tbuckley/cabot-search huggingface dataset:
Abstract 4019: High TERT expression in NSCLC is associated with poor prognosis
Authors: Tianhong Li, Weijie Ma, Qianping Li, Sixi Wei, Tao Wang, Jingyi Xiang, Cheng Liu
Journal: Cancer Research (2019)

Abstract Background: Activation of human telomerase reverse transcriptase (TERT) has been linked to tumorigenesis and aggressive tumor behavior. This study was undertaken to evaluate if TERT expression was correlated with clinicopathological parameters and survival in patients with non-small cell lung cancer (NSCLC). Methods: TMA slides made from 254 NSCLC patients (cohort 1 and cohort 2), including 127 adenocarcinoma (LUAD), 78 squamous carcinomas (LUSC) and 46 other types, were included. TMA Formalin-fixed and paraffin-embedded (FFPE) tissue sections were stained using the immunohistochemistry stain (IHC). The percentage of positive nuclei was determined for each case and the cut-off value was set as 5%, 20% and 50% positive tumor cells. TERT expression levels were analyzed for associations with patient survival rates and clinicopathological parameters (such as age, gender, tumor grade, tumor stage, metastasis). Survival analysis was performed using the Kaplan-Meier method. Results: TERT was positive in 199/254 (78%) of the samples. High TERT expression was seen in tumor specimens compared with normal adjunct tissues (p &amp;lt; 0.001). Kaplan-Meier curves indicated that high TERT expression was significantly associated with poor overall survival in NSCLC patients (p &amp;lt; 0.001 and p &amp;lt; 0.0001, 20% and 50% cut-off, respectively). Multivariate analysis of survival demonstrated that TERT expression at 50% cutoff was an independent prognostic factor for NSCLC patients (HR = 0.1461, 95% CI: 0.0862-0.2475, p &amp;lt; 0.0001). High TERT expression was also associated with short survival of LUSC and LUAD patients at 50% cutoff (p &amp;lt; 0.0001). No significant association with OS was observed at 5% cutoff. There was also significant correlation between TERT expression with metastasis but no correlation with clinical stage, histological type and tumor differentiation. Conclusion: Our study showed that high TERT expression is present in 78% of NSCLC tumors and is associated with poor prognosis. TERT may serve as a prognostic biomarker and novel drug target for NSCLC. Citation Format: Tianhong Li, Weijie Ma, Qianping Li, Sixi Wei, Tao Wang, Jingyi Xiang, Cheng Liu. High TERT expression in NSCLC is associated with poor prognosis [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 4019.
Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
Authors: Liang Wei Wang, Hongying Shen, Luis Nobre, Ina Ersing, Joao A. Paulo, Stephen Trudeau, Zhonghao Wang, Nicholas A. Smith, Yijie Ma, Bryn Reinstadler, Jason Nomburg, Thomas Sommermann, Ellen Cahir-McFarland, Steven P. Gygi, Vamsi K. Mootha, Michael P. Weekes, Benjamin E. Gewurz
Journal: Cell Metabolism (2019)

Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid B cell outgrowth remains largely unknown. To gain insights, primary human B cells were profiled by tandem-mass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 1C enzyme MTHFD2, which played key roles in EBV-driven B cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production, and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism.
Abstract 2498: MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73
Authors: Hayley Widden, Aneta Kaczmarczyk, Robert H. Whitaker, William J. Placzek
Journal: Cancer Research (2019)

Abstract MCL1 is an anti-apoptotic member of the Bcl-2 family, which has become a popular therapeutic target in cancer research over the past decade due to its propensity to promote cancer cell survival and facilitate chemoresistance. Through a phage display screen, we identified a novel MCL1 binding motif that is the reverse of the canonical BH3-binding helix that mediates interactions amongst Bcl-2 family members. Upon a BLAST sequence analysis of native proteins, we identified a putative reverse BH3 (rBH3) motif in the tumor suppressor protein, p73. Here, we show that MCL1 and p73 bind through a direct protein-protein interaction. Using fluorescence polarization assay, we characterize the strength of this interaction and reduce binding down to the rBH3-containing alpha helix in the tetramerization domain of p73. To elucidate biological function, we employ electrophoretic mobility shift assay to show that excess MCL1 negatively impacts p73 binding to DNA. Finally, using two p53-/- cancer cell lines, we demonstrate that MCL1 inhibits the transcriptional function of p73 through analysis of p73 target gene expression. In summary, we characterize a novel protein-protein interaction between MCL1 and p73 and show that MCL1 negatively impacts p73 target gene activation. This work establishes a novel function of MCL1 outside of apoptotic regulation at the mitochondria and provides new evidence of cross talk between the Bcl-2 family and the DNA damage response pathway. Citation Format: Hayley Widden, Aneta Kaczmarczyk, Robert H. Whitaker, William J. Placzek. MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73 [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 2498.
Abstract 3198: Therapeutic potential of MET inhibitor combined with immune checkpoint blockade in pancreatic cancer
Authors: Mei Gao, Miranda Lin, Yachao Yang, Joseph Kim
Journal: Cancer Research (2019)

Abstract Novel Combination Therapeutic Targeting of the Immune Checkpoint PD-1 and c-MET in Pancreatic Cancer Introduction: Therapeutic regimens incorporating immune checkpoint inhibitors (ICIs) have improved survival in many cancers, but have had little impact in pancreatic ductal adenocarcinoma (PDAC). We previously discovered that these ICIs directly target autonomously expressed and functional PD-1 on PDAC cells. We sought to investigate downstream effectors of PD-1 signaling in PDAC cells as potential novel therapeutic targets. Methods: We performed a Phospho Explorer Array, which measures the levels of over 200 phospho-specific antibodies and their corresponding total proteins, to determine activated signaling pathways following exposure of PDAC cells to PD-L1 (the ligand for PD-1). Upon detecting upregulation of PD-1 mediated MET signaling, we verified MET pathway activation by exposing PDAC cells (MIAPaCa-2 and PANC-1) to PD-L1 and measuring levels of phosphorylated MET by immunoblotting. Then, we tested whether the MET small molecule inhibitor blocked PD-1 mediated MET signaling. Finally, PDAC patient-derived organoids (PDOs) were utilized to test the cytotoxicity of ICIs alone or in combination with cabozantinib. Results: The phospho-protein array revealed 10-fold upregulation of MET activity followed exposure of PDAC cells to PD-L1. Western blot assay verified increased levels of MET phosphorylation that varied in a time-dependent manner following PD-L1 treatment in both PANC-1 and MIAPaCa-2 cell lines. Pre-treatment of PDAC cells with cabozantinib completely blocked PD-1/PD-L1 mediated MET phosphorylation. By CellTiter-Glo assay the IC50 of cabozantinib was calculated in MIAPaCa-2 and PANC-1 cells as 9.5 µM and 8.6 µM, respectively. Combining cabozantinib with clinical grade anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab revealed synergistic cytotoxicity in PDAC cells and PDOs. Conclusion: In these preliminary studies, we report PD-1 activation of the MET pathway and synergy killing of PDAC cancer models with novel combination therapy of cabozantinib and ICIs in PDAC. This positive data warrants further exploration of the interaction of MET with the PD-1/PD-L1 axis and its role in PDAC progression. Note: This abstract was not presented at the meeting. Citation Format: Mei Gao, Miranda Lin, Yachao Yang, Joseph Kim. Therapeutic potential of MET inhibitor combined with immune checkpoint blockade in pancreatic 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 3198.
Abstract 717: Erianin induces autophagy-dependent apoptosis in oral cancer cells
Authors: Chiao-Wen Lin, Shun-Fa Yang
Journal: Cancer Research (2019)

