tbuckley/cabot-search huggingface dataset:
Abstract 157: APE1 upregulates MMP-14 to promote invasion of esophageal adenocarcinoma via redox-sensitive ARF6-mediated recycling
Authors: Heng Lu, Ajaz A. Bhat, Dunfa Peng, Zheng Chen, Shoumin Zhu, Jun Hong, Selma Maacha, David Robbins, Abbes Belkhiri, Wael El-Rifai
Journal: Cancer Research (2019)

Abstract The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) has increased dramatically in the past three decades. The development of BE and its progression to EAC is highly correlated with exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). A stimulated overexpression of APE1 has been identified in response to bile acids for oxidative DNA repair and oncogenic signal transduction in BE and EAC, but function and mechanism of APE1 in BE and EAC development remains largely unknown. Here, we demonstrate a new function of APE1 in promoting invasion of dysplastic BE and EAC cells that is dependent on its redox function. We observed aberrant overexpression of APE1 in the cell lines and patients’ samples of dysplastic BE and EAC. In contrast to wild-type APE1, overexpression of redox-defective mutant, C65A, or treatment with APE1-redox-specific inhibitor, E3330, abrogated the pro-invasive phenotype of APE1. Mechanistically, we found that APE1 upregulated protein levels of the key matrix metalloproteinase MMP-14. Knockdown of APE1 decreased MMP-14 protein levels in dysplastic BE and EAC cells. Zymography assays indicated APE1 silencing reduced MMP-14 activity, subsequently impaired MMP-2 activation, and repressed extracellular matrix (ECM) degradation. Further, endocytosis and recycling assays revealed decreased endocytosis/recycling of MMP-14 protein in APE1-knockdown cells. Interestingly, our immunoprecipitation and proximity ligation assay (PLA) revealed a novel interaction between APE1 and ARF6, a key regulator of MMP-14 recycling. This interaction between APE1 and ARF6 activates ARF6 to regulate MMP-14 recycling through APE1-dependent redox function. Conclusion: Our findings demonstrate, for the first time, the role of APE1 redox function in upregulating MMP-14 protein levels through activation of ARF6-mediated MMP-14 recycling. We propose APE1/ARF6/MMP-14 as a novel signaling axis in the invasion and progression of dysplastic BE and EAC. Citation Format: Heng Lu, Ajaz A. Bhat, Dunfa Peng, Zheng Chen, Shoumin Zhu, Jun Hong, Selma Maacha, David Robbins, Abbes Belkhiri, Wael El-Rifai. APE1 upregulates MMP-14 to promote invasion of esophageal adenocarcinoma via redox-sensitive ARF6-mediated recycling [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 157.
Abstract 1764: Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma
Authors: Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Stanley M. Kanai, Tyson D. Todd, Shiqi Wang, Thomas J. Broekelmann, Prabakar Kumar Rao, John A. Cooper, Kendall J. Blumer
Journal: Cancer Research (2019)

Abstract Constitutively activating mutations in the G-protein alpha subunits GNAQ(Gαq) and GNA11(Gα11) act as oncogenic drivers in over 90% of uveal (eye) melanoma (UM) tumors. We show that constitutively active Gαq and Gα11 can be targeted in UM cells by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP guanine nucleotide exchange allosterically to trap constitutively active Gαq/11 in inactive GDP-bound Gαβγ heterotrimers. FR inhibits second messenger signaling, arrests proliferation and reinstates melanocytic differentiation in UM cells driven by constitutively active Gαq or Gα11. At higher doses, FR also induces apoptosis. The re-differentiation and anti-proliferative effects of FR are not seen in UM cells that lack mutations in Gαq or Gα11. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, and this re-differentiation can be blocked with an EZH2 inhibitor. The effector system regulating PRC2 downstream of constitutively active Gαq/11 in UM is currently under investigation. Preliminary data from human primary tumor samples suggest that targeting constitutively active Gαq/11 with FR could provide an important therapeutic approach for UM. Citation Format: Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Stanley M. Kanai, Tyson D. Todd, Shiqi Wang, Thomas J. Broekelmann, Prabakar Kumar Rao, John A. Cooper, Kendall J. Blumer. Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma [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 1764.
Effect of t(11;14) on outcomes of patients (pts) with newly diagnosed multiple myeloma (NDMM) in the connect MM registry.
Authors: Cristina Gasparetto, Sundar Jagannath, Robert M. Rifkin, Brian G. Durie, Mohit Narang, Howard R. Terebelo, Kathleen Toomey, James W. Hardin, Lynne I. Wagner, Sikander Ailawadhi, James Omel, Hans Chulhee Lee, Shankar Srinivasan, Mazaher Dhalla, Donna Catamero, Amit Agarwal, Rafat Abonour
Journal: Journal of Clinical Oncology (2019)

