tbuckley/cabot-search huggingface dataset:
Abstract 2236: High-throughput screen for chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation
Authors: Vanessa Benham, Debrup Chakraborty, Blair Bullard, Thomas S. Dexheimer, Jamie J. Bernard
Journal: Cancer Research (2017)

Abstract Epidemiological studies have established a link between excess adiposity and cancer risk. Our previous data demonstrate that adipose tissue stimulates the transformation (steps a cell undergoes to become malignant) of both skin and mammary epithelial cells as measured by anchorage-independent growth in soft agar. Therefore, agents that influence growth in soft agar may be used therapeutically for skin and breast cancer prevention. However, soft agar in a 24-well format is unsuitable for high-throughput screens. Our objective was to develop a high-throughput assay to evaluate chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation. We demonstrate that growth in low attachment conditions in a 384-well plate format is strongly correlated with growth in soft agar. We utilized this methodology and discovered the ability of several compounds to inhibit adipose tissue-stimulated transformation. These compounds will be used in vivo in our models of adipose tissue- or HFD-promoted tumor formation. Citation Format: Vanessa Benham, Debrup Chakraborty, Blair Bullard, Thomas S. Dexheimer, Jamie J. Bernard. High-throughput screen for chemopreventative agents that influence adipose-tissue driven epithelial neoplastic transformation [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 2236. doi:10.1158/1538-7445.AM2017-2236
Abstract 3471: Replication of megabase-size alpha-satellite DNA arrays in human centromere
Authors: Indri Erliandri
Journal: Cancer Research (2017)

Abstract Alphoid centromere array is composed by 171 bp AT rich alphoid monomer that tandemly arranged into high order repeat unit up to 4 MB array. Hallmark of centromeric DNA is CENPB box, a 17 bp motif that is a binding site of CENPB. As the chromosomal site that regulates the precise and accurate chromosome segregation, understanding DNA replication in centromere will reveal insight into faithful chromosome segregation that potentially influence cellular behavior in normal and cancer cell. The present of active replicons within alphoid centromere array are detected by enrichment of nsDNA abundance. This finding is supported by evident of Orc2, Cdt1 and Treslin accumulation on the alphoid centromere array. Chromatin fiber analysis revealed that inter origin distance within alphoid centromere array is irregular. CENPB depletion that is affected centromeric chromatin structure enhances DNA replication activity within alphoid centromeric array, indicates centromeric chromatin landscape alteration affected centromeric DNA replication dynamic. Citation Format: Indri Erliandri. Replication of megabase-size alpha-satellite DNA arrays in human centromere [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 3471. doi:10.1158/1538-7445.AM2017-3471
Comparing The Cost Of Talc Pleurodesis Vs. Indwelling Pleural Catheter For Malignant Pleural Effusions: A Detailed Cost Analysis Done Alongside A Randomized Clinical Trial
Authors: Penz, E K Mishra, H E Davies, B J Manns, R F Miller, B C Kahan, N M Rahman
Journal: American Journal of Respiratory and Critical Care Medicine (2013)
Abstract 2202: FABP5 in urinary extracellular vesicles is a potential biomarker of high Gleason score prostate cancer
Authors: Kazutoshi Fujita, Hideaki Kume, Kyosuke Matsuzaki, Atsunari Kawashima, Takeshi Ujike, Akira Nagahara, Motohide Uemura, Yasushi Miyagawa, Takeshi Tomonaga, Norio Nonomura
Journal: Cancer Research (2017)

Abstract Urine collected after prostate massage is a promising source of new biomarkers of prostate cancer, and was reported to contain extracellular vesicles (EVs) that are secreted from prostate cancer cells. EVs are microvesicles secreted from various cell types. EVs contain microRNAs, proteins, and mRNAs and play a role in intercellular communications via the mechanisms of exocytosis and endocytosis. We aimed to discover a new biomarker for high Gleason score (GS) prostate cancer (PCa) in urinary EVs via quantitative proteomics. Material and methods: Urine samples after massage were collected from 18 patients before prostate needle biopsy. Six patients had negative biopsy outcomes, 6 had Gleason score 6 prostate cancer (GS6), and 6 had Gleason score 8 to 9 prostate cancer (GS8-9). Urinary EVs were isolated from urine with ultracentrifuge. Protein extracted from EVs were labeled with 4-plex iTRAQ and liquid chromatography tandem mass spectrometry (LC-MS/MS) was used for proteome analysis. The candidate proteins were quantitated in the independent set by selected reaction monitoring/multiple reaction monitoring analysis (SRM/MRM). Results: Seven proteins increased in patients with PCa compared to those with negative biopsy (ratio &amp;gt; 2.0, p-value &amp;lt; 0.05). Thirteen proteins were chosen for further analysis and verified in 29 independent urine samples (negative [n = 11], PCa [n = 18]) using selected reaction monitoring/multiple reaction monitoring. Among these candidate markers, fatty acid binding protein 5 (FABP5) was higher in the cancer group than in the negative group (p-value = 0.009) and was significantly associated with GS (p-value for trend = 0.011). Conclusions: We applied the proteomic analysis to discover biomarkers in EVs in urine collected after prostate massage. FABP5 in urinary EVs could be a potential biomarker of high GS prostate cancer. Additional large-scale studies are warranted to confirm this finding. Citation Format: Kazutoshi Fujita, Hideaki Kume, Kyosuke Matsuzaki, Atsunari Kawashima, Takeshi Ujike, Akira Nagahara, Motohide Uemura, Yasushi Miyagawa, Takeshi Tomonaga, Norio Nonomura. FABP5 in urinary extracellular vesicles is a potential biomarker of high Gleason score prostate 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 2202. doi:10.1158/1538-7445.AM2017-2202
Novel Radiotherapy Techniques for Breast Cancer
Authors: Julie A. Bradley, Nancy P. Mendenhall
Journal: Annual Review of Medicine (2017)

During the early decades of radiation therapy for breast cancer, local control of disease was documented consistently but, enigmatically, an anticipated impact on breast cancer survival was not observed, leading to confusion in our understanding of the natural history of breast cancer and radiation effects. Now, almost 90 years after its first use in breast cancer, technology developments in diagnostic imaging and radiation therapy have elucidated parts of this enigma. The data now available demonstrate a significant impact of radiation therapy on survival as well as disease control and treatment-related mortality, opening a doorway to understanding the powerful impact of radiation therapy on both breast cancer and critical organs. Efforts are focused on leveraging novel techniques to maximize the benefits of radiation for breast cancer patients.
Abstract 656: PD-L1 expression in primary lesions vs metastatic sites and by demographics in advanced urothelial carcinoma samples
Authors: M Zajac, A M. Boothman, Y Ben, A Gupta, X Jin, J Antal, A Sharpe, M Scott, M Rebelatto, J Walker
Journal: Cancer Research (2017)

Abstract Background: Determination of programmed cell death ligand-1 (PD-L1) expression levels in tumors may help physicians understand which patients (pts) are most likely to respond to anti-PD-1/PD-L1 therapies in urothelial carcinoma (UC). Understanding the impact of different sample types and demographics on PD-L1 expression is important to determine suitability of tumor biopsies for testing. Methods: As of July 24, 2016, 363 pts screened in the UC cohort of Study CD-ON-MEDI4736-1108 (NCT01693562) had tissue available for analysis and 47 pts had provided paired primary and metastatic samples. FFPE samples were tested in a central laboratory with the VENTANA PD-L1 (SP263) Assay using a BenchMark ULTRA instrument. Pts were classified as having either PD-L1 high (PD-L1 expression ≥25% either on tumour cells [TC] or immune cells [IC]) or PD-L1 low/negative (&amp;lt;25% on TC and IC) tumors. PD-L1 high prevalence was reported in primary vs metastatic sites, and by age, sex and race. Results: PD-L1 status was evaluable for 332/363 (91.5%) pts (175/332 [52.7%] PD-L1 high and 157/332 [47.3%] PD-L1 low/negative) whose UC specimens were tested (intent to diagnose [ITD] population). Overall percentage agreement between paired primary and metastatic samples, based on combined TC/IC scoring ≥25%, was 74.5% (95% CI 59.7 - 86.1%). In the ITD population, using only the samples from which patient PD-L1 expression status was determined, PD-L1 high prevalence in primary and metastatic samples was 57.1% and 50.9% respectively (p=0.343, not significant). The proportion of pts with PD-L1 high status was not enriched in any demographic group (Table). Conclusions: Initial data from UC pts in Study 1108 showed similar PD-L1 high prevalence in primary and metastatic lesions and good concordance between paired primary and metastatic samples. These results build optimism that samples obtained from either location could be used to determine PD-L1 status. Further data are needed to confirm these findings. Patients screened for UC cohort with evaluable PD-L1 result - ITD population (n = 332)ParameterPD-L1 high, n (%)P valueAge, years&amp;lt;65 (n=131)73 (55.7%)0.438≥65 (n=201)102 (50.8%)SexMale (n=236)127 (53.8%)0.610Female (n=96)48 (50.0%)RaceAsian (n=52)23 (44.2%)Asian vs White: 0.406Black or African American (n=10)6 (60.0%)White (n=218)113 (51.8%)Other (n=9)4 (44.4%) Citation Format: M Zajac, A M. Boothman, Y Ben, A Gupta, X Jin, J Antal, A Sharpe, M Scott, M Rebelatto, J Walker. PD-L1 expression in primary lesions vs metastatic sites and by demographics in advanced urothelial carcinoma samples [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 656. doi:10.1158/1538-7445.AM2017-656
Abstract 4807:Brafmutations initiate the development of rat gliomas induced by postnatal exposure toN-ethyl-N-nitrosourea (ENU)
Authors: Kaishi Satomi, Qi Wang, Ji Eun Oh, Barbara Hutter, Benedikt Brors, Nicolle Diessl, Hai-Kun Liu, Stephan Wolf, Otmar Wiestler, Paul Kleihues, Bernd Koelsch, Andrea Kindler-Rohrborn, Hiroko Ohgaki
Journal: Cancer Research (2017)

Abstract Purpose A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T -&amp;gt; A mutations in the transmembrane domain of the neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas was unknown. The objectives of this study were to identify driver mutations in ENU-induced rat gliomas. Methods We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one. Results T:A-&amp;gt;A:T and T:A-&amp;gt;C:G mutations, which are typical for ENU-induced mutagenesis, were predominant (41-55% of all somatic single nucleotide mutations). T-&amp;gt;A mutations were detected in all 5 rat gliomas at Braf codon 545 (V545E), which corresponds to the human BRAF V600E. Additional screening revealed that 33 gliomas in BDIV rats and 12 gliomas in BDIX rats all carried a Braf V545E mutation, while peritumoral brain tissue of either strain (n=16) had the wild-type sequence. The gliomas were immunoreactive to BRAF V600E antibody. Conclusions Braf mutation is a frequent early event in the development of rat gliomas caused by a single dose of ENU. Citation Format: Kaishi Satomi, Qi Wang, Ji Eun Oh, Barbara Hutter, Benedikt Brors, Nicolle Diessl, Hai-Kun Liu, Stephan Wolf, Otmar Wiestler, Paul Kleihues, Bernd Koelsch, Andrea Kindler-Rohrborn, Hiroko Ohgaki. Braf mutations initiate the development of rat gliomas induced by postnatal exposure to N-ethyl-N-nitrosourea (ENU) [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 4807. doi:10.1158/1538-7445.AM2017-4807
Abstract PL01-03: Earlier detection as a key to lower cancer death rates
Authors: Bert Vogelstein
Journal: Cancer Research (2017)

Abstract Two disciplines within cancer research—secondary prevention and cancer therapeutics—have historically been viewed as distinct. I will argue that these two disciplines are intertwined and that their joint pursuit is the optimal way to reduce cancer deaths. At present, the preferred way to treat cancers, in fact the only way that generally cures patients, is surgery. It is therefore widely recognized that the detection of cancers prior to the onset of metastasis is vital to reducing cancer deaths. What is less widely recognized is that the detection of metastatic cancers can also be life-saving—as long as this detection occur priors to the formation of bulky metastatic disease. Therapies that only modestly extend life when administered to patients with measurable metastases can be curative when administered to patients with metastatic disease that is present but undetectable by imaging. Such therapies include conventional cytotoxic drugs as well as genome-targeted agents and immunotherapeutics. A new paradigm for designing clinical trials to test such agents in adjuvant settings will be described. Genome-based diagnostic approaches for detecting cancers earlier will be discussed, as these are integral to the design of the next generation of adjuvant trials. In aggregate, these issues support the importance of modulating the focus of cancer research and treatment from patients with advanced disease towards patients with less-advanced disease. They also highlight the importance of developing novel diagnostic approaches that will allow the detection of smaller tumors. Citation Format: Bert Vogelstein. Earlier detection as a key to lower cancer death rates [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 PL01-03. doi:10.1158/1538-7445.AM2017-PL01-03
Abstract 292: Synthesis and characterization of the novel benzylindazole-based BUB1 kinase inhibitor BAY 1816032 with potent anti-tumor activity
Authors: Marion Hitchcock, Anne Mengel, Carl Nising
Journal: Cancer Research (2017)

Abstract BUB1 (budding uninhibited by benzimidazoles 1) is a serine/threonine protein kinase. The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression prior to anaphase. Inhibition of BUB1 kinase represents a novel approach for cancer treatment: whereas cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids), BUB1 inhibition results in aneuploidy and cell death by driving cells through mitosis irrespective of misattached chromosomes. Here, we disclose for the first time the structure and functional characterization of a novel, first-in-class Bub1 kinase inhibitor. Medicinal chemistry efforts resulted in BAY 1816032 featuring high potency, long target residence time and good oral bioavailability. BAY 1816032 is highly selective for BUB1 displaying single digit nanomolar biochemical potency and double-digit nanomolar cellular potency (H2A induced HeLa-cells). Synergistic effects can be observed when BUB1 inhibitor BAY 1816032 is combined with low doses of paclitaxel affecting chromosome segregation and cell proliferation. X-ray data of benzylindoles allowed a better understanding of the binding mode. Further data on structure-activity relationships including pharmacokinetic characterization, drug metabolism and the synthesis of BAY 1816032 and analogues will be presented. These results validate the innovative concept of interference with mitotic checkpoints and justify clinical proof of concept studies evaluating BUB1 inhibitor BAY 1816032 in combination with taxanes in order to enhance their efficacy and to potentially overcome resistance. Citation Format: Marion Hitchcock, Anne Mengel, Carl Nising. Synthesis and characterization of the novel benzylindazole-based BUB1 kinase inhibitor BAY 1816032 with potent anti-tumor activity [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 292. doi:10.1158/1538-7445.AM2017-292
Abstract LB-138: Runx1 enhancer element marks stem cells in multiple organs
Authors: Akihiro Yamamura, Junichi Matsuo, Yi Hui Melissa Lim, Naing Naing Mon, Dede Liana Heng, Michiaki Unno, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito
Journal: Cancer Research (2017)

Abstract Enhancer element (270bp) in the non-coding region between P1 and P2 promoters of Runx1 gene, termed eR1, drives the expression of Runx1 in hematopoietic stem cells (1). This element also targets the expression in stem cells in multiple tissues, including stomach (fundus and corpus) (2), intestine, colon, pancreas, liver, mammary gland and lung. Location of the cells identified by eR1 in each tissue was different from that previously shown by other stem cell markers, such as Lgr5. Nevertheless, in vivo lineage tracing results showed that eR1+ cells are differentiated into all the cell types in the tissue until one year post tamoxifen injection. To demonstrate the stem/progenitor activity in eR1+ cells, we isolated functional units of each organ from eR1-CreERT2; Rosa-tdTomato mice 1 day after tamoxifen injection, dissociated them into single cells and incubated in vitro. Mature organoids were generated from eR1+ cells, suggesting that eR1+ cells have potential to function as stem cells. When we examined the organoids generated from the stomach fundus, all the cells within the organoid showed Tomato color, suggesting they were originated from eR1+ cells. On the contrary, the antral organoids were mixture of Tomato positive and Tomato negative cells. Possible explanation for the mixture of color would be that there are more than one type of stem cells in the antrum and eR1+ and eR1- cells jointly made organoids. Since Lgr5+ stem cells have been described at the base (3) and CCK2R stem cells at +4 position (4) of antrum, whereas eR1+ stem cells are at isthmus of antrum (2), we must examine whether eR1- cells are Lgr5+ cells or CCK2R cells. Interestingly, mixture of eR1+ and eR1- organoids were observed in other GI tract organs. We found that contribution of eR1+ is 100% in proximal stomach and gradually decreased towards rectum (18%). Growth factor requirement of eR1+ stem cells were analyzed by withdrawing each factor. We found that eR1+ stem cells do not require Wnt and jagged1 but eR1- cells require Wnt in antrum. We are studying step-wise carcinogenesis using these organoids. Reference 1. Ng et al. Stem Cells 2010, 28:1869-81. 2. Matsuo J, Yamamura A et al, Gastroenterology 2016, PMID 27670082. 3. Barker et al, Cell Stem Cells 2010, 6:25-36. 4. Hayakawa et al, Gut 2015, 64:544-553. Citation Format: Akihiro Yamamura, Junichi Matsuo, Yi Hui Melissa Lim, Naing Naing Mon, Dede Liana Heng, Michiaki Unno, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito. Runx1 enhancer element marks stem cells in multiple organs [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 LB-138. doi:10.1158/1538-7445.AM2017-LB-138
Abstract 234: Transcriptional Profiling of Neuregulin-Induced Myocardial Recovery After Infarction in Rats and Swine
Authors: Cristi L Galindo, Abigail Murphy, Michael Hill, John Cleator, Ehab Kasasbeh, Anthony O Caggiano, Tom Parry, Douglas B Sawyer
Journal: Circulation Research (2012)

Neuregulin-1 (NRG-1) mediates cell-cell interactions and is a critical growth and developmental signaling molecule in the heart. We have been examining whether the recombinant NRG-1 isoform known as glial growth factor 2 (GGF2) has therapeutic potential for heart failure. In rats and swine with experimental myocardial infarction we have found that GGF2 treatment improves myocardial function and limits progressive myocardial remodeling. To understand potential mechanisms for this effect, we compared gene expression in these animals using microarrays. In rats we compared Sham operated, MI treated with vehicle, and MI treated with GGF2 at a single dose. We found that GGF2 treatment was associated with correction of mitochondrial and metabolic genes altered by MI compared to Sham-operated rats. When compared to 9 published datasets of ∼400 samples from rodents and human heart failure, we identified 563 genes associated with heart failure that were also reversed in expression in response to GGF2. Ingenuity pathway analysis demonstrated clusters of genes associated with energy production and cardiovascular tissue development as particularly enriched in GGF2-treated versus untreated MI rats. In swine our analysis was confined to animals with MI +/- GGF2 treatment at two doses. There were 527 genes altered by GGF2 at both doses compared to untreated controls, with a clear GGF2 dose response. Transcripts altered in response to GGF2 treatment were mainly those associated with extracellular matrix structure and function, MAPK signaling, and p53-mediated apoptosis. Electron microscopy of remote infarct left ventricular tissue from swine confirmed extreme morphological differences in mitochondria from GGF2-treated and vehicle-treated control pigs. Most striking was recovery of intercalated discs in response to GGF2, compared to severe disruption of intercalated disc structures in vehicle-treated control animals.