells, to be separate from their melanoma cells. These findings indicate that the specific melanoma T cells bind with higher efficiency and higher avidity than the non-specific ones, and that they can be separated with this method. Furthermore, 1.4 to 3.6-fold enrichment of high avidity T cells from a mixed specific: non-specific (1:10) T cell population was obtained after their isolation using acoustic forces and confirmed using FACS measurements. Therefore, we demonstrate here that acoustic forces can be use as a tool to measure avidity.
Citation Format: Ali Raja, Wouter Scheper, Elena Merino, Rens Braster, Gerrit Sitter, Felix Oswald, Ton Schumacher, Andrea Candelli, Leif Anderson. Measuring T-cell avidity and enrichment using an acoustic force based technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5153.
Abstract 516: Metformin inhibits monocyte differentiation to tumor associated macrophage (TAM) and may restore anti-tumor immunity
Authors: Saito Akira , Ohzawa Hideyuki , Tojo Mineyuki , Kumagai Yuko , Kanamaru Rihito , Tsukui Hidenori , Shiba Satomi , Ito Homare , Sata Naohiro , Kitayama Joji 
Published: August 2019

Abstract
Background: Tumor-associated macrophages (TAMs) play pivotal roles to regulate tumor cell behavior in tumor microenvironment and a high density of TAMs is associated with poor prognosis in various cancers. Recent studies have demonstrated that metformin, the first-line medication for the treatment of type 2 diabetes, have suppressive effects on tumor growth. Here, in this study, we investigated the effect of metformin on monocyte differentiation to TAMs.
Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and CD14+ peripheral blood monocytes(PBMo) were purified by positive selection using the magnetic cell separation system. The PBMo were co-cultured with Panc-1, a human pancreas cancer cell, with metformin (10μM~10mM) using double chamber inserts of 0.4-μm sized pores at 37°C in 5% CO2 conditions for 5 days. Separately, PBMo were cultured with M-CSF for 5 days and then with IL-10 (20ng/ml)+TGF-β(20ng/ml) for addition 2 days with or without metformin. The differentiation to TAM were evaluated by the expression of M1/M2 markers as well as PD-L1/L2 by flowcytometry. The macrophages were co-cultured with autologous T cells stimulated with anti-CD3 and anti-CD3 and anti-CD28 microbeads and the effect on T cell proliferation was evaluated with CFSE dilution assay.
Results: PBMo co-cultured with Panc-1 showed significantly enhanced expression of CD163, CD206, as well as markedly increased side scatter, suggesting the differentiation to M2-type macrophages. The macrophage also highly expressed PD-L1 and strongly inhibited the proliferation of autologous T cells. However, the expression of these antigens and inhibition of T cell growth were significantly suppressed by the presence of metformin with dose dependent manner. Metformin was effective at 100μM and almost nullified the effects of Panc-1 at 1mM. Metformin did not affect the antigen expression pattern during the treatment by M-CSF, but did downregulate the expression of CD206 and PD-L1 if added together with IL-10 +TGF-β.
Conclusion: During the co-culture with tumor cells, metformin suppresses the monocyte differentiation to TAM at relatively late stage. Metformin can restore T cell mediated-tumor immunity in tumor microenvironment, at least partly, through the effects on TAM, that may result in tumor inhibition.
Citation Format: Akira Saito, Hideyuki Ohzawa, Mineyuki Tojo, Yuko Kumagai, Rihito Kanamaru, Hidenori Tsukui, Satomi Shiba, Homare Ito, Naohiro Sata, Joji Kitayama. Metformin inhibits monocyte differentiation to tumor associated macrophage (TAM) and may restore anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 516.
Abstract 5167: Cell autonomous and non-autonomous actions of CCL22 in oral carcinogenesis
Authors: Wu Li-Wha 
Published: August 2019