8032 Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]
Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in <i>EGFR</i>-mutated non-small cell lung cancer (NSCLC)
Authors: Ni Fan, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, Haiying Cheng
Journal: Cancer Research (2019)

Abstract Background: Molecularly-targeted therapy has significantly improved the therapeutic efficiency and clinical outcome in a subgroup of NSCLC patients. However, drug resistance inevitably emerges, such as resistance to EGFR TKIs in EGFR-mutated NSCLC. RICTOR is a key component of the mTORC2 complex and plays important roles in cell survival, proliferation, migration and invasion. RICTOR has also been suggested to play a part in the regulation of drug resistance to HER2-targeted therapy in HER2-amplified breast cancer, a niche close to EGFR-targeted therapy. In our current study, we hypothesize that RICTOR modulates the activity of EGFR TKIs in EGFR-mutated NSCLC. Co-targeting RICTOR and EGFR signaling pathways could be a new therapeutic strategy for patients with EGFR-mutated lung cancer. Results: Genetically modified EGFR-mutated NSCLC cell lines with different RICTOR expression levels have been developed. RICTOR knockdown significantly increases the sensitivity to all three generations of TKI inhibitors (erlotinib, afatinib and osimertinib), whereas overexpression of RICTOR renders the cells more resistant to EGFR TKIs. In addition, RICTOR knockdown restores the sensitivity of erlotinib-resistant HCC827 cells due to AXL overexpression (IC50: 216µM vs. 0.256 µM with RICTOR knockdown, P&amp;lt;0.001). Pharmacological inhibition of the RICTOR signaling pathway with the mTOR1/2 inhibitor (sapanisertib) also improves EGFR TKI sensitivity. Taken together, RICTOR signaling modulates the efficacy of EGFR TKIs in the EGFR-mutated lung cancer models. Conclusion: Our study provides a new insight into the role of RICTOR signaling modulation in increasing efficacy of EGFR TKI therapy in EGFR-mutated NSCLC. The combination of mTOR1/2 inhibitor and EGFR inhibitor could be a potential novel strategy leading to better therapeutic efficacy. Note: This abstract was not presented at the meeting. Citation Format: Ni Fan, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, Haiying Cheng. RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC) [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 4748.
Abstract LB-274: Identification and characterization of LY3410738, a novel covalent inhibitor of cancer-associated mutant Isocitrate Dehydrogenase 1 (IDH1)
Authors: Nathan Brooks, Robin DeWalt, Serge Boulet, ZhaoHai Lu, Lisa Kays, Rachel cavitt, Sandra Gomez, John Strelow, Paul Milligan, Kenneth Roth, Renato Bauer, Stephen Antonysamy, Patric Hahn, Zoran Rankovic, Denis McCann, Gary Mo, Ramon Tiu, Timothy Burkholder, Sandaruwan Geeganage, Raymond Gilmour
Journal: Cancer Research (2019)

Abstract Somatic gain-of-function mutations in IDH1 have been identified in multiple tumor types including AML, glioma, cholangiocarcinoma and chondrosarcoma. The neo-enzymatic activity of mutant IDH1 results in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), leading to a hyper-methylation phenotype, a block in cell differentiation, and tumor growth. Using a structure-based drug design approach, we have developed a highly potent covalent inhibitor of mutant IDH1. LY3410738 modifies a single cysteine (Cys269) in the allosteric binding pocket and rapidly inactivates the enzyme with a KI/Kinact = 84,257 M-1sec-1. The compound selectively inhibits the 2-HG in IDH1 mutant tumor cells without depleting the levels of a-ketoglutarate. Using patient-derived primary AML cells, we demonstrated that LY3410738 was more potent than AG120 in reversing the block in differentiation associated with IDH1 mutant activity. In vivo, LY3410738 displayed prolonged pharmacodynamic activity, depleting 2-HG levels in tumors at low circulating exposures and for an extended time after clearance of compound. Importantly, LY3410738 has the ability to cross the blood-brain barrier and can achieve concentrations in the brain that exceed those needed to engage the target. Consistent with this, LY3410738 effectively inhibits 2HG in orthotopic glioma models. Using patient-derived IDH1 mutant orthotopic AML models, we demonstrated that LY3410738 effectively inhibited 2-HG, induced differentiation, and cleared AML from mice. Collectively, LY3410738 represents the first covalent brain-penetrant mutant IDH1 inhibitor with potential for Best-in-Class activity. Citation Format: Nathan Brooks, Robin DeWalt, Serge Boulet, ZhaoHai Lu, Lisa Kays, Rachel cavitt, Sandra Gomez, John Strelow, Paul Milligan, Kenneth Roth, Renato Bauer, Stephen Antonysamy, Patric Hahn, Zoran Rankovic, Denis McCann, Gary Mo, Ramon Tiu, Timothy Burkholder, Sandaruwan Geeganage, Raymond Gilmour. Identification and characterization of LY3410738, a novel covalent inhibitor of cancer-associated mutant Isocitrate Dehydrogenase 1 (IDH1) [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 LB-274.
Next Generation Sequencing of Castleman Disease and Follicular Dendritic Cell Sarcomas Associated with Castleman Disease
Authors: Alexandra Nagy, Aparna Bhaduri, Nahid Shahmarvand, Jahanbanoo Shahryari, James L. Zehnder, Roger Warnke, Tariq I Mughal, Siraj M Ali, Robert S. Ohgami
Journal: Blood (2017)
ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17–Mutant KIT
Authors: Beth Apsel Winger, Wilian A. Cortopassi, Diego Garrido Ruiz, Lucky Ding, Kibeom Jang, Ariel Leyte-Vidal, Na Zhang, Rosaura Esteve-Puig, Matthew P. Jacobson, Neil P. Shah
Journal: Cancer Research (2019)

Abstract KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17–mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. Significance: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.
Abstract 2790: Characterization of the immune microenvironment in brain metastasis from non-small cell lung cancer
Authors: Yujin Kudo, Cara Haymaker, Jiexin Zhang, Alexandre Reuben, Dzifa Yawa Duose, Junya Fujimoto, Sinchita Roy-Chowdhuri, Luisa Maren Solis, Hitoshi Dejima, Edwin Roger Cuentas, Barbara Mino, Ronald Abraham, Norihiko Ikeda, Rajyalakshmi Luthra, Jack J. Lee, Humam Kadara, Jason T. Huse, Ignacio I. Wistuba
Journal: Cancer Research (2019)

Abstract Purpose Brain metastases can induce life-threatening events and their immune microenvironment is still unrevealed. To elucidate the probability of immune-oncology therapy for brain metastases, we utilized immune profiling of resected brain metastases and paired non-small cell lung cancer (NSCLC). Methods To compare pure tumor-infiltrating lymphocytes (TILs) or tumor tissues between NSCLC and brain metastases, macro-dissection was performed before extracting DNA and RNA from 39 patients who received surgical resection of local NSCLC tumor lesions and brain metastases from matched patients. We applied gene expression analysis of mRNA by using a 770 gene panel related with cancer immune cells. Targeted sequencing of 50 cancer hotspot genes on extracted DNA was performed for genotyping. TCRß sequencing of extracted DNA was utilized for profiling of TCR repertoire. Results We identified 161 differentially expressed genes, which reflected inhibition of dendritic cell maturation pathway, Th1 pathway, and leukocyte extravasation signaling pathway in brain metastases (p &amp;lt; 0.01). VCAM1 was one of highly inter-connected network genes with low expression level in brain metastases. Immune cell profiling analysis illustrated low T-cell infiltration and higher ratio of macrophages against TILs in the brain metastases (p &amp;lt; 0.001). The detected mutations in genotyping analysis were completely shared in 28 patients (71%). TCR sequencing analysis revealed that T-cell clones were expanded in 64% of patients with brain metastases. The majority of TCR repertoire in brain metastases were principally shared with the paired NSCLC, while the density of T cells was sparse in the brain metastases. Conclusion The microenvironment in brain metastases from NSCLC was revealed to be immunosuppressive, with the majority of T-cell clones in brain metastases being shared with the primary lesion. Citation Format: Yujin Kudo, Cara Haymaker, Jiexin Zhang, Alexandre Reuben, Dzifa Yawa Duose, Junya Fujimoto, Sinchita Roy-Chowdhuri, Luisa Maren Solis, Hitoshi Dejima, Edwin Roger Cuentas, Barbara Mino, Ronald Abraham, Norihiko Ikeda, Rajyalakshmi Luthra, Jack J. Lee, Humam Kadara, Jason T. Huse, Ignacio I. Wistuba. Characterization of the immune microenvironment in brain metastasis from non-small cell lung 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 2790.
Assessing Nonculprit Coronary Disease in ST-Segment Elevation Myocardial Infarction With Physiological Testing
Authors: William F. Fearon
Journal: JAMA Cardiology (2019)

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The Pricing of Care Under Medicare for All
Authors: Zirui Song
Journal: JAMA (2019)

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Abstract 20402: Radial versus Femoral Access With or Without Vascular Closure Device in Patients With or Without St-Segment Elevation: Propensity Score Matched Analysis
Authors: Jang Hoon Lee, Hong Nyun Kim, Joon Hyuk Song, Namkyun Kim, Jae Hyung Roh, Myung Hwan Bae, Dong Heon Yang, Hun Sik Park, Yongkeun Cho, Shung Chull Chae, Jihyun Sohn, Se Yong Jang
Journal: Circulation (2017)

Background: Radial access for PCI can reduce vascular bleeding compared with femoral access, and this result in lowering major adverse cardiovascular and cerebrovascular events (MACCE) in patients ...
Epstein–Barr virus in pleural effusions: protagonist or pretender?
Authors: David T. Arnold, Tim Suri, Fergus Hamilton, Anna Morley, Andrew Medford, Ian B. Vipond, Peter Muir, Nick A. Maskell
Journal: European Respiratory Journal (2019)

<b>Previous studies have suggested an association between Epstein–Barr virus (EBV) and inflammatory pleuritis (IP). The incidence of IP in this 1005-patient cohort was 3%, with no evidence of increased pleural fluid EBV DNA compared to controls.</b>http://bit.ly/2lVGvNV
Abstract 17379: Untargeted Metabolomic Analyses Reveal Mechanistic Links Between a Mediterranean-Style Diet and Incident Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis
Authors: Alexis C Frazier-Wood, Ioanna Tzoulaki, Trudy Voortman, John Lindon, Timothy Ebbels, Paul Elliot, Claire L Boulange, Manuja Kaluarachchi, Elena Chekmeneva, Ibrahim Karaman, Oscar H Franco, Philip Greenland, Russel Tracy, David Herrington
Journal: Circulation (2017)

Introduction: Randomized controlled trials indicate that a Mediterranean-style Diet (MSD) reduces the risk of recurrent CVD, protects against adverse cardiovascular events, and improves biomarkers ...
Prognostic role white blood cell levels in patients with advanced pancreatic adenocarcinoma undergoing first-line chemotherapy
Authors: A. Ioannou, S. Demiri, G. Papaxoinis, V. Rapti, E. Klouva, E. Sarris, P. Baxevanos, G. Garefalakis, G. Goumas, P. Gouveris, P. Kourakos, G. Koumakis
Journal: Annals of Oncology (2019)
c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies
Authors: Jochem H. Bernink, Yoichiro Ohne, Marcel B. M. Teunissen, Jingya Wang, Jincheng Wu, Lisette Krabbendam, Christine Guntermann, Richard Volckmann, Jan Koster, Sophie van Tol, Ivan Ramirez, Yashaswi Shrestha, Menno A. de Rie, Hergen Spits, Xavier Romero Ros, Alison A. Humbles
Journal: Nature Immunology (2019)