tbuckley/cabot-search huggingface dataset:
Abstract 2109: Transcriptional analysis of human leukemia cells treated with the experimental anticancer drug laromustine
Authors: Amanda J. Loya, Dylan J. Cincotta, Abdel Elkahloun, David Bodine, Kevin P. Rice
Journal: Cancer Research (2017)

Abstract Laromustine is an experimental anticancer prodrug that demonstrated significant activity against acute myeloid leukemia in human clinical trials. Upon base-catalyzed activation, laromustine yields two reactive, electrophilic species in situ: 90CE, which can chloroethylate the O6 position of guanine in DNA causing lethal interstrand crosslinks, and methyl isocyanate, which can carbamoylate biochemically relevant nucleophiles, such as cysteine sulfhydryl groups. Previous in vitro and ex vivo investigations into laromustine’s molecular mechanism of action reveal several biochemical consequences of methyl isocyanate, many of which may explain either the acute cytotoxicity of the drug’s carbamoylating activity or the observed synergism with the cytotoxicity of guanine O6 chloroethylation. The combined activities of the electrophilic subspecies of laromustine are believed to induce apoptosis in leukemia cells. Presented herein are extensive flow cytometry experiments using FITC-AnnexinV and propidium iodide suggesting a dose-dependent cytotoxicity that includes apoptotosis. So as to gain a more complete understanding of the drug’s toxicity, an investigation into how laromustine modulates gene transcription in HL60 cells is also carried out and reported here. Total mRNA was harvested from cultured HL60 cells treated with sub-lethal doses of laromustine or analogs lacking either carbamoylating or chloroethylating activity. These samples were subjected to GeneChip analyses against control mRNA. More than 4,000 genes were significantly dysregulated upon the cells’ exposure to laromustine. The analog of laromustine possessing only carbamoylating activity caused the dysregulation of nearly 3,000 genes, the vast majority of which were also dysregulated in response to laromustine. 90CE, which lacks carbamoylating activity but retains chloroethylating activity, understood to be principally responsible for therapeutic cytotoxicity, demonstrated very little effect on gene transcription in HL60 cells. Preliminary analysis of gene pathways affected by laromustine suggests that among the altered pathways, those associated with cancer progression, the G1/S checkpoint, and hematological disorders are particularly stressed. The carbamoylating activity of laromustine is responsible for most of these effects. Identifying genetic pathways disrupted by this potentially useful drug may inform clinical strategies or identify potential targets for co-therapeutic agents. Citation Format: Amanda J. Loya, Dylan J. Cincotta, Abdel Elkahloun, David Bodine, Kevin P. Rice. Transcriptional analysis of human leukemia cells treated with the experimental anticancer drug laromustine [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 2109. doi:10.1158/1538-7445.AM2017-2109
Abstract 2381: The effect of ERK5 inhibition in clear cell renal cell carcinoma
Authors: Hidenori Kanno, Sei Naito, Osamu Ichiyanagi, Norihiko Tsuchiya
Journal: Cancer Research (2017)