Abstract Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide. It has a very poor prognosis with 5-year over survival rate of only 50%. Thus, it is important to identify effective therapeutic interventions against oral cancer. The present study was designed to evaluate the effect of erianin, a natural bibenzyl compound found in a traditional Chinese orchid Dendrobium chrysotoxum, on human oral cancer cell proliferation. Results of the study revealed that treatment with erianin significantly reduced the viability of different OSCC cell lines. Erianin exerted its cytotoxic effect by inducing cell cycle arrest at G2/M phase and caspase-dependent apoptotic pathways. Both intrinsic and extrinsic pathways were found to be involved in erianin-mediated cell death. In addition, treatment with erianin also increased autophagy in OSCC cells. With further analysis, it was found that erianin induced both apoptosis and autophagy by regulating MAPK signaling pathways. Taken together, our study indicates that erianin plays an important role in reducing oral cancer cell viability, and thus, can be considered as a potential anticancer agent. Citation Format: Chiao-Wen Lin, Shun-Fa Yang. Erianin induces autophagy-dependent apoptosis in oral cancer cells [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 717.
MIRROS: An ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia.
Authors: Pau Montesinos, Jordi Esteve, Marina Konopleva, Giovanni Martinelli, Oliver Ottmann, Rebeca Rodriguez-Veiga, Christoph Röllig, Andrew Wei, Norbert Vey, Idy Chiu, Annabelle Monnet, Marion Gabriele Ott, Pierre Fenaux
Journal: Journal of Clinical Oncology (2019)

TPS7063 Background: The prognosis for patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with 3-year overall survival rates ~10–30% after intensive chemotherapy-based approaches. Despite the advent of targeted therapies, considerable unmet medical need remains in this population. Idasanutlin (RG7388; RO5503781) is an orally available small molecule that binds to the murine double minute 2 (MDM2) protein and blocks MDM2 interaction with p53. This stabilizes and activates p53 and facilitates cell cycle arrest and apoptosis, preventing tumor growth. A phase 1b study of idasanutlin + ARA-C in pts with R/R AML, irrespective of TP53 mutation status (NCT01773408), has shown a composite complete remission (CR) rate (CR plus CR with incomplete platelet or hematologic recovery) of 29% (Martinelli et al. 2016). Methods: MIRROS (NCT02545283; WO29519) is an international, phase 3, double-blind, randomized study comparing idasanutlin (300 mg bid) + ARA-C (1 g/m 2 qd) days 1–5 versus placebo + ARA-C in 440 pts with first or second R/R AML, with or without TP53 mutation. The primary endpoint is overall survival in pts with wild-type (WT) TP53. Secondary endpoints include CR, overall remission rates, event-free survival (EFS) and percentages of pts undergoing hematopoietic stem cell transplantation. MIRROS integrates phase 2 trial methodology into the phase 3 design by incorporating an interim analysis (IA) in 120 pts with WT TP53, using a high bar on the odds ratio for durable CR and EFS to assess for futility. Stop/go gating criteria for safety were also implemented. The IA was performed by an independent data monitoring committee and study continuation criteria were successfully met in mid-2017. This innovative strategy has allowed acceleration of the idasanutlin development program while maintaining a robust trial design. As of December 31 2018, 351 pts had been enrolled. The MIRROS study is ongoing and its results will inform the potential role of idasanutlin and MDM2 inhibition in the treatment of R/R AML. Clinical trial information: NCT02545283; WO29519.
Use of Busulfan in Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Adults: A Survey By the Complications and Quality of Life Working Party of the EBMT
Authors: Tapani Ruutu, Steffie van der Werf, Anja van Biezen, Janne Backman, Arnon Nagler, Silvia Montoto, Mohamad Mohty, Dietger Niederwieser, Claudia Langebrake, Zinaida Peric, Rafael F Duarte, Grzegorz Basak
Journal: Blood (2017)
Abstract 12826: Systolic Velocity of the Tricuspid Annulus Decreases After Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Darrin Wong, Omid Yousefian, William Auger, Teri Dittrich, Michael Madani, Lori Daniels, Ajit Raisinghani, Anthony DeMaria, Daniel Blanchard
Journal: Circulation (2015)

Introduction: Echocardiographic assessment of RV function is problematic. Systolic velocity of the tricuspid annulus (tS m ) has been shown to correlate with RV ejection fraction. Furthermore, tS m is generally depressed in chronic pulmonary hypertension. We sought to evaluate RV systolic function in chronic thromboembolic pulmonary hypertension (CTEPH) using 2D speckle tracking before and after pulmonary thromboendarterectomy (PTE). Hypothesis: We hypothesized that tS m would increase after PTE. Methods: We measured tS m from 2D echocardiography using speckle tracking in 127 consecutive CTEPH patients (52 ± 14 years, 49% female) with adequate images pre- &amp; post- PTE. tS m was measured 9.7 ± 17.3 days before and 11.3 ± 17.0 days after PTE using Epsilon Imaging EchoInsight software. Results: Unexpectedly, tS m worsened after PTE (8.2 ± 3.5 to 5.4 ± 2.8 cm/sec [p=&lt;0.0001]). Pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), and cardiac output (CO) all improved: 723 ± 258 to 246 ± 133 dyne-sec/cm 5 (p=&lt;0.0001), 46 ± 12 to 24 ± 7 mm Hg (p=&lt;0.0001), and 4.4 ± 1.3 to 5.6 ± 1.2 L/min (p=&lt;0.0001) respectively after PTE (Table 2). Preoperatively, tS m correlated inversely with PVR (p=&lt;0.0001) and mPAP (p=0.003) and directly with CO (p=0.0002) (Table 1). Postoperatively, tS m did not significantly correlate with PVR, mPAP, or CO. Conclusions: tS m correlates significantly with PVR, mPAP, and CO in patients referred for CTEPH. Early after PTE, however, tS m decreases by 34% and demonstrates no correlation with postoperative right heart catheterization data. In conclusion, tS m cannot be used to accurately predict RV function immediately following successful PTE.
Abstract 5129: Actionable activating oncogenic HER2 transmembrane and juxtamembrane domain mutations
Authors: Kanika Bajaj
Journal: Cancer Research (2019)

Abstract Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) including G660D, R678Q, E693K and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade. Citation Format: Kanika Bajaj. Actionable activating oncogenic HER2 transmembrane and juxtamembrane domain mutations [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 5129.
Infographic. The road to the ergogenic effect of caffeine on exercise performance
Authors: Joao Gabriel Baltazar-Martins, Diego Brito de Souza, Millán Aguilar, Jozo Grgic, Juan Del Coso
Journal: British Journal of Sports Medicine (2019)

The high prevalence of caffeine intake by athletes has prompted researchers to explore its effects on sport and exercise performance, with a particular focus on optimal guidelines for caffeine supplementation.1 The 2018 International Olympic Committee consensus statement on dietary supplements has identified caffeine as one of the few supplements that have good evidence of benefits for performance.2 A recent umbrella review examined caffeine’s effect on exercise performance and highlighted that caffeine ingestion has a small—but significant—ergogenic effect on muscle strength and anaerobic power, along with moderate effect sizes for aerobic and muscle endurance.3 These data explain why caffeine is similarly consumed in sports with very different physiological demands4 and support the notion that caffeine is ergogenic across a broad range of exercise tasks. …
Abstract P129: Confirmatory Factor Analysis of Multivariate Lipid Distributions Across Time and Race/Ethnic Groups: United States, 2003-2012
Authors: Ann Von Holle, Kari North
Journal: Circulation (2017)

Plasma concentrations of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are important risk factors for metabolic and cardiovascular diseases and are widely-used as targets for therapeutic intervention. Consideration of the multivariate distribution of these lipid traits could be informative for studies involving pleiotropic genetic variants, variants associated with more than one lipid outcome, but featuring only univariate lipid outcome models. Confirmatory factor analysis (CFA) is one way to characterize the multivariate distribution of biologically plausible, related indicators such as lipids with a continuous latent factor. Although CFA has been used to characterize metabolic syndrome, a cardiovascular disease (CVD) risk factor involving many correlated indicators, dyslipidemia is a CVD risk factor that remains relatively unexplored in this literature. Thus, the primary aim of this study is to conduct CFA with LDL-C, HDL-C and TG as indicators representing a single continuous latent lipid factor and assess its suitability as an outcome measure in a United States representative sample by racial/ethnic groups stratified by age and gender over five 2-year time periods (2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012) from NHANES. First, we used principal component analyses (PCA) to visually examine clustering by race and gender in biplots. Second, we tested for scale differences in the lipid factor across a) calendar time and b) racial/ethnic groups (Mexican-American, non-Hispanic White, non-Hispanic Black, Other Hispanic and Other race/ethnicity). All analyses were stratified by medication use, gender and three age groups: 12-19 years, 20 to 49 years and 50-80 years, and adjusted for age and body mass index (BMI). We found significant scale differences across racial/ethnic groups. In particular, the center of the distribution differed across racial/ethnic groups for ages 12-19 years (p&lt;0.0001), 20-49 years (p&lt;0.0001) and 50-80 years (p&lt;0.0001), suggesting joint distributions of TG, HDL-C, and LDL-C vary across racial/ethnic groups. In summary, one continuous latent factor representing all three lipids and their concomitant associations provides a means to characterize lipid values simultaneously and can serve as an outcome when studying exposures influencing multiple lipid values, pleiotropic genetic variants being just one example of many. Differences in the lipid latent factor across racial/ethnic groups emphasizes distinct multivariate distributions necessitating stratification. Limited analyses exist using this CFA framework for lipids, and future efforts considering the joint distribution of lipids may improve our understanding of the genetic architecture of dyslipidemia.
Novel predictive markers of PSA response to abiraterone acetate in men with metastatic castration-resistant-prostate-cancer (mCRPC).
Authors: Raya Leibowitz-Amit, Arnoud J. Templeton, Eshetu G. Atenafu, Francisco Emilio Vera-Badillo, Muralidharan Chllamma, Henry L. Solow, Jennifer J. Knox, Ian Tannock, Srikala S. Sridhar, Anthony Michael Joshua
Journal: Journal of Clinical Oncology (2013)

5058 Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC pre- and post- chemotherapy. To date, clinical predictive biomarkers of response remain poorly characterized. The aim of this retrospective study was to identify and analyze predictors of response to AA in men with mCRPC. Methods: All men receiving AA at the Princess Margaret Cancer Centre between November 2009 and December 2012 were reviewed. PSA response rate (RR) was defined according to PCWG2 criteria and assessed 12 weeks after AA start. Potential predictive factors were analyzed using uni- and multivariable logistic regression models. Results: In total, 70 patients were evaluable for response: 34 men were chemotherapy naive and had a PSA RR of 44% (95% CI 27-62%); 36 men had prior chemotherapy and had a PSA RR of 33% (95% CI 17-50%). In univariable analysis, pre-treatment lactate dehydrogenase (LDH) level &gt;220 U/L (ULN) and a neutrophil-to-lymphocyte ratio (NLR) &gt;5 were both significantly associated with a lack of PSA response. On multivariable analysis, NLR&gt;5 remained significantly associated with lack of a PSA response (Table 1A). Men were then stratified into three groups according to these two variables. These groups were significantly associated with RRs (Table 1B). PSA RR was not found to be associated with the Gleason score, initial stage, time from initial diagnosis to mCRPC or to AA initiation, prior ketoconazole or docetaxel treatment, pre-treatment alkaline phosphate or PSA doubling time. Conclusions: A pretreatment NLR&gt;5 and an LDH&gt;ULN were both strongly associated with a lack of PSA response to AA. These factors may be key in stratifying men into different response groups to AA. [Table: see text]