Abstract
Oral cancer, a subtype of head and neck cancer, has been the 4th leading cause of male cancer death in Taiwan for the past decade. Smoking, alcohol consumption, and betel quid chewing are major risk factors for oral cancer in Taiwan. The crosstalk between immunity and cancer cells can both inhibit and enhance tumor growth and is now classified as a cancer hallmark. The accumulation of regulatory T cells (Tregs) in several tumor types potentially plays a critical role in tumor evasion of immune surveillance. Oral cancer is also characterized by an increase in the number of infiltrating Tregs; however, the significance of the increase on the patient prognosis remains controversial. We found that the expression of CCL22, a chemokine for Treg recruitment, was not only positively with poor prognosis in oral cancer patients but also significantly correlated with that of FOXP3, a master regulator for Treg development and functions, in the same patients. The correlation is also validated in TCGA database analysis of head and neck cancer patients. The depletion of CCL22 expression reduced oral cancer cell proliferation, migration and invasion, suggesting an oncogenic role of CCL22 in oral cancer. Since CCR4 is the receptor for CCL22, we studied the in vitro and in vivo impact of deregulated CCL22-CCR4 signaling axis in oral carcinogenesis. We first confirmed the surface expression of CCR4 in oral cancer cells by flow cytometry. Ectopic CCL22 overexpression increased oral cancer cell migration and invasion without the effect on proliferation. Through injection of CCL22-altered oral cancer cells in both syngeneic and athymic backgrounds, the cell autonomous and non-autonomous actions of CCL22 and the mechanism responsible for the CCL22 deregulation in oral cancer will be discussed. This study will not only further the role of CCL22-CCR4 signaling axis in modulating the crosstalk between oral cancer and its microenvironment but also provide a novel therapeutic strategy for treating oral cancer.
Citation Format: Li-Wha Wu. Cell autonomous and non-autonomous actions of CCL22 in oral carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5167.
Abstract 5186: Discovery of a novel histone deacetylase 6 inhibitor that kills drug-resistant breast cancer
Authors: Dowling Catríona , Dillion Eugene , Hemann Michael , Cagney Gerard , Letai Anthony , Chonghaile Triona Ni 
Published: August 2019

Abstract
Cytotoxic chemotherapy is the standard of care for patients with triple negative breast cancer (TNBC). Most patients with advanced TNBC progress after chemotherapy and die from metastatic disease. Currently, no established targeted therapeutics or biomarkers of outcome/response have been clinically approved in the context of TNBC. The aggressive nature of TNBC is reflected by an increased likelihood of distant recurrence and death within five years following primary intervention and a shorter survival once diagnosed with metastatic disease. To identify novel therapeutics for the treatment of chemoresistant TNBC, we performed a high-throughput screen to identify small molecules that are cancer selective but can kill drug-resistant TNBC cells. We screened a total of 30,000 compounds in duplicate across the TNBC cell line MDA-MB-321 in which the pro-death proteins BAX/BAK were knocked down, and the non-transformed "normal" MCF10A cell line. There was a hit rate of 0.3% in the screen and 85 compounds were retested in the validation cherry pick screen. From this screen 18 compounds were further validated with low-throughput assessment for mitochondrial independent killing and selectivity for cancer cells. To identify the mechanism of action of the lead compound we used a genetic approach to generate an RNAi signature for the compound, which indicated the lead compound was most likely that of histone deacetylase inhibitor (HDAC). Using an in vitro HDAC inhibitor screen, we identified that the compound specifically inhibited HDAC6. Using a series of cell based assays, we determined that treatment of cells with the compound BAS-2 resulted in the same phenotypical response (inhibition of migration, invasion and 3D spheroid formation) as HDAC6 knockout. To identify substrates of HDAC6 in cells we analyzed the proteome for increased acetylation by mass spectrometry following HDAC6 knockout or inhibition with the specific inhibitor, BAS-2. Remarkably, we identified a series of new substrates for HDAC6 that are common in both the HDAC6 knockdown and BAS-2 treated cells. In conclusion, we have identified a novel HDAC6 specific inhibitor that selectively kills cancer cells independent of mitochondrial apoptosis, alters acetylation of over a 50 common proteins and inhibits spheroid formation of TNBC.
Citation Format: Catríona Dowling, Eugene Dillion, Michael Hemann, Gerard Cagney, Anthony Letai, Triona Ni Chonghaile. Discovery of a novel histone deacetylase 6 inhibitor that kills drug-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5186.