Abstract Introduction Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and is characterized by von Hippel-Lindau tumor suppressor gene (VHL) mutation. VHL protein acts in a ubiquitin ligase complex, mediating the proteasomal degradation of ubiquitinized proteins, including hypoxia-inducible factor (HIF). Therefore, HIF accumulates in VHL-defective cell lines. A recent study revealed that extracellular signal-regulated kinase 5 (ERK5) is degraded through the ubiquitin-proteasome system, in a process mediated by VHL and HIF. Our objectives were to examine the effects of ERK5 in ccRCC and to investigate ERK5 as a potential therapeutic target. Methods ERK5 expression was investigated in surgically resected ccRCC specimens using immunohistochemistry. To confirm that ERK5 is degraded by the VHL pathway, ERK5 levels were examined by western blotting in Caki-1 VHL wildtype renal cell carcinoma (RCC) cells and in A498 and A704 VHL-mutant RCC cells with or without the MG132 proteasome inhibitor. Furthermore, VHL-mutant cell lines were examined, with or without siRNA and XMD8-92-mediated ERK5 inhibition, to investigate the role of ERK5 in RCC cells using flow cytometry, MTS assays, and western blotting . Results In surgical specimens, RCC cells showed higher levels of ERK5 expression than did normal cells. In addition, MG132 enhanced ERK5 expression in wildtype cell lines, but not in VHL-mutant cell lines. Therefore, ERK5 degradation involves the VHL pathway. Furthermore, ERK5 inhibition resulted in increase of the sub-G1 population as observed by flow cytometry and cleaved RARP expression as seen by western blotting, indicating an increase in apoptotic cells. ERK5 inhibition also suppressed cell viability and downregulated p16 and Bcl-2 expression. Conclusion Our results show that ERK5 inhibition contributes to the downregulation of anti-apoptotic and cell cycle proteins and suggest that ERK5 is a promising therapeutic target for ccRCC. Citation Format: Hidenori Kanno, Sei Naito, Osamu Ichiyanagi, Norihiko Tsuchiya. The effect of ERK5 inhibition in clear cell renal cell carcinoma [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 2381. doi:10.1158/1538-7445.AM2017-2381
Corrigendum re: “Percutaneous Nephrolithotomy: Update, Trends, and Future Directions for Simultaneous Supine Percutaneous Nephrolithotomy and Retrograde Ureterolithotripsy in the Galdakao-modified Supine Valdivia Position for Large Proximal Ureteral Calculi” [Eur Urol 2017;71:837–8]
Authors: Tsung-Yi Huang, Kathy Ming Feng, Ing-Shiang Lo
Journal: European Urology (2017)
Abstract 3048: A noncoding function of TYRP1 mRNA promotes melanoma growth
Authors: Marie-Dominique Galibert, David Gilot, Mélodie Migault, Laura Bachelot, Fabrice Journé, Aljosja Rogiers, Emmanuelle Donnou-Fournet, Ariane Mogha, Nicolas Mouchet, Marie-Laure Pinel-Marie, Bernard Mari, Tristan Montier, Sébastien Corre, Arthur Gautron, Florian Rambow, Petra El Hajj, Rania Ben Jouira, Sophie Tartare-Deckert, Jean-Christophe Marine, Brice Felden, Ghanem Ghanem
Journal: Cancer Research (2017)

Abstract RNAs competition to bind miRNA has been proposed to influence biological systems whether these RNAs are implicated in diseases onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly governs cell proliferation by sequestering miR-16 on non-canonical miRNA response elements (MREs). Consequently, sequestered miR-16 is no longer able to repress its mRNA targets such as RAB17, which we show is involved in melanoma cell proliferation and invasion. Restoration of miR-16 tumor suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression levels. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo using small oligonucleotides that mask miR-16 binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic noncoding function to TYRP1 mRNA and underscore miRNA displacement as a new antimelanoma targeted therapeutic approach. Citation Format: Marie-Dominique Galibert, David Gilot, Mélodie Migault, Laura Bachelot, Fabrice Journé, Aljosja Rogiers, Emmanuelle Donnou-Fournet, Ariane Mogha, Nicolas Mouchet, Marie-Laure Pinel-Marie, Bernard Mari, Tristan Montier, Sébastien Corre, Arthur Gautron, Florian Rambow, Petra El Hajj, Rania Ben Jouira, Sophie Tartare-Deckert, Jean-Christophe Marine, Brice Felden, Ghanem Ghanem. A noncoding function of TYRP1 mRNA promotes melanoma growth [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 3048. doi:10.1158/1538-7445.AM2017-3048
Abstract 1275: Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility
Authors: Liren Zhang, Yanwei Zhang, Rong Li, David W. Chang, Yuanqing Ye, John D. Minna, Jack A. Roth, Baohui Han, Xifeng Wu
Journal: Cancer Research (2017)

Abstract Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatics analyses, The Cancer Genome Atlas (TCGA) project has recently identified panels of genetic mutations that contributed to or associated with the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these highly mutated genes and lung cancer susceptibility. In this multi-phase study, we aimed to comprehensively evaluate the 1655 tagSNPs located in the 127 significantly mutated genes (SMGs) identified by TCGA, and test their association with risk of lung cancer in a total of 7355 patients and 7301 healthy controls. We found that 11 SNPs in 8 genes showed consistent association (P&amp;lt;0.1) and 8 SNPs significantly associated with lung cancer risk (P&amp;lt;0.05) in both discovery and validation phases. The most significant SNP A was associated with a decreased risk of lung cancer (OR=0.91, 95%CI: 0.87-0.96, P=2.3×10-4). Cumulative analysis of the 11 SNPs showed consistently elevated risk with increasing number of unfavorable genotypes (P for trend=1.2×10-10). In stratified analyses, the association of SNP A and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The eQTL-analysis indicated that genotypes of four SNPs significantly correlated with the expression of their genes respectively. From TCGA data, expression of the identified genes were significantly different in lung tumors compared with normal tissues, and the genes’ highest mutation frequency was found in lung cancers. Integrative pathway analysis (IPA) indicated the identified genes were mainly involved in major cell cycle regulatory pathway suggesting the underlying biological processes. In summary, this study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development. Citation Format: Liren Zhang, Yanwei Zhang, Rong Li, David W. Chang, Yuanqing Ye, John D. Minna, Jack A. Roth, Baohui Han, Xifeng Wu. Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility [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 1275. doi:10.1158/1538-7445.AM2017-1275
Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults: 2015 National Survey on Drug Use and Health
Authors: Beth Han, Wilson M. Compton, Carlos Blanco, Elizabeth Crane, Jinhee Lee, Christopher M. Jones
Journal: Annals of Internal Medicine (2017)

Despite the continuing epidemic of opioid misuse, data on the prevalence of prescription opioid use, misuse, and use disorders are limited.To estimate the prevalence of prescription opioid use, misuse, and use disorders and motivations for misuse among U.S. adults.Survey.The 2015 National Survey on Drug Use and Health (NSDUH).72 600 eligible civilian, noninstitutionalized adults were selected for NSDUH, and 51 200 completed the survey interview.Prescription opioid use, misuse, and use disorders.Weighted NSDUH estimates suggested that, in 2015, 91.8 million (37.8%) U.S. civilian, noninstitutionalized adults used prescription opioids; 11.5 million (4.7%) misused them; and 1.9 million (0.8%) had a use disorder. Among adults with prescription opioid use, 12.5% reported misuse; of these, 16.7% reported a prescription opioid use disorder. The most commonly reported motivation for misuse was to relieve physical pain (63.4%). Misuse and use disorders were most commonly reported in adults who were uninsured, were unemployed, had low income, or had behavioral health problems. Among adults with misuse, 59.9% reported using opioids without a prescription, and 40.8% obtained prescription opioids for free from friends or relatives for their most recent episode of misuse.Cross-sectional, self-reported data.More than one third of U.S. civilian, noninstitutionalized adults reported prescription opioid use in 2015, with substantial numbers reporting misuse and use disorders. Relief from physical pain was the most commonly reported motivation for misuse. Economic disadvantage and behavioral health problems may be associated with prescription opioid misuse. The results suggest a need to improve access to evidence-based pain management and to decrease excessive prescribing that may leave unused opioids available for potential misuse.U.S. Department of Health and Human Services.
Abstract 1801: Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts
Authors: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad
Journal: Cancer Research (2017)

Abstract Background: Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors. Methods: R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker. Results: Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors. Conclusions: Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts. Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad. Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts [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 1801. doi:10.1158/1538-7445.AM2017-1801
Abstract 4554: Unified theoretical algorithms for graphics dynamic multiple transformations of dose-effect relationships with computer simulation
Authors: Ting-Chao Chou
Journal: Cancer Research (2017)

Abstract Based on physico-chemical principle of the mass-action law, bio-system analysis (arrangement &amp; combinatorial) several hundred rate equations have been derived and published. Mathematical induction allows the deduction of them into the unified general median-effect equation (MEE) that makes dose &amp; effect “interchangeable” for the 1st order and higher order dynamics. Based on the MEE plot, all dose-effect curves can be “linealized” which allows the quantitative determination of x-intercept (log Dm which signifies potency) and slope (m which signifies shape or dynamic order). Extension of MEE to multi-drug combinations resulted the combination index (CI) theorem which quantifies synergism (CI&amp;lt;1), additive effect (CI=1), and antagonism (CI&amp;gt;1). This unprecedented approach and multi-step logics have been summarized in [Chou TC. Pharmacol Rev 58: 621-681, 2006] which has been cited 1,261 times in 485 bio-medical journals (http://www.researcherid.com/rid/B4111-2009 as of 10.19.2016). Dose-effect curves (single &amp; multi-drugs) can be quantitatively transformed into the MEE plot, Fa-CI plot, isobologram, Fa-DRI Plot for dose-reduction index, and when n&amp;gt;2, the polygonogram. This presentation will illustrate of combinations (1:5) of docetaxel (TXT) with T-compound against HCT-116 colon carcinoma xenograft in nude mice. In all, only 66 nude mice have been used, i.e. TXT 3 doses, T 3 doses and TXT+T 4 doses, plus a control group, each N=6. The MEE “Linearization” allows the “Econo-Green Bio-research”, with small experimental size and small number of data points, using small number of animals. The algorithms based computer simulation using CompuSyn software can be completed within one second after the dose and effect data entries. The CompuSyn has been offered for free download upon registration via www.combosyn.com. Note: This abstract was not presented at the meeting. Citation Format: Ting-Chao Chou. Unified theoretical algorithms for graphics dynamic multiple transformations of dose-effect relationships with computer simulation [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 4554. doi:10.1158/1538-7445.AM2017-4554
Abstract 5001: Functional biomarker discovery from cancer patient serum with PEP technology
Authors: David L. Wang, Guofeng Fu, Micheal Davies, Xing Wang
Journal: Cancer Research (2017)

Abstract Proteins play essential roles in numerous biological processes and being able to pinpoint functional differences between cell or tissue samples can greatly aid in understanding disease processes and metabolic changes. The PEP technology allows systematic analysis of protein functions within a proteome. Hundreds of functional proteins can be separated and functionally assayed to generate a comprehensive three-dimensional landscape of protein families such as protein kinases, phosphatases, proteinases and oxido-reductases. This information can then be integrated into other genomic and proteomic knowledge bases to provide further insight of important biological processes such as cancer development and aging. In the PEP technology, complex protein mixtures are first separated by a modified two-dimensional gel electrophoresis process, giving enhanced resolution while still maintaining protein function. This is followed by an efficient protein transfer to a specially designed 1536-well Protein Elution Plate. After further transfer of the samples from the PEP plate to multiple 384-well microplates, functional assays can be performed on each well to generate an enzyme activity profile displayed in 3-D. Protein components of each well can be further characterized by mass spectrometry if desired. Using the PEP technology, functional biomarker candidates have been identified from lung and breast cancer patient serum. Both qualitative and quantitative differences of metabolic enzymes and proteases were observed when comparing the cancer patient serum and normal serum. Some of the active enzymes were identified by mass spectrometry and validated in selected bioassays. It is believed that this functional proteomics technology provides a unique approach in the discovery of potential cancer biomarkers for diagnostic and prognostic applications. Citation Format: David L. Wang, Guofeng Fu, Micheal Davies, Xing Wang. Functional biomarker discovery from cancer patient serum with PEP technology [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 5001. doi:10.1158/1538-7445.AM2017-5001
Sixty seconds on . . . drinking and diabetes
Authors: Susan Mayor
Journal: BMJ (2017)

That’s what the research says. A Danish study hit the headlines this week, showing that people who drink alcohol three to four days a week had around a 30% lower risk of developing type 2 diabetes than teetotallers.1 The lowest risks of diabetes were in men who consumed 14 alcoholic drinks and women who knocked back nine drinks a week.

Well, the …
Abstract 5543: Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid
Authors: Enrico Garattini, Marco Bolis, Maddalena Fratelli, Mineko Terao
Journal: Cancer Research (2017)

Abstract Background: All-trans retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and Methods: RNA-Sequencing data for 10080 patients and 33 different tumor-types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was performed using machine learning methods and network analysis. Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor-types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor-types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor-types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor-types which are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity. Citation Format: Enrico Garattini, Marco Bolis, Maddalena Fratelli, Mineko Terao. Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid [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 5543. doi:10.1158/1538-7445.AM2017-5543