tbuckley/cabot-search huggingface dataset:
Abstract 4466: The key role of Abi1 loss in dysregulating cell-cell adhesion during prostate cancer tumorigenesis
Authors: Disharee Das, Anita Hryniewicz-Jankowska, Heidi Hehnly, Dawn Post, Gennady Bratslavsky, Leszek Kotula
Journal: Cancer Research (2017)

Abstract Prostate cancer accounts for 20-25% of cancer cases every year and is predicted at over 180,000 new cases in 2016. However, the mechanisms of prostate cancer initiation and castration resistance still remains poorly understood. Our previous research shows mutations and deletions in Abelson interactor 1 (Abi1), an integral part of WAVE complex, in prostate tumor samples. Moreover, WAVE complex levels are inversely correlated to prostate cancer recurrence and castration resistance, outlining their clinical significance. A common phenomenon found early on in most cancers, including prostate cancer, is dysregulated cell-cell adhesion. This points towards a possible tumor suppressor mechanism, since Abi1 and the WAVE complex are in fact the primary regulators of branched actin polymerization via the Arp2/3 complex, and are critical for the formation and maintenance of cell-cell adhesion complexes. Hence, to study Abi1 in prostate cancer, we generated a prostate-specific conditional Abi1 knock-out (KO) mouse. In these mice, we observed evidence of prostatic intraepithelial neoplasia (PIN), a precursor of invasive carcinoma, with changes in proliferation and cell-cell adhesion markers. The goal of this study is to elucidate the mechanism by which the loss of Abi1 leads to the development of PIN in these mice. We are leading this analysis by primary 3D cultures with cells from our Abi1 KO prostates, and 2D cultures with mouse embryonic fibroblasts (MEFs). Loss of Abi1 leads to increase in size of the cultured spheroids, which indicates increased proliferation and dysregulated cell-cell adhesion. Also, adherens junction (AJ) markers E-cadherin and β-catenin levels are lower in western blots and immunostaining, suggesting defects in cell-cell adhesion. In MEFs, we observe loss of membrane localization of AJ proteins in Abi1 KO cells. Loss of Abi1 is often associated with upregulation of Abi2, which may be a contributing factor to the phenotype. To validate our findings in a human system, we have recently developed a CRISPR-mediated KO of Abi1 in the RWPE-1 non-tumor prostate cell line. We will use this KO cell line to determine cell-cell adhesion formation and maintenance in 2D and 3D cultures. In conclusion, loss of Abi1 leads to dysregulation of cell-cell adhesion in prostate epithelial cells, which may be a key mechanism for tumor development and progression in prostate cancer. Supported by NCI R01 CA161018 (LK). Citation Format: Disharee Das, Anita Hryniewicz-Jankowska, Heidi Hehnly, Dawn Post, Gennady Bratslavsky, Leszek Kotula. The key role of Abi1 loss in dysregulating cell-cell adhesion during prostate cancer tumorigenesis [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 4466. doi:10.1158/1538-7445.AM2017-4466
18F-FDG PET/CT Demonstrating Chorioadenoma Destruens After Evacuation of Complete Hydatidiform Mole
Authors: Punit Sharma
Journal: Clinical Nuclear Medicine (2017)

Gestational trophoblastic neoplasias (GTNs) are a group of pregnancy-related neoplasms, which include chorioadenoma destruens (invasive mole), placental site trophoblastic tumor, and choriocarcinoma. Although the role of F-FDG PET/CT is still undefined in GTN, in selected cases, it can have significant impact on patient management. Here, we present the case of a 29-year-old woman with hydatidiform mole suggestive of GTN 3 months after evacuation. F-FDG PET/CT demonstrated chorioadenoma destruens (invasive mole) and ruled out metastasis in this case.
Abstract 1744: RNAseq identified immune signatures associated with adverse outcome in high-risk neuroblastoma
Authors: Jun S. Wei, Shile Zhang, Igor Kuznetsov, Young K. Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Jaime M. Guidry Auvil, Daniela S. Gerhard, Robert Seeger, John M. Maris, Javed Khan
Journal: Cancer Research (2017)

Abstract Despite the success of multimodal therapies, the mortality and morbidity remains substantial for patients with high-risk neuroblastoma (NBL). Sequencing of paired tumor/normal DNA of NBL has revealed a low somatic mutation burden and few recurrent somatically-mutated genes. Here we hypothesize that whole transcriptome sequencing (WTS) in patients with high-risk NBL tumor will yield valuable insights into the biology of this disease. We performed deep WTS of 150 NBLs (129 high-risk stage 3 and 4; and 21 stage 4S tumors) of which majority of them had whole genome sequencing or whole exome sequencing of case-matched tumor/normal pairs through the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. We identified correlations between gene expression and clinical parameters of patients such as MYCN-amplification and survival to provide understandings of high-risk NBL biology. Consensus clustering using gene expression profiles of tumors revealed 4 subgroups with distinct survival probability (p&amp;lt;0.01). Among them, the group with the best outcome consisted of all stage 4S and 4S-like young patients; whereas the worst survival group was made up mostly of high-risk patients with MYCN-amplification. In order to identify the gene expression patterns correlating with outcome in the high-risk patients without MYCN-amplification, we further examined if any other known gene expression signatures can further stratify these patients using Gene Set Enrichment Analysis (GSEA). Among several molecular signatures, a previously reported 157-gene MYCN activation signature was significantly correlated with the poor outcome in high-risk patients without MYCN-amplification. Of note, we identified CD8, cytolytic, and activated nature killer (NK) cell signatures that were significantly associated with outcome in these patients. These findings were validated in an independent dataset. Our data has an important clinical implication for a subset of high-risk neuroblastoma patients without MYCN-amplification that have an activated MYCN signature may benefit from immune-modulating agents such as immune check point inhibitors which should be tested in context of clinical trials. Citation Format: Jun S. Wei, Shile Zhang, Igor Kuznetsov, Young K. Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Jaime M. Guidry Auvil, Daniela S. Gerhard, Robert Seeger, John M. Maris, Javed Khan. RNAseq identified immune signatures associated with adverse outcome in high-risk neuroblastoma [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 1744. doi:10.1158/1538-7445.AM2017-1744
RORγt-Mediated TNF-α Production from Human FoxP3+ Regulatory T Cells Contributes to Tissue Inflammation in Acute Viral Infection
Authors: Yoon Seok Choi, Ji Young Moon, Seung Woo Baek, Hyewon Ryu, Ik Chan Song, Hyo Jin Lee, Hwan-Jung Yun, Deog-Yeon Jo, Eui-Cheol Shin
Journal: Blood (2016)
Abstract 4567: Immunoclassification of gastric cancer in the context of clinical outcome
Authors: Weili Wang, Ping Liao, Shangchen Xie, Dongya Shen, Chengfang Zhou, Howard Mcleod, Yijing He
Journal: Cancer Research (2017)

Abstract Background: Gastric cancer (GC) plays a leading role in all cancer deaths especially in Eastern Asia. Current classifications including WHO, Lauren, and TCGA defined molecular classification have illuminated the clinicopathological characteristics or genetic profile of GC. However, these classifications were lack of association with clinical outcome and guidance for medication selection. Objective: We aimed to identify a new immunoclassification for GC to predict patient’s prognosis and provide evidence for choosing proper medication. Methods: Formalin-fixed and paraffin-embedded (FFPE) samples of GC were obtained along with the clinical outcome of the patient. Epstein-Barr virus (EBV) infection was measured by RT-PCR. Immune markers including CD3, CD8 and PD-L1 were measured by immunohistochemistry (IHC) at tumor infiltration area (TI) and invasive margin area (IM). The expression of PD-L1 in tumor microenvironment (TME) was assessed by immune reactive score (IRS) system. For immunoclassification, patients were classified into two subgroups: strong immunoreaction (SIR) and weak immunoreaction (WIR) defined by the number of CD8+ T cells and PD-L1 expression at TI. Results: EBV infection was associated with the number of CD3+T cells and PD-L1 expression in TME. EBV+ patients also showed a poor overall survival (OS) compared with EBV- patients. Importantly, WIR patients lived significantly shorter than SIR patients. Moreover, patients who were treated by taxanes in WIR group had a shorter OS compared with those not using taxanes. Conclusion: In this study, we suggest a new immunoclassification for gastric cancer which is associated with patients’ outcome and may provide a way to guide chemotherapy. Citation Format: Weili Wang, Ping Liao, Shangchen Xie, Dongya Shen, Chengfang Zhou, Howard Mcleod, Yijing He. Immunoclassification of gastric cancer in the context of clinical outcome [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 4567. doi:10.1158/1538-7445.AM2017-4567
The Direct Notch1 Cofactor Zmiz1 Differentially Regulates Notch1 Signals in a Stage-Specific Manner to Preserve Early T-Cell Precursors and Expand Committed T Cells
Authors: Qing Wang, Ran Yan, Nancy Pinnell, Yiran Liu, Amparo Serna Alarcon, Jason Qin, Yitong Chen, Erin Kim, Noah Garber, Ivan Maillard, Tomasz Cierpicki, Mark Chiang
Journal: Blood (2016)
Abstract 661: Evaluating "harmonization" of PD-L1 assays using image analysis
Authors: Nathan T. Martin, Joshua C. Black, Zachary Pollack, Famke Aeffner, Joseph Krueger
Journal: Cancer Research (2017)

Abstract The current diagnostics landscape for therapeutics that target the PD1/PD-L1 pathway is highly complex. Four different companion or complementary diagnostics have been developed for pembrolizumab in NSCLC, nivolumab in NSCLC and melanoma, and atezolizumab in urothelial carcinoma. The need to reconcile diagnostics for this class of targeted therapies has been recognized by the creation of the FDA-AACR-ASCO “PD-L1 Blueprint” working group to explore means to “harmonize” PD-L1 testing in tissue based IHC assays. The results reported from this working group noted similarities, but also several important discrepancies, between the current assays. Since each test uses a specific interpretation for each assay and indication, this creates a highly complex diagnostic landscape, which is likely to continue to increase in complexity as more PD-1/PD-L1 therapeutics and potentially novel diagnostics continue to be approved in additional indications. To address the need for adaptive, sustainable harmonization for PD-L1 diagnostics, Flagship Biosciences evaluated the utility of image analysis-based methods to harmonize multiple PD-L1 tests. We executed a proof-of-concept study utilizing a cohort of serial tissue sections from the same NSCLC patients, stained with the FDA approved Dako PD-L1 tests (28-8 and 22C3 clones), and our in-house PD-L1 assays (SP142 and E1L3N clones) for comparison. We digitized the tissue slides using a whole slide scanner, and evaluated the samples with our tissue Image Analysis (tIA™) technology. As expected, the patient samples stained with the separate PD-L1 assays yielded differences in staining and, thus, the reported scores for PD-L1 expression based on each test used, despite serial sections being derived from the same patient. To attempt to harmonize the scoring approaches for each test, we leveraged our computational Tissue Analysis (cTA™) platform to create a mathematically-derived “virtual slide score” for each sample, which enabled calibration of the various tests to deliver cross PD-L1 comparative scores. Based on the proof-of-concept demonstrated in this study, the cTA™ approaches could enable harmonization of the various PD-L1 tests through use of a digital pathology platform. The data presented provides a foundation for potential application of the cTA™ platform in the clinical laboratory setting to achieve harmonization of multiple PD-L1 tests. Citation Format: Nathan T. Martin, Joshua C. Black, Zachary Pollack, Famke Aeffner, Joseph Krueger. Evaluating "harmonization" of PD-L1 assays using image analysis [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 661. doi:10.1158/1538-7445.AM2017-661
Abstract 4032: Synergistic effects of Bortezomib and JQ1 for human and canine osteosarcoma treatments
Authors: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2017)

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor of both humans and dogs, with the incidence in dogs being nearly 15 times that observed in humans. Despite advances in treatment of other cancers, the clinical outcome of OS remains poor for the past several decades. Therefore, identifying novel and effective treatments for osteosarcoma is an urgent need. Among the small molecular compounds we tested in a drug screening study, we identified a bromodomain inhibitor (JQ1) that targets bromodomains which modify chromatin and block transcription of key factors, and a proteasome inhibitor that induces cell death through various mechanisms (bortezomib) as having good growth inhibition effects on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS). We then determined the IC50 values of these two drugs, the concentration capable of inhibiting proliferation by 50%. The IC50 values of bortezomib and JQ1 are both within achievable plasma concentrations and tolerable levels. JQ1 inhibited OS cell proliferation and survival by inducing G2 cell cycle arrest, while bortezomib induced G1 cell cycle arrest. In addition, these two drugs decreased cell migration ability in wound healing assay as well as invasion ability in a Matrigel assay. Furthermore, in combination studies using both JQ1 and bortezomib, we identified synergistic effects. With these promising results from in vitro studies, we further examined JQ1 as therapeutic agent in an orthotopic tumor xenograft mouse model. Using OS cells stably transfected with a lucerifase vector, we were able to track the tumor progression during the treatment period. Mice treated with JQ1 did not show any signs of adverse effect to the drug, indicating that JQ1 was safe and well tolerated at a daily dosage of 50 mg/kg (IP). While some of the mice in treatment group showed decreasing tumor growth compared to the control group, tumor growth trends in the two groups were not consistent, suggesting that we have to optimize the model and the treatment protocol as well as to evaluate combination treatments with bortezomib and JQ1 in in vivo models. Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan. Synergistic effects of Bortezomib and JQ1 for human and canine osteosarcoma treatments [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 4032. doi:10.1158/1538-7445.AM2017-4032
Abstract P091: Transcriptional Profiling of Pluripotent Stem Cell--Derived Neuropilin-1+CD34- Vascular Precursors Reveals Significant Overlap with Ventral Mesoderm and Identifies Signaling Pathways in Differentiation from Vascular Cells
Authors: Jennifer K Lang, Fraser J Sim, Thomas Cimato
Journal: Circulation Research (2011)

Background: Pluripotent stem cells are a model to understand the mechanisms of vascular differentiation in humans. We previously showed that the onset of Neuropilin-1 (NRP1) expression identifies vascular precursors in mouse and human embryonic stem cells. Our goal was to determine the degree of overlap between NRP1+CD34- cells and embryonic primitive streak, and identify novel growth factor signaling pathways controlling their differentiation. Methods: Human pluripotent stem cells were differentiated, and NRP1+CD34- cells were isolated. Following RNA extraction, whole genome transcriptional profiling was performed. Microarray data were compared with undifferentiated stem cells and human umbilical vein endothelial cells (HUVECs) using differential gene expression analysis with a false discovery rate of 5%, and greater than two-fold change between groups. We compared significantly enriched transcripts in NRP1+CD34- cells against genes expressed in the primitive streak in Xenopus embryos using hypergeometric testing. Functional annotation-based clustering was used to identify putative cell signaling pathways. Results: A total of 785 transcripts were significantly enriched in NRP1+CD34- vascular precursors vs. hESCs, and 605 transcripts were unique to NRP1+CD34- vascular precursors. NRP1+CD34- cells shared a significant number of transcripts (46 of 357 human homologs) with ventral mesoderm isolated from Xenopus embryos, (p ≤ 1 x 10-14). We then identified CXCL14, Neuregulin 2, Leptin and Apelin receptors as significantly upregulated in NRP1+CD34- vascular precursors, potentially controlling human ventral mesoderm and new vessel formation. Conclusions: NRP1+CD34- vascular precursors have significant transcript identity with ventral mesoderm from embryonic primitive streak, and a unique transcriptional profile compared with HUVECs. These findings suggest NRP1+CD34- human vascular precursors significantly resemble ventral mesoderm, and provide a model of human vascular development. The identification of a comprehensive database of cell-surface receptors expressed by the human ventral mesoderm analogs permits future pharmacological approaches to induce vascular differentiation from human pluripotent stem cells.
Abstract 3237: Development of direct inhibitors of KRAS mutants for the treatment of cancer
Authors: Xiaohong Tian, Guoyan Geng, Jian Hui Wu
Journal: Cancer Research (2017)

Abstract Oncogenic KRAS mutations occur in ~ 30% of all human cancer. All attempts to develop inhibitors of oncogenic KRAS have failed to reach the clinic for decades and promote the perception of ‘undruggable’ KRAS proteins. Given the recent advances in understanding of mechanism of oncogenic KRAS, there is renewed enthusiasm toward development of direct inhibitors of KRAS. In a recent breakthrough, Shokat et al. discovered a “pocket," where they designed a series of mutant-specific small molecular inhibitors that are covalently binding to the mutant Cys 12 in KRAS protein (KRAS G12C). In human cancer, G12C, G12D and G12V are the predominant KRAS mutants. The G12C mutation accounts for 29,700 new diagnoses annually (lung, colon and pancreatic). The G12D and G12V, annually account for 53,700 and 39,100 new cancer diagnoses, respectively, occurring most frequently in Pancreatic ductal adenocarcinoma (PDAC) (51% G12D and 30% G12V) and colorectal cancer (45% G12D and 27% G12V). Thus, there is an urgent need to develop direct inhibitor of KRAS 12D and 12V mutants. By computer-aided drug design techniques, we have discovered a series of novel chemical inhibitors that potently inhibit KRAS G12D mutant in reporter assays using HEK293 cells and in Western blot analysis using PANC10.05 and SNU-C2B cells, which express endogenous KRAS G12D mutant. The direct binding of our compounds with KRAS G12D mutant was confirmed by Surface Plasmon Resonance (SPR) analysis. Our compounds also inhibit KRAS G12V mutant. Chemical optimization of these initial hits as direct inhibitors of multiple KRAS mutants is in progress. Citation Format: Xiaohong Tian, Guoyan Geng, Jian Hui Wu. Development of direct inhibitors of KRAS mutants for the treatment of cancer [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 3237. doi:10.1158/1538-7445.AM2017-3237
In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells
Authors: Francesca Bortolotti, Giulia Ruozi, Antonella Falcione, Sara Doimo, Matteo Dal Ferro, Pierluigi Lesizza, Lorena Zentilin, Lawrence Banks, Serena Zacchigna, Mauro Giacca
Journal: Circulation (2017)

Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here, we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell engraftment into the heart both in normal conditions and after myocardial infarction.An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral vectors. Pools from this library were then used for the batch transduction of bone marrow-derived mesenchymal stromal cells ex vivo, followed by intramyocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines.The most effective molecule identified by this competitive engraftment screening was cardiotrophin-1, a member of the interleukin-6 family. Intracardiac injection of mesenchymal stromal cells transiently preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least 2 months after injection. Engraftment of cardiotrophin-1-treated mesenchymal stromal cells was consequent to signal transducer and activator of transcription 3-mediated activation of the focal adhesion kinase and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells.These results support the feasibility of selecting molecules in vivo for their functional properties with adeno-associated viral vector libraries and identify cardiotrophin-1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium.