bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5675: A novel PI3K inhibitor suppresses tumor progression by immune modulation
Authors: Xu Zusheng , Lou Yangtong , Qu Yingying , Wang Wei , Wu Xiaodong , Ge Xiaomei , Gu Ying , Zhang Yingjia , Zhou He 
Published: July 2017

Abstract
Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors have shown anti-tumor efficacy in leukemia in the clinic and one such compound, idelalisib, was approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia (CLL) in 2014. A novel PI3Kδ inhibitor, YY-20394, was developed with specific selectivity against PI3Kδ and inhibited PI3Kδ expressing human tumor cells growth both in vitro and in vivo. In addition, our previous data have shown YY-20394 significantly inhibited primary tumor growth in immune-competent mice with 4T1 and CT26 tumors, as well as 4T1 lung metastasis with dose dependency. The anti-tumor efficacy of YY-20394 was largely mediated by T cells. More importantly, YY-20394 synergistically enhanced the anti-tumor efficacy of anti-PD-L1 antibody in CT26 model and achieved long-term immune memory which is specific for CT26 tumors, but not for unrelated A20 tumors. In vitro mechanistic studies showed YY-20394 significantly inhibited T cell differentiation into Treg both in mouse splenocyte and in human primary CD4+ T cells, and was especially potent inhibiting their IL-10 secretion in vitro. Analyses of tumors treated with YY-20394 reviewed that YY-20394 decreased the percentage of Treg in the tumor infiltrating leukocytes, as well as IL-10 secretion. It also showed some effects on the myeloid populations in the tumors. These data suggest the YY-20394, a novel PI3Kδ inhibitor, represents a promising and safe immune modulator and shows great potential as a cancer immuno-therapeutics.
Citation Format: Zusheng Xu, Yangtong Lou, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou. A novel PI3K inhibitor suppresses tumor progression by immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5675. doi:10.1158/1538-7445.AM2017-5675
Abstract 5689: Identify tissue-of-origin in cancer cfDNA by whole genome sequencing
Authors: Liu Yaping , Reed Sarah , Choudhury Atish D. , Parsons Heather A. , Stover Daniel G. , Ha Gavin , Gydush Gregory , Rhoades Justin , Rotem Denisse , Freeman Samuel , Adalsteinsson Viktor , Kellis Manolis 
Published: July 2017

Abstract
Cell free DNA (cfDNA) has been shown to be an emerging non-invasive biomarker to monitor tumor progression in cancer patients. Elevated cfDNA has been found not only from tumors, but also from normal tissues. Thus, the identification of cfDNA’s tissue-of-origin is critical to understand the mechanism of cfDNA release and tumor progression. Recent efforts to identify cfDNA’s tissue-of-origin begin to utilize cfDNA’s epigenomic status, such as DNA methylation and nucleosome spacing. However, both of these methods have limitations: (1) For nucleosome positioning, lack of reference nucleosome maps in different tumor and normal tissues has limited its application to tissue-of-origin deconvolution; (2) For DNA methylation, large DNA degradation during whole genome bisulfite sequencing (WGBS) library preparation, even with current low-input DNA technology, is still the major hurdle for its clinical application, although extensive DNA methylation studies by WGBS in tumor and normal tissues during the last decade have provided many reference maps. Very recently, a pioneer study showed significant differences between DNA fragment lengths of methylated and unmethylated cfDNA. Taking advantage of this experimental observation, we developed a machine learning approach to infer the base pair resolution DNA methylation level from fragment size information in whole genome sequencing (WGS). The predicted DNA methylation, from not only high coverage but also dozens of ultra-low-pass WGS (ULP-WGS), showed high concordance with the ground truth DNA methylation level from WGBS in the same cancer patients. Furthermore, by using hundreds of WGBS datasets from different tumor and normal tissues/cells as the reference map, we deconvoluted cfDNA’s tissue-of-origin status by inferred DNA methylation level at ULP-WGS from thousands of breast/prostate cancer samples and healthy individuals. The cfDNA’s tissue-of-origin status in cancer patients showed high concordance with confirmed metastasis tissues from physicians. Interestingly, some clinical information, such as cancer grades/stages, seemed to be correlated with cfDNA’s tissue-of-origin status. Overall, our methods here pave the road for cfDNA’s application in clinical diagnosis and monitoring.
Citation Format: Yaping Liu, Sarah Reed, Atish D. Choudhury, Heather A. Parsons, Daniel G. Stover, Gavin Ha, Gregory Gydush, Justin Rhoades, Denisse Rotem, Samuel Freeman, Viktor Adalsteinsson, Manolis Kellis. Identify tissue-of-origin in cancer cfDNA by whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5689. doi:10.1158/1538-7445.AM2017-5689
Abstract 5692: Cross-platform detection and quantification of actionable mutations in cell-free DNA shows high concordance and correlation between next-generation sequencing and droplet digital PCR
Authors: Ulrich Bryan C. , Nagy Rebecca J. , Odegaard Justin I. , Lanman Richard B. , Oxnard Geoffrey R. , Paweletz Cloud P. 
Published: July 2017

Abstract
Background: Non-invasive genotyping of cell-free DNA (cfDNA) provides physicians with the ability to identify genomic alterations, evaluate response to treatment, and uncover potential mechanisms of resistance. Here, we analyze the concordance of next-generation sequencing (NGS) and droplet digital PCR (ddPCR) in detecting and quantifying actionable mutations from cfDNA of lung, colorectal, and breast cancer patients.
Methods: We studied a cohort of 221 advanced cancer cfDNA samples with completed Guardant360 digital sequencing results. Variant allele frequencies (% AFs) ranged from less than 0.2% to greater than 90% for common driver and resistance mutations. Blinded to plasma NGS results, we performed ddPCR using our validated assays for EGFR L858R, exon19 del, T790M (113 presumed lung cases); BRAF V600E, KRAS G12X (77 colorectal cases); ESR1 D538G, Y537C and PIK3CA H1047R (31 breast cases). Following unblinding, qualitative and quantitative accuracy were compared.
Results: Qualitative results (Table 1) show a high concordance between NGS and ddPCR, with 98.3% (576/586) of all assays run being concordant. 9/22 of samples that had an AF below 0.4% were discordant, while only one sample above 0.4% AF was discordant. AFs calculated by NGS and ddPCR were strongly correlated by linear regression (R between 0.951 and 0.999). Notably, the slope of the ddPCR AF versus NGS AF graph for EGFR ex19del was 0.725, which improved to 0.95 with the adoption of an alternate calling method.
Conclusions: This interlaboratory comparison of actionable mutations in cfDNA from lung, colorectal, and breast cancers by orthogonal genotyping platforms demonstrates a substantial concordance in detection and quantification between NGS and ddPCR. Our cross-platform study establishes the feasibility of standardization of qualitative and quantitative measurements of cfDNA-detected alterations.
Table 1LungEGFR L858REGFR Ex19 delEGFR T790M(n=113)G360+G360-G360+G360-G360+G360-ddPCR+580510530ddPCR-055458456BreastESR1 Y537CESR1 D538GPIK3CA H1047R(n=31)G360+G360-G360+G360-G360+G360-ddPCR+1022020ddPCR-03009029ColorectalBRAF V600EKRAS G12X(n=78)G360+G360-G360+G360-ddPCR+220571ddPCR-055118
Citation Format: Bryan C. Ulrich, Rebecca J. Nagy, Justin I. Odegaard, Richard B. Lanman, Geoffrey R. Oxnard, Cloud P. Paweletz. Cross-platform detection and quantification of actionable mutations in cell-free DNA shows high concordance and correlation between next-generation sequencing and droplet digital PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5692. doi:10.1158/1538-7445.AM2017-5692
Abstract 570: Transparent tumor tomography (T3): 3D spatial immunoanalysis for PD-L1 immune checkpoint blockade therapy
Authors: Lee Steve Seung-Young , Bindokas Vytautas P. , Kron Stephen J. 
Published: July 2017

Abstract
Untangling the complexity of programmed death-ligand 1 (PD-L1) expression within a heterogeneous tumor microenvironment is an urgent challenge in PD-1/PD-L1 immune checkpoint blockade therapy. Here, we address this challenge with a method, termed transparent tumor tomography (T3), facilitating three-dimensional (3D) visualization and spatial analysis of distributions of multiple biomarkers regarding to cancer cells, vasculature, and immune cells in context in the tumor microenvironment. With T3 analysis of transgenic mouse mammary tumors immunostained against Her2, CD45, Ki-67, CD31, and PD-L1, we reveal that PD-L1 expression within the tumor microenvironment is highly adaptable for efficiently preventing immune cell infiltration into the tumor. Stronger correlation of Her2 and PD-L1 expression in the tumor periphery where has a high CD45+ immune infiltrate density is determined by tumor-wide analysis. Also, tomographic analysis shows blood vessels expressing PD-L1 in the tumor core, where PD-L1 expression is lower. Furthermore, high-resolution T3 image localizes PD-L1 expression to a region between the endothelium and the surrounding smooth muscle cells in blood vessels. We investigate spatial pharmacokinetics of anti-PD-L1 antibody in the whole mouse mammary tumor in the context of hypoxia, CD31+ blood vessels, and target PD-L1+ cells. The 3D anti-PD-L1 antibody distribution is fit to a two-compartment pharmacokinetic model, yielding estimated distribution half-life of 4.7 min and terminal half-life of 2.5 days. We also evaluate anti-tumor immune responses after PD-L1 blockade therapy using T3. We observe broad distribution of tumor infiltrating CD3+CD8+ cytotoxic T cells in 3D tumor section following combination therapy of radiation and anti-PD-L1 antibody compared to PBS, anti-PD-L1 antibody alone, or radiation alone treatment group. Moreover, we apply T3 for immunoanalysis of whole core needle biopsy. We spatially map PD-L1 expression and granzymeB-producing CD3+CD8+ cytotoxic T cells in pre-treatment and in-treatment core needle biopsies at cellular resolution and in three dimensions. Meanwhile, T3 analysis is nondestructive, allowing secondary analysis by IHC and/or IF. We anticipate that T3 can be applied broadly to facilitate preclinical studies of immunotherapy and also find use in spatial, multiparameter analysis of patient biopsies, particularly to improve predictive testing and analysis of immune responses to tumor immunotherapy.
Citation Format: Steve Seung-Young Lee, Vytautas P. Bindokas, Stephen J. Kron. Transparent tumor tomography (T3): 3D spatial immunoanalysis for PD-L1 immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 570. doi:10.1158/1538-7445.AM2017-570
Abstract 5701: Innovative approach for isolation of circulating cell-free DNA from liquid biopsies
Authors: Malykh Andrei , Evtushenko Vladimir 
Published: July 2017

Abstract
We developed a new approach for isolation of circulating cell-free DNA (cfDNA) from liquid biopsies (plasma or serum). Our technology is based on using the proprietary bi-functional substance X (SubX®) that binds DNA under physiological conditions (e.g. directly in biological liquids), followed by adsorption of [DNA- SubX®] complex on a solid phase matrix. Since SubX®) captures DNA via phosphate groups it allows for elimination of bias related to both AT/CG content and DNA fragments length, thus improving extraction efficacy and accuracy of downstream applications. All currently available commercial kits are [silica-chaotropic salt]-based and exhibit bias for either short or long DNA fragments, as well as for the GC content. In addition, such systems require at least 4- fold dilution of starting volume of bio liquid with concentrated (~5.0 M) guanidine thiocyanate (GTC) to keep resulted GTC concentration at about least 3.0 M. Thus, already low concentrations of cfDNA are significantly reduced and may negatively influence extraction efficacy of low abundance DNA fragments. Since our method does not require chaotropic salt for DNA capture, no dilution of starting material (and thus cfDNA) takes place. DNA-binding matrix SubX® allows either scaling the procedure to either large volumes of starting material or extra low volumes and adaptation of the protocol for 96/384 well format. Separation of cfDNA from the bulk of proteins occurs in a single vortex-spin step without employing chaotropic agents thus speeding-up isolation procedure and reducing the costs. The whole procedure can be completed within an hour and cfDNA is eluted in small volume of TE buffer. Average DNA yield from 0.2 ml of double centrifuged blood plasma from normal donors, cancer and multiple sclerosis patients was 7.5±4.2 ng (n=96).
Citation Format: Andrei Malykh, Vladimir Evtushenko. Innovative approach for isolation of circulating cell-free DNA from liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5701. doi:10.1158/1538-7445.AM2017-5701
Abstract 5710: PGRMC1 is a biomarker for breast cancer cell proliferation and early relapse
Authors: McDonald Elizabeth S. , Pant Dhruv K. , Pan Tien-chi , Mankoff David A. , Mach Robert H. , Chodosh Lewis A. 
Published: July 2017

Abstract
Background: Breast cancers may recur following a long latency period, implying a dormant or quiescent phase, however little is known about the biology of cellular quiescence and few markers exist for this clinically important state. The purpose of this study was to investigate whether progesterone receptor membrane component family 1 (PGRMC1), which is expressed in both proliferating and quiescent tumor cells, is a prognostic biomarker in human breast cancer and to define its expression in breast cancer subtypes.
Methods: Seventeen publicly available data sets were combined to analyze PGRMC1 expression in 4,463 invasive breast cancers as a function of established molecular and phenotypic markers, estimates of cellular proliferation, and recurrence-free survival data. A gene expression signature-based assay was utilized to estimate cellular proliferation. Association between gene expression and relapse-free survival was assessed using Cox proportional hazards regression while controlling for the effect of proliferation.
Results: PGRMC1 expression was analyzed stratified by immunohistochemical and molecular subtype, tumor grade and size and compared with a known triple negative breast cancer biomarker, BCL11a. PGRMC1 and BCL11a each exhibited a robust positive correlation of comparable magnitude with proliferation across all breast cancer subtypes (r=0.27, p=6.5x10-17 and r=0.29, 1.7x10-41, respectively), and PGRMC1 was strongly associated with proliferation within the basal subtype (r=0.42, p=2.4x10-37 PGRMC1 versus 0.31, p=1.1x10-8 BCL11a). PGRMC1 expression was associated with a higher risk of early breast cancer recurrence (HR=1.25, 95% CI [1.12,1.39], p=6.4x10-5) and this association was dependent upon its association with proliferation.
Conclusions: PGRMC1 is a breast cancer proliferation biomarker. Further study of the function of this protein is warranted.
Citation Format: Elizabeth S. McDonald, Dhruv K. Pant, Tien-chi Pan, David A. Mankoff, Robert H. Mach, Lewis A. Chodosh. PGRMC1 is a biomarker for breast cancer cell proliferation and early relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5710. doi:10.1158/1538-7445.AM2017-5710
Abstract 5713: PIGN gene expression aberration weakens chromosomal stability via altering its interaction with the spindle assembly checkpoint protein complex during leukemogenesis
Authors: Pu Jeffrey J. , Teye Emmanuel K. , Sido Abigail , Kawasawa Yuka I. , Xin Ping , Finnberg Niklas K. , El-Deiry Wafik S. , Shimko Sara 
Published: July 2017

Abstract
Previous studies have linked increased frequency of glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency with genomic instability and the risk of carcinogenesis. Recently, Phosphatidylinositol Glycan Anchor Biosynthesis; Class N (PIGN), a gene participating in GPI-AP synthesis, was suggested as a cancer chromosomal instability suppressor in a colon cancer model. We investigated the association of PIGN with genomic instability and leukemogenesis. A Random Forest analysis of the gene expression array data from 55 MDS patients (GSE4619) demonstrated a significant (p = 0.0007) correlation (Pearson r =-0.4068) between GPI-anchor biosynthesis gene expression and genomic instability, in which PIGN was ranked as the third most important in predicting risk of MDS progression. We observed that PIGN gene expression aberrations (increased transcriptional activity but diminished to no protein production) were associated with increased frequency of GPI-AP deficiency in leukemic cells during leukemic transformation/progression. The PIGN gene expression aberrations were attributed to partial intron retentions between exons 14 and 15 resulting in frameshifts and premature termination which were confirmed by examining the RNA-seq data from a group of AML patients (phs001027.v1.p1). PIGN gene expression aberration correlated with the elevation of genomic instability marker expression that was independent of the TP53 regulatory pathway. PIGN protein expression suppression/elimination caused a similar pattern of genomic instability that was rescued by PIGN restoration. Furthermore, PIGN bound to the spindle assembly checkpoint proteins and regulated their expression during the cell cycle. In conclusion, PIGN gene is crucial in the regulation of mitotic integrity to maintain chromosomal stability and prevents leukemic transformation/progression.
Citation Format: Jeffrey J. Pu, Emmanuel K. Teye, Abigail Sido, Yuka I. Kawasawa, Ping Xin, Niklas K. Finnberg, Wafik S. El-Deiry, Sara Shimko. PIGN gene expression aberration weakens chromosomal stability via altering its interaction with the spindle assembly checkpoint protein complex during leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5713. doi:10.1158/1538-7445.AM2017-5713
Abstract 5729: Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma
Authors: Song Joon Seon , Cho Hanbyoul , Chung Joon-Yong , Hwang Ilseon , Lee Hee Jin , Hong Seung-Mo , Hewitt Stephen M. 
Published: July 2017

Abstract
Ubiquitin Specific Peptidase 10 (USP10) is a member of the ubiquitin-specific protease family and its related pathways are apoptosis, autophagy and DNA damage. P14ARF is encoded by an alternative reading frame within the INK4a/ARF locus at chromosome 9p21, which is related with cell cycle arrest and apoptosis. Recently, ablation of USP10 prevented c-myc induced cellular senescence by destabilization of p14ARF and p53, and accelerated hyper-proliferation and transformation of normal cells, suggesting USP10 have a crucial role in oncogenes induced senescence by keeping the stability of p14ARF and p53, key regulator of cellular senescence. However, knowledge on the clinical and prognostic significance of USP10 and p14ARF expression in patients with small intestine adenocarcinoma is limited. In the present study, we investigated the prognostic significance of USP10 and p14ARF by immunohistochemistry. 195 of resected small intestine adenocarcinomas were retrieved from 22 South Korean institutions by Korean Small Intestinal Cancer Study Group. Tissue microarrays were constructed using formalin-fixed paraffin-embedded specimen. 70 (35.9 %) out of 195 patients showed immunoreactivity for USP10 and 124 (63.6 %) showed loss of immunoreactivity for USP10. 120 (61.5 %) of 195 patients were immunopositive for p14ARF and 75 (38.5 %) patients showed loss of immunoreactivity for p14ARF. Loss of USP 10 was correlated with male predominancy (p=0.014), higher pT stage (p=0.044), presence of lymphatic invasion (p=0.033), absences of sporadic adenoma (p=0.024) and absences of peritumoral dyplasia (p=0.019). On multivariate survival analysis, loss of USP10 expression was independent poor prognostic factor ( HR=3.04, 95% CI= 1.79-5.18, p &lt; 0.001) and also both loss of USP10 and p14ARF expressions showed similar result ( HR=3.76, 95% CI= 1.93-7.23, p &lt; 0.001) while loss of p14ARF was not an independent prognostic factor ( p= 0.587). Our findings indicate that loss of USP10, associated with loss of p14ARF protein expression, could be poor prognostic factors in small intestine adenocarcinoma.
Citation Format: Joon Seon Song, Hanbyoul Cho, Joon-Yong Chung, Ilseon Hwang, Hee Jin Lee, Seung-Mo Hong, Stephen M. Hewitt. Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5729. doi:10.1158/1538-7445.AM2017-5729