tbuckley/cabot-search huggingface dataset:
Abstract 5116: Identification of new treatment options for Merkel cell carcinoma using high throughput chemical screening
Authors: Tara Gelb, Daniel Urban, Kenneth Daily, Ying Xiao, Min Shen, Matthew Hall, Isaac Brownell
Journal: Cancer Research (2017)

Abstract Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer with limited treatment options. Approximately 80% of MCC tumors have Merkel cell polyomavirus (MCPyV) DNA integrated into the host genome, and viral oncogenes are thought to drive carcinogenesis. In contrast, MCPyV-negative (MCPyV-) tumors have higher rates of proto-oncogene mutations. Transcriptome differences between MCPyV+ and MCPyV- tumors further suggests divergent underlying pathologies. In order to develop efficacious treatments for MCC and elucidate the pathophysiologies underlying MCPyV+ and MCPyV- MCC, we screened the effects of mechanistically annotated drug libraries on MCC cell viability (CellTiter-Glo). We screened ~4,500 compounds including the NCGC Pharmaceutical Collection of approved and investigational drugs and the oncology-focused MIPE (Mechanism Interrogation PlatE) library against six MCC cell lines (3 MCPyV+ and 3 MCPyV-). We ran follow-up screens on the above cell lines as well as non-MCC control cells to identify agents that specifically reduced viability in MCC. DNA topoisomerase inhibitors, proteasome inhibitors, and PI3K inhibitors potently and efficaciously reduced viability in all MCC cell lines tested. Moreover, using hierarchical clustering we found that viral status impacted pharmacological responses. For example, a subset of HDAC inhibitors were more potent in MCPyV+ than MCPyV- MCC cells. In contrast, a dual RasGAP/ERK inhibitor more potently reduced viability in MCPyV- MCC cells relative to MCPyV+ MCC cells. Together these results identify existing drugs that can be repurposed for treating MCC. Moreover, they help elucidate the distinct pathophysiology driving MCPyV+ and MCPyV- MCC. Citation Format: Tara Gelb, Daniel Urban, Kenneth Daily, Ying Xiao, Min Shen, Matthew Hall, Isaac Brownell. Identification of new treatment options for Merkel cell carcinoma using high throughput chemical screening [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 5116. doi:10.1158/1538-7445.AM2017-5116
Abstract 1000: Estrogen receptor coactivator MED1 in breast tumorigenesis and therapeutic resistance
Authors: Xiaoting Zhang
Journal: Cancer Research (2017)

Abstract Recent studies have established Mediator Subunit 1 (MED1) as a key ER transcriptional coactivator for in both normal mammary gland development and breast cancer. Significantly, the MED1 gene is located at the chromosome 17q12 region, also known as the HER2 amplicon, and co-amplifies with HER2 in almost all instances. Importantly, we found that MED1 serves as a key crosstalk point for the HER2 and ER pathways in anti-estrogen resistance of breast cancer. Significantly, MED1 expression highly correlates with poor disease-free survival of breast cancer patients; and most recent studies have discovered increased frequency of MED1 mutations in circulating tumor cells of human patients following anti-estrogen and anti-HER2 treatments. To determine the role of MED1 in HER2-driven tumorigenesis, we have crossed the MMTV-HER2 mammary tumor model with our established MED1 mutant knockin and newly generated MED1 mammary specific overexpression mouse models. Collectively, our studies revealed critical roles for MED1 in tumor progression, metastasis, cancer stem cell formation and therapeutic resistance in HER2-mediated mammary tumorigenesis. These studies not only for the first time reported key roles for a HER2 amplicon co-amplified gene in HER2-driven tumorigenesis but also support MED1 as a potential therapeutic target. To test that, we have assembled highly innovative RNA nanotechnology-based pRNA-HER2apt-siMED1 nanoparticles. We found these RNA nanoparticles have a very high Tm value, and is ultra-stable under RNase A, 8 M urea, serum and PBS conditions. Importantly, pRNA-HER2apt-siMED1 nanoparticles could specifically target HER2+ human breast cancer, efficiently deplete the expression of MED1 and decrease ER-mediated gene transcription both in vitro and in vivo. Most significantly, pRNA-HER2apt-siMED1 nanoparticles not only greatly reduce the growth, metastasis and cancer stem cell formation of HER2+ breast cancer, but are also able to overcome their therapeutic resistance. (This work is supported by Susan G. Komen for the Cure Foundation Career Catalyst Grant, American Cancer Society Research Scholar Grant and NIH/NCI Grant Number R01CA197865). Citation Format: Xiaoting Zhang. Estrogen receptor coactivator MED1 in breast tumorigenesis and therapeutic resistance [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 1000. doi:10.1158/1538-7445.AM2017-1000
Abstract 3574: A survey of mutations in biomedical literature using a machine based approach
Authors: Takahiko Koyama, Kahn Rhrissorrakrai, Laxmi Parida
Journal: Cancer Research (2017)

Abstract Introduction: Being able to characterize mutations for both pathogenicity and drug response is indispensable to the analysis of tumor genomics and the development of therapeutic options. While a great deal of data has been deposited in various structured, genomic databases, a large portion of insights are primarily and often times solely found in biomedical literature. Medline contains about 26 million literature citations; a number that is unrealistic for a human to read. Thus machine based approaches are needed to comprehensively capture the landscape of reported mutations. Method: An automated pattern matching method is utilized to extract mutations from Medline abstracts as presented in Human Genome Variation Society (HGVS) format and RefSNPs (rs) number. A typical HGVS protein mutation is described as [reference amino acid][position][new amino acid], as in p.His1047Arg, His1047Arg, or simply H1047R in HGVS format. This method identifies and consolidates all mentioned protein mutations and their alternate formulations. Result: Over 300,000 unique abstract-mutation pairs were identified including 90,000 unique mutations. Well known cancer mutations such as BRAF V600E, JAK2 V617F and EGFR L858R are among the most frequent appearing in oncology literature. At the other end, 51,000 mutations are mentioned in just a single abstract, 16,000 mutations in two abstracts, 7,600 in three abstracts, and so forth. Conclusion: The number of mutations appearing in Medline abstracts represents just a small portion of the 2 million unique coding mutations contained in the COSMIC database. While we expect the actual coverage of mutations by literature to be more comprehensive if this approach is extended to the full text body, the number would likely remain small compared with the total reported COSMIC mutations. One of the great challenges in oncology is characterizing variants of unknown significance (VUS), and by first extracting all reported mutations, even those mentioned in only one article, and their specific biological context, we can begin to identify broader patterns in mutations’ pathogenicity and their impact on drug response. Citation Format: Takahiko Koyama, Kahn Rhrissorrakrai, Laxmi Parida. A survey of mutations in biomedical literature using a machine based approach [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 3574. doi:10.1158/1538-7445.AM2017-3574
Abstract 2152: Protein phosphatase Mg2+ and Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated p53-induced signals
Authors: Li-Ching Chen
Journal: Cancer Research (2017)

Abstract Previously we demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy. Citation Format: Li-Ching Chen. Protein phosphatase Mg2+ and Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated p53-induced signals [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 2152. doi:10.1158/1538-7445.AM2017-2152
Abstract P333: A Study of Miniature Catheters' Spatial Electric Field Heterogeneity During Murine Cardiac Catheterizations
Authors: Stelios Angeli, Richard Mean, Christakis Constantinides
Journal: Circulation Research (2011)

Conductance catheters allow real-time quantification of hemodynamics, allowing cardiac functional characterization, an important predictor of long-term prognosis in cardiac disease. The technique’s accuracy is, however, inherently limited by the signal contribution from surrounding structures (spatially and temporally varying). Despite prior attempts to quantify this effect (known as parallel conductance) no prior study assessed the spatial heterogeneity of the catheter's E-field. This study quantifies the E-field penetration pattern, accounting for tissue properties and geometry. Ten C57BL/6J mice were induced and maintained with 1.5% isoflurane mixed in 100% O 2 . One C57BL/6J mouse underwent a right carotid catheterization for placement of a 1.4 Fr Pressure-Volume Millar catheter in the left ventricle (LV), followed by microCT imaging (80kV/160mA/10ms exposure/240 projections/rotation angle=1.5 o ). Multiphase MRI was performed using a 4D radial spiral pulse sequence (TE=300μs/TR=2.4ms/BW=125kHz/flip angle=45 o /110μm 3 resolution). Segmentation allowed LV myocardial and blood region extractions from MRI and construction of finite element End-Diastolic and End-Systolic models. The catheter’s orientation in the LV was determined from micro-CT image data renditions. Generated LV and blood models were then imported in the software XFdtd and electrical properties were assigned for all materials. Simulations used a 20 μA, 20 kHz sinusoidal current, and ran for a lump component equivalent and a constructed blood-myocardial geometrical model. Specific absorption rate (SAR) maps yielded total tissue deposited power. Simulations show that the catheter’s E-field in lump component and geometrical models, drops to 10% of its peak value at 0.4-0.6mm, and 1.1-2mm, respectively, away from the excitation electrodes. SAR maps yielded a &lt;1% power leakage into surrounding structures at two different myocardial permittivity values of ε r =11844 and 38615. Results from this study map the spatial dependence of the generated catheter E-field. Spatial E-field maps indicate that the field is primarily confined within the ventricular chamber with a relatively uniform spatial pattern, and with &lt;1% of the input power leaking in surrounding structures.
Underreporting of Research Biopsies from Clinical Trials in Oncology
Authors: Christine M. Parseghian, Kanwal Raghav, Robert A. Wolff, Joe Ensor, James Yao, Lee M. Ellis, Alda L. Tam, Michael J. Overman
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Research biopsies are frequently incorporated within clinical trials in oncology and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting. Experimental Design: We identified a cohort of therapeutic clinical trials where research biopsies were performed between January 2005 and October 2010 from an IR database at our institution. Clinical trial protocols were compared with the highest level of corresponding publication as a manuscript or registry report. Results: A total of 866 research biopsies were performed across 46 clinical trials, with a median of 8 patients biopsied/trial and 19 biopsies collected/trial. After a median follow-up time of 4.3 years from trial completion, 36 of 46 trials (78%) reported trial results: published manuscripts (n = 35), or registry report (n = 1). A total of 635 conducted biopsies were reported in 18 of the 46 trials (39%). Six (33%) of these 18 trials underreported the number of biopsies performed. Of 33 trials with mandatory research biopsies, 13 (39%) trials reported on these biopsies. Biopsy complications occurred in 8 trials [n = 39 patients, 6 grade 3/4 adverse events (AE)] but only 1 trial reported these. Factors associated with biopsy reporting included a larger number of biopsies (P ≤ 0.001) and serial biopsies (P &amp;lt; 0.001). Twelve of 16 (75%) trials with &amp;gt;12 biopsies performed reported on these biopsies compared with only 20% (6/30) that performed ≤12 biopsies. Conclusions: Despite ethical obligations to report research biopsies, the majority (61%) of trials do not report results from research biopsies. Complications are rarely reported in these studies. Improved reporting of results and AEs from research biopsies is needed. Clin Cancer Res; 23(21); 6450–7. ©2017 AACR.
Abstract 16935: Underuse of Cardiovascular Prevention and Lifestyle Counseling in Peripheral Artery Disease
Authors: Jeffrey S Berger, Joseph A Ladapo
Journal: Circulation (2016)

Introduction:  Previous studies suggest that cardiovascular prevention medications are underutilized in the setting of peripheral artery disease. Using nationally representative data, we sought to evaluate trends in the medical therapy and lifestyle counseling of PAD in the United States from 2005 through 2012.   Methods:  Data from 1,982 outpatient visits among patients with PAD were obtained from the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS), a nationally representative assessment of office-based and hospital outpatient department practice. We assessed trends in medication use (antiplatelet therapy [aspirin and/or clopidogrel], statins, cilostazol, and ACE-Inhibitors [ACE-I] or Angiotensin receptor blockers [ARB]) and lifestyle counseling (exercise or diet counseling and smoking cessation).   Results:  Over the 8-year period, the average annual number of ambulatory visits in the U.S. for PAD was 3,883,665. Across all visits, mean age was 69.2 years, 51.8% were female and 56.6% were Non-Hispanic white. Comorbid coronary artery disease (CAD) was present in 24.3% of visits. Medication use for cardiovascular prevention and symptoms of claudication was low: any antiplatelet therapy in 35.7% (standard error [SE] 2.7), statin 33.1% (SE, 2.4), ACE-I/ARB 28.4% (SE, 2.0), and cilostazol in 4.7% (SE, 1.0) of visits. Exercise or diet counseling was used in 22% (SE, 2.3) of visits. Among current smokers with PAD, smoking cessation counseling or medication was used in 35.8% (SE, 4.6) of visits. There was no significant change in medication use or lifestyle counseling over time. Compared to visits for patients with PAD alone, comorbid PAD and CAD were more likely to be prescribed antiplatelet therapy (OR 2.6 [1.8-3.9]), statins (OR 2.6 [1.8-3.9]), ACE-I/ARB (OR 2.6 [1.8-3.9]), and counseled for smoking cessation (OR 4.4 [2.0-9.6]).   Conclusions:  The use of guideline recommended therapies in patients with PAD was much lower than expected. These data highlight a clear opportunity to improve the quality of care in this high-risk group of patients.
Ethylenebisdithiocarbamates and Ethylenethiourea: Possible Human Health Hazards
Authors: Paul Houeto, Gabriel Bindoula, Jerome R. Hoffman
Journal: Environmental Health Perspectives (1995)

Humans are exposed to ethylenebisdithiocarbamates (EBDCs) from environmental sources. Exposure to EBDCs is chronic for workers in a variety of industries, where EBDCs are used for their properties as slimicides, vulcanization accelerators, antioxidants, and scavengers in waste-water treatment. EBDCs, and particularly the EBDC metabolite ethylenethiourea, have clearly defined, important toxic effects in various animal species, and there is reason to suspect they are carcinogenic in humans. In the absence of definitive information regarding human risk, further studies need to be done. In the interim, regular surveillance of workers with high levels of exposure to EBDCs, with specific attention to markers of thyroid and hepatic pathology, should be considered.
Abstract 2751: Automatic DNA extraction system can improve theEGFRpoint mutation detection rate of liquid biopsy
Authors: Chiho Nakashima, Akemi Sato, Tomonori Abe, Tomomi Nakamura, Kazutoshi Komiya, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane, Junichi Kato, Mitsuharu Hirai
Journal: Cancer Research (2017)

Abstract The usefulness of liquid biopsy to detect mutations from cancer patients has been well recognized today. However, because the mutation detection rates from plasma DNA were relatively lower than those of tissue re-biopsy, its clinical utility has not been confirmed yet. As previously we reported, we have developed fully automatic high-sensitive point mutation detecting system named mutation-biased PCR and quenched probe (MBP-QP) system for liquid biopsy. Recently, the importance of pre-analytical procedures for plasma DNA anazysis has been highlighted. In this study, we examined whether the automatic DNA extraction system can improve the mutation detection rate in our MBP-QP system. Sixty-one plasma samples were obtained from advanced non-small cell lung cancer patients, and plasma DNA extraction was performed from 200μl plasma by manually (200-M), and 200μl (200-A), 1000μl (1000-A) plasma by automatically. We used silica membrane spin column system for manual DNA extraction, and magnet beads system for automatic DNA extraction procedure. The median DNA concentrations quantified by quantitative real-time PCR of 200-M, 200-A, 1000-A were 4.92, 6.00, 20.1 ng/mL plasma, respectively. In terms of the epidermal growth factor receptor (EGFR) L858R point mutation detection, the sensitivity of 200-M, 200-A, 1000-A were 36.6%, 58.5%, 77.5%, that of the specificity were 93.3%, 100%, 96.7%, and the concordance rates were 60.6%, 76.1%, 85.7%, respectively. The size distribution of automatically extracted plasma DNA represented two peaks characteristics at 170 bp and 5 kb. In this study, we indicate the automatic DNA extraction can improve mutation detection rates in plasma DNA. Citation Format: Chiho Nakashima, Akemi Sato, Tomonori Abe, Tomomi Nakamura, Kazutoshi Komiya, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane, Junichi Kato, Mitsuharu Hirai. Automatic DNA extraction system can improve the EGFR point mutation detection rate of liquid biopsy [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 2751. doi:10.1158/1538-7445.AM2017-2751
Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials
Authors: Alexander Jobs, Shamir R Mehta, Gilles Montalescot, Eric Vicaut, Arnoud W J van't Hof, Erik A Badings, Franz-Josef Neumann, Adnan Kastrati, Alessandro Sciahbasi, Paul-Georges Reuter, Frédéric Lapostolle, Aleksandra Milosevic, Goran Stankovic, Dejan Milasinovic, Reinhard Vonthein, Steffen Desch, Holger Thiele
Journal: The Lancet (2017)
Abstract 3485: Identification and characterization of circular RNAs in cancer
Authors: Charlotte A. Thrue, Andreas Petri, Marianne B. Løvendorf, Karen Dybkær, Dimitrios Papaioannou, Ramiro Garzon, Sakari Kauppinen
Journal: Cancer Research (2017)

Abstract Circular RNAs (circRNAs) are an abundant class of non-coding RNAs that are formed by a backsplice event resulting in formation of covalently closed circular RNA molecules. The efficiency of backsplicing is inferior to linear splicing, however, due to their long half-lives circRNAs can accumulate to high levels in cells. Functional characterization of a few circRNAs has shown that they can act as endogenous microRNA sponges and transcriptional regulators; one example is CDR1as/ciRS-7, which has been shown to act as a sponge for miR-7. However, the functions of most circRNAs are still unknown. To study the potential role of circRNAs in cancer, we identified exonic circRNA candidates by analysing ENCODE RNAseq data from a panel of cancer cell lines. We used chimeric alignment detection implemented in the STAR aligner and subsequent filtering of output files to identify chimeric alignments consistent with circRNA backsplice sites. The circular nature of the identified putative circRNAs was validated by testing their resistance to RNase R digestion, and sequences surrounding the backsplice sites were used as target recognition sequences for designing LNA-modified gapmer antisense oligonucleotides (ASOs) to specifically knock down the circular isoforms of the RNA transcripts. Data from ongoing studies on knockdown of several abundant circRNAs in cancer cell lines, assessment of the specificity of backsplice-targeting ASOs relative to the linear mRNA counterparts, and analyses to identify biological effects of modulating circRNA levels in cultured cells will be presented. Citation Format: Charlotte A. Thrue, Andreas Petri, Marianne B. Løvendorf, Karen Dybkær, Dimitrios Papaioannou, Ramiro Garzon, Sakari Kauppinen. Identification and characterization of circular RNAs in 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 3485. doi:10.1158/1538-7445.AM2017-3485