tbuckley/cabot-search huggingface dataset:
Abstract 4590: Mechanism of PI3K activation by the HER3/ErbB3 receptor
Authors: Nicole Michael, Michael Hopkins, Natalia Jura
Journal: Cancer Research (2016)

Abstract Human epidermal growth factor receptor 3 (HER3, also known as ErbB3) is a receptor tyrosine kinase that lacks catalytic activity but is essential for cellular homeostasis due to its ability to allosterically activate its heterodimeric partners, EGFR and HER2 (also known as HER1/ErbB1 and ErbB2, respectively). HER3 is an important therapeutic cancer target because the signaling emanating from HER3 heterodimers is critical for the progression and maintenance of several human epithelial malignancies. This is primarily due to the potent ability of HER3 to recruit and activate the phosphoinositide 3-kinase (PI3K). This ability has been attributed to the presence of multiple direct binding sites for PI3K located in the intracellular tail of HER3. The advantage of having multiple recruitment sites is unclear and our recent data show that they provide little advantage to the ability of HER3 to activate PI3K. In addition, we have identified an alternative mode by which HER3 can activate PI3K, demonstrating a complex mechanism by which HER3 phosphorylation is coupled to activation of PI3K/Akt signaling pathway. Our results have important implications for therapeutic targeting of a number of human cancers in which HER3/PI3K signaling axis is abnormally activated and contributes to disease progression. Citation Format: Nicole Michael, Michael Hopkins, Natalia Jura. Mechanism of PI3K activation by the HER3/ErbB3 receptor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4590.
Abstract 4530: EpiCapture: Benchmarking commercially available targeted bisulfite-sequencing platforms to gold-standard whole genome bisulfite sequencing
Authors: Miljana Tanic, Simon Rodney, James Barrett, Hannah Parker, Andrew Feber, Stephan Beck
Journal: Cancer Research (2016)

Abstract Genomic DNA methylation is one of the most important epigenetic modifications in eukaryotes necessary for cellular differentiation and plays a crucial role in gene regulation of many oncogenes and tumor suppressor genes. Aberrant DNA methylation at the level of both individual gene promoters and on a genome-wide scale has been heavily implicated in cancer initiation and progression. Whole genome bisulfite sequencing (WGBS) is the gold standard method for studying alterations in DNA methylation at a single base pare resolution. However, the high cost of WGBS is still prohibitive for high-throughput observational studies on large sample cohorts. Moreover, the WGBS data analysis requires substantial IT resources and a complex bioinformatics analysis. Targeted bisulfite sequencing enables a cost-effective and focused analysis of genomic regions of interest where most of DNA methylation alterations occur, such as promoters, CpG islands and shores, and enhancer regions. Currently, there are 2 main approaches for targeted bisulfite sequencing of medium-to-large genomic regions, reduced representation bisulfite sequencing (RRBS) and hybridization-based enrichment. We have performed a comparison of 5 commercially available platforms for RRBS and in-solution hybridization-based enrichment panels. We analyzed a panel of two cancer cell lines (Hela and Coriell NA12878) and a normal blood reference gDNA sample, in duplicate on each platform using recommended sample inputs, and compared the results to WGBS data. Given that sample input requirements differ significantly between RRBS (∼100ng or less), and hybridization based methods (500ng - 1 μg), we have analyzed the normal blood reference gDNA sample at 500ng input in duplicate across all platforms. All samples were sequenced to a ∼30x depth on an Illumina HiSeq 2500 sequencer. We compared the genomic coverage, precision and off-target effects and overall concordance in methylome profiles for each method. In summary, here we provide a comprehensive comparison of the performance of 5 different commercially available methods for medium to large scale targeted bisulfite sequencing, facilitating information to researchers for selection of appropriate method depending on required application. Citation Format: Miljana Tanic, Simon Rodney, James Barrett, Hannah Parker, Andrew Feber, Stephan Beck. EpiCapture: Benchmarking commercially available targeted bisulfite-sequencing platforms to gold-standard whole genome bisulfite sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4530.
Abstract 2743: Finding determinants of PARP inhibitor sensitivity using genome-wide and focused CRISPR screens
Authors: Stephen Pettitt, Dragomir B. Krastev, Feifei Song, Alan Ashworth, Christopher J. Lord
Journal: Cancer Research (2016)

Abstract We are using genomic approaches to study the mechanism of action of targeted cancer drugs, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. One of these drugs, olaparib was recently approved for use in ovarian cancers with germline BRCA1/2 mutations and many other clinical trials with this and other PARP inhibitors are underway. Experimental study of potential resistance mechanisms can inform the ongoing clinical development of these drugs. We previously carried out a loss of function mutagenesis screen in haploid cells, which showed that PARP1 was required for cellular toxicity of olaparib and other PARP inhibitors. This supported the hypothesis that PARP inhibitor toxicity occurs via a poisoning mechanism where inhibited PARP is tightly bound to DNA, forming a toxic lesion. Recently we carried out a similar screen using genome-wide lentiviral CRISPR-Cas9 mutagenesis in diploid cells. Many PARP inhibitor resistant clones had loss of function Parp1 mutations as expected. However, we also isolated a point mutation affecting a single amino acid in the Parp1 DNA binding domain. This mutant encodes a stable Parp1 protein that cannot bind DNA and does not become trapped in the presence of inhibitors. Thus the CRISPR screen implicated PARP1 DNA binding directly in determination of PARP inhibitor toxicity and was extremely informative about the mechanism of action compared to conventional loss-of-function mutagenesis. We extended this approach by synthesising a high-density focused sgRNA library targeting only PARP1. We developed a reporter cell line that allows us to selectively isolate in-frame mutations that preserve PARP1 protein expression. By deep sequencing mutagenised and appropriately selected cells we identified a series of subtle mutations in PARP1 that result in PARP inhibitor resistance, giving us a detailed insight into structure-function relationships in PARP1. The approach is applicable to other drug targets, providing a framework for understanding drug action and predicting clinical resistance. Citation Format: Stephen Pettitt, Dragomir B. Krastev, Feifei Song, Alan Ashworth, Christopher J. Lord. Finding determinants of PARP inhibitor sensitivity using genome-wide and focused CRISPR screens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2743.
Abstract 3191: Molecular testing in lung cancer: Patient and caregiver experiences
Authors: Jennifer C. King, Maureen Rigney
Journal: Cancer Research (2016)

Abstract Increasingly over the past decade, new targeted therapeutics and immunotherapies with associated companion diagnostics have been approved for the treatment of lung cancer. