bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4597: The Blood Profiling Atlas in Cancer: Accelerating progress through collaboration in liquid biopsy
Authors: Godsey Jim 
Published: August 2018

Abstract
Liquid biopsies have the potential to improve early cancer detection, reduce the need for
invasive tumor biopsies, and improve personalized oncology treatment. To help drive
development within this space, the Blood Profiling Atlas in Cancer (BloodPAC) was
created as an initiative born out of the 2016 White House Cancer Moonshot. The
BloodPAC seeks to create an open database commons for liquid biopsies with the goal of
accelerating the development and approval of safe and effective blood profiling
diagnostic technologies for patient benefit.
BloodPAC was established as an independent not-for-profit in February 2017 and has
made exciting progress in advancing the liquid biopsy landscape. Today, BloodPAC is
comprised of over 30 member groups with a diverse range of stakeholders, representing
government agencies, academia, pharmaceutical, and diagnostic companies as well as
disease specific foundations, payers groups and patient advocates. BloodPAC members
actively contribute datasets that include sequencing data from circulating tumor cells,
circulating tumor DNA (ctDNA), and exosome assays, alongside relevant clinical data
into the BloodPAC Data Commons. The BloodPAC Data Commons helps facilitate the
aggregation and harmonization of submitted datasets, allowing researchers to generate
study cohorts size to make statistically significant inference in a scalable, reproducible,
and secure way. Establishing a comprehensive knowledge base through the BloodPAC
Data Commons provides an invaluable reference for anyone entering into the liquid
biopsy field, helps develop the evidence required to support clinical utility, assay
reproducibility, and provides support for FDA approval and payer reimbursement.
This presentation will discuss current progress made within the BloodPAC as an
innovative consortium along with the development of the BloodPAC Data Commons,
lessons learned, and upcoming next steps. The discussion will focus on examining the
BloodPAC consortium's strategy over the past year, the group's work in developing pre-
analytical standards, an overview of the contributed data, as well as the collaborative
process that has been established with the FDA and CAP to maximize the organization's
impact and effectiveness.
Citation Format: Jim Godsey. The Blood Profiling Atlas in Cancer: Accelerating progress through collaboration in liquid biopsy [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 4597.
Abstract 4624: The sTRA glycan is complementary to CA19-9 as a serologic biomarker of pancreatic cancer
Authors: Liu Ying , Barnett Daniel , Staal Ben , Huang Ying , Partyka Katie , Zeh Herbert , Singhi Aatur , Drake Richard R. , Brand Randall E. , Haab Brian B. 
Published: August 2018

Abstract
The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic cancer, but not enough to be reliable for detection, diagnosis, or monitoring of the disease. We hypothesized that a glycan called sTRA complements CA19-9, and that the two biomarkers in combination provide added information over either biomarker individually. As an individual marker, the sTRA assay performed equivalently with CA19-9 for distinguishing cancers from benign pancreatic diseases, but in combination, CA19-9 and sTRA showed exclusive elevations in significantly different groups of patients. Using high-specificity cutoffs giving one false-positive detection in each marker, sTRA was elevated in 34/46 (74%) patients with low CA19-9 in stage III/IV cancers and 28/70 (40%) with low CA19-9 in stage I/II cancers. A three-marker panel consisting of CA19-9 and two versions of the sTRA assay gave 81% sensitivity and 88% specificity (84% accuracy) in a training set of 72 stage I-IV cancers and 75 benign disease controls, compared to 57% sensitivity and 92% specificity (75% accuracy) for CA19-9 alone. The application of the fixed three-marker classifier to a test set of 25 cancers and 25 benign controls gave 80% sensitivity and 84% specificity, compared to 56% sensitivity and 96% specificity for CA19-9 alone. In an analysis of patient-matched tumor tissue and plasma samples, we found that the tumors secreting both sTRA and CA19-9 into the blood tended to be conventional PDAC with well-to-moderate differentiation and heavy marker staining in the ductal lumens, but the tumors secreting only sTRA showed sTRA staining in glands with extremely large and unpolarized nuclei and vacuolated or foamy cytoplasm. Those without plasma elevations in either marker did not have glandular features of typical adenocarcinoma. Surprisingly, about half of the patients without plasma elevations of CA19-9 nevertheless showed strong tumor staining. Such tumors expressed CA19-9 mostly in poorly differentiated patches of cells with compact nuclei and cytoplasm. Thus, sTRA and CA19-9 are complementary serologic biomarkers that together could increase the diagnostic accuracy for PDAC and potentially identify distinct subgroups of tumors.
Citation Format: Ying Liu, Daniel Barnett, Ben Staal, Ying Huang, Katie Partyka, Herbert Zeh, Aatur Singhi, Richard R. Drake, Randall E. Brand, Brian B. Haab. The sTRA glycan is complementary to CA19-9 as a serologic biomarker 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 4624.
Abstract 465: Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis
Authors: Im Keon-Il , Nam Young-Sun , Kim Nayoun , Song YuneJin , Jeon Young-Woo , Lim Jung-Yeon , Cho Seok-Goo 
Published: August 2018

Abstract
Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here, we show that high-mobility group box 1 (HMGB1), a “danger signal” that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal-layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF-α, IL-1β and MIP-1β, as well as the expression of p53-upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM.
Citation Format: Keon-Il Im, Young-Sun Nam, Nayoun Kim, YuneJin Song, Young-Woo Jeon, Jung-Yeon Lim, Seok-Goo Cho. Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis [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 465.
Abstract 4652: Targeted nanomedicines improve therapeutic indices of RAF and MEK inhibitors
Authors: Heller Daniel A. , Shamay Yosi 
Published: August 2018

Abstract
Potent kinase inhibitors have been developed to treat tumors, but they suppress signaling in normal cells so that their dosing and ability to inhibit the pathway are limited by toxicity, resulting in a narrow therapeutic index. We developed a novel drug delivery strategy which efficiently encapsulates and targets kinase inhibitors to the tumor microenvironment while obviating the sources of dose-limiting toxicities. The platform employs nanoparticle scaffolds that we modified to target caveolae and P-selectin, that can both be overexpressed on tumor vasculature. We assessed the targeted drug delivery properties of the nanoparticles, encapsulating the RAF inhibitor sorafenib and MEK inhibitor trametinib. Strikingly, we found selective tumor uptake and exceptional net anti-tumor efficacies in patient-derived xenografts and genetically modified mouse models. The nanomedicine strategy also prevented the inhibition of ERK phosphorylation in the skin, demonstrating that this targeting strategy may abrogate dose-limiting toxicities of kinase inhibitors to improve their therapeutic indices.
Citation Format: Daniel A. Heller, Yosi Shamay. Targeted nanomedicines improve therapeutic indices of RAF and MEK inhibitors [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 4652.
Abstract 4654: A cell-based translocation assay system identifies active fractions from plant that inhibit growth of FGFR3 overactivation cancers
Authors: Lee Yi-Ching , Lin Yun-Wen 
Published: August 2018

Abstract
Fibroblast growth factor receptor 3 (FGFR3) is one of four tyrosine kinase receptors that bind and respond to fibroblast growth factors (FGFs). Gain-of-function mutations in FGFR3 cause a group of skeletal dysplasias. The overactivation of FGFR3 in somatic cells is reported to be associated with human cancers, including multiple myeloma (MM), urothelial bladder carcinoma, cervical carcinoma, as well as benign seborrheic keratosis. Patients with FGFR3 overactivation have demonstrated an overall poor prognosis, and the treatment remains a substantial challenge. Several tyrosine kinase inhibitors (TKIs) have been proposed for treatment of FGFR3-activating cancers and some of them are currently in clinical trials. However, the side effects and a modest efficacy of the compounds towards FGFR3 promote the need to identify high-selectivity and high-potency specific FGFR3 inhibitors. We established a cell-based protein translocation assay system that can monitor FGFR3 activity and be used for high-throughput screening of complex mixtures. With this system we identified plant ethanol extract as a FGFR3 inhibitor and performed bioassay-guided fractionation to identify potent active fractions. The functionality of extract and active fractions was validated in vitro in FGFR3-activated primary multiple myeloma cells. The active fractions can preferentially inhibit the proliferation of MM with FGFR3 activation compared with MM without FGFR3 activation and inhibit the FGFR3 downstream signaling pathways. Furthermore, we demonstrated that the active fractions enhance FGFR3 degradation but not FGFR1, 2, 4 in a Western blot analysis. Our results demonstrate the applicability of this discovery approach. The identified plant extracts and active factions hold therapeutic potential for the treatment of FGFR3-activated skeletal dysplasias and cancers.
Citation Format: Yi-Ching Lee, Yun-Wen Lin. A cell-based translocation assay system identifies active fractions from plant that inhibit growth of FGFR3 overactivation 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 4654.
Abstract 4656: Development of an RNA-based cancer therapeutic targeting the let-7-LIN28 interaction
Authors: Myoung Sunghyun , Savinov Sergey , Chen Lan , Chopra Gaurav , Avramova Larisa , Welch James , Loren Bradley , Thompson David , Kasinski Andrea L. 
Published: August 2018

Abstract
Based on the knowledge that microRNAs (miRNAs) are dysregulated in diseases such as cancer, various attempts have been explored to develop miRNA-based cancer therapeutics. Although many strategies have been used to restore the levels of therapeutically relevant microRNAs, clinical delivery of the processed or mature miRNA to cancer cells still remains a challenge. To overcome this challenge, innovative methods are being explored to increase the pools of tumor-suppressive miRNAs, such as enhancing miRNA biogenesis. This is especially true for the let-7 family of tumor-suppressive miRNAs, which has an additional layer of regulation over the canonical miRNA biogenesis pathway. In particular, the DROSHA and DICER cleavage steps are blocked when unprocessed let-7 is bound by the RNA-binding protein LIN28. LIN28 interacts specifically with unprocessed let-7 via a sequence-specific motif, GGAG, contained in most let-7 family members. Because previous attempts to restore mature let-7 levels through increasing let-7 pools have been quite successful at reducing tumor burden, identifying novel and clinically relevant ways to increase the level of this tumor-suppressive miRNA represents a critical need. In this study, we hypothesize that small-molecule inhibitors that disrupt the LIN28-let-7 interaction will lead to enhanced processing and increased levels of mature, tumor-suppressive let-7. Thus, an in vitro high-throughput fluorescence polarization screen has been conducted using His-tagged LIN28 and a Cy5 fluorophore-tagged let-7 RNA probe. The nine-nucleotide RNA probe was designed through in silico modeling to include the GGAG motif, which associates with LIN28 through the zinc knuckle domain of LIN28. Due to the size difference between unbound let-7 probe and LIN28-bound let-7 probe, a wide window of polarization values was achieved, resulting in a Z′ score of 0.61, indicating that the assay was robust to proceed with the screen. The screen was performed against 23,680 compounds, which consist of FDA-approved LOPAC and blood-brain barrier-permeable CNS library compounds. Eight compounds were identified as positive hits from the screen. These compounds are currently being characterized in secondary assays both in vitro and in cell culture. The significance of this research is that small-molecule inhibitors may provide novel therapeutic strategies to increase the pool of mature, tumor-suppressive let-7 in tumors with elevated LIN28.
Citation Format: Sunghyun Myoung, Sergey Savinov, Lan Chen, Gaurav Chopra, Larisa Avramova, James Welch, Bradley Loren, David Thompson, Andrea L. Kasinski. Development of an RNA-based cancer therapeutic targeting the let-7-LIN28 interaction [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 4656.
Abstract 4666: An evaluation of breast cancer cellular membrane lipid-extracted nanoliposomes (CLENs) in relation to formulation design, stability, mechanism of cellular entry and cardioprotective function in vitro
Authors: Alharbi Hanan M. , Campbell Robert B. 
Published: August 2018

Abstract
One of the longstanding issues limiting the use of chemotherapeutic agents is the lack of tumor specificity, which leads to systemic toxicity. Therefore, various targeted nanocarriers have been developed to concentrate the cytotoxic drug agents at tumor regions to avoid uptake by normal healthy tissues. Previous studies from our laboratory have demonstrated that cell membrane lipid-extracted nanoliposomes (CLENs) are capable of selective targeting compared to nanoliposomes consisting of mainly conventional lipid materials. Also, CLENs were relatively nontoxic when employed at concentrations traditionally used to evaluate nanoparticles in vitro. However, parameters such as lipid composition, size, and surface charge all have a direct impact on liposomal cellular uptake. In this study, we prepared different CLENs different molar ratios of natural and cellular-derived lipids extracted directly from breast cancer cells (4T1), cholesterol, and DPPE-PEG-5000. The formulations were used to investigate the mechanisms of CLENs uptake and determine the underlying mechanisms regulating cellular entry. In the study, CLENs were used to evaluate cytotoxicity and cellular uptake for both target and off-target cell populations. CLENs containing cholesterol and DPPE-PEG-5000 (70/25/5) were able to retain doxorubicin in relevant therapeutic concentrations. CLEN formulations were able to exert selective cytotoxic drug effects against different target breast cancer cells in vitro. 4T1 CLENs containing cholesterol and DPPE-PEG-5000 (70/25/5) demonstrated greater binding to 4T1 (target) cells compared to CLENs prepared using 4T1 lipid extracts alone. The binding was not only temperature- and time-dependent, but also composition- and cell type-dependent. Off-target effect studies showed that 4T1 CLENs were taken up minimally by off-target cells (including normal breast fibroblasts and normal myocytes), compared to controls. Our studies collectively support the use of lipid extracts derived from target cells for selective drug targeting and enhanced cytotoxicity. Future studies will explore underlying mechanisms of cellular entry and cardioprotective function.
Citation Format: Hanan M. Alharbi, Robert B. Campbell. An evaluation of breast cancer cellular membrane lipid-extracted nanoliposomes (CLENs) in relation to formulation design, stability, mechanism of cellular entry and cardioprotective function in vitro [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 4666.
Abstract 4669: Role of CD8+ tissue-resident memory T (TRM) cells in anti-tumor T-cell response and cancer immunotherapy
Authors: Mami-Chouaib Fathia 
Published: August 2018

Abstract
Tissue-resident memory T (TRM) cells, very often defined by the expression of CD103 integrin, correspond to a new subset of long-lived memory T lymphocytes that reside in tissues and are highly protective during localized reinfections. CD8+ TRM cells also frequently reside in human epithelial tumors and play an essential role in anti-tumor T-cell responses. In this context, our previous results indicated that the interaction of CD103 integrin with its ligand, the epithelial cell marker E-cadherin, favors adhesion of TRM cells to their specific epithelial cancer cells and participate to the potentiation of T-cell receptor (TCR)-mediated cytotoxic activity and cytokine production. We also demonstrated that an enhanced CD103+ tumor-infiltrating lymphocytes (TIL) subset correlates with improved early-stage non-small cell lung carcinoma (NSCLC) patient survival and increased intraepithelial T-lymphocyte infiltration. Notably, TRM cells are enriched with tumor-specific T cells and express high levels of inhibitory receptors, including PD-1 and Tim-3, making them an attractive target for cancer immunotherapy, such as checkpoint blockade. Moreover, we provided evidence that CD103 is involved in T-cell recruitment within epithelial tumor islets and in local early T-cell signaling. Our more recent results indicated that integrin-linked kinase (ILK) and paxillin adaptor protein are directly involved in CD103 bidirectional signaling events and defined the CD103 cytoplasmic domain that controls TRM adhesion, migratory behavior and TCR-mediated T-cell functions. Data emphasizing the contribution of CD8+/CD103+ TRM cells in promoting intra-tumoral cytotoxic T lymphocyte (CTL) responses and in success of cancer immunotherapy will be discussed.
Citation Format: Fathia Mami-Chouaib. Role of CD8+ tissue-resident memory T (TRM) cells in anti-tumor T-cell response and 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 4669.
Abstract 4683: Distinct subsets of dysfunctional CD8+ T cells underlie response to checkpoint blockade
Authors: Miller Brian C. , Sen Debattama R. , Al-Abosy Rose , Bi Kevin , Yates Kathleen B. , Gjini Evisa , Felt Kristen , Manguso Robert T. , Rodig Scott J. , Sharpe Arlene H. , Haining Nicholas 
Published: August 2018

Abstract
T-cell exhaustion is a heterogeneous state, with recent work in chronic viral infections revealing at least two subtypes with different functional properties: "stem-like" and "terminal" exhausted cells. Whether these two populations exist in tumors and have different roles to control tumor growth remains unknown. We performed single-cell RNA-seq on exhausted CD8+ T cells from chronic virally infected mice, generating unique transcriptional signatures of both exhausted populations. By transcriptional enrichment and flow cytometry, we discovered both the stem-like and terminal exhausted populations in the B16 mouse melanoma model and confirmed their presence in human melanoma samples with multiplex immunofluorescence. ATAC-seq revealed that these two subpopulations are defined by state-specific changes in chromatin accessibility. These states are shared between exhausted CD8+ T cells from both viral and tumor models, demonstrating a common epigenetic program of T-cell dysfunction. The two populations have different functional properties, with the stem-like cells having a more polyfunctional cytokine response whereas terminal cells are more cytotoxic. When transferred into new tumor-bearing mice, stem-like cells were better able to control tumor growth, suggesting superior long-term functionality. Checkpoint blockade with anti-PD-1 is known to increase CD8+ T cell numbers in the tumor microenvironment, but it is not known which subpopulation responds to therapy. Treatment with anti-PD-1 antibody resulted in proliferation of the stem-like population, which differentiate into the more cytotoxic terminal exhausted cells. We have shown that two subpopulations of exhausted CD8+ T cells exist in mouse and human tumors, and anti-PD-1 therapy activates the stem-like CD8+ T cells to promote tumor control.
Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al-Abosy, Kevin Bi, Kathleen B. Yates, Evisa Gjini, Kristen Felt, Robert T. Manguso, Scott J. Rodig, Arlene H. Sharpe, Nicholas Haining. Distinct subsets of dysfunctional CD8+ T cells underlie response to checkpoint blockade [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 4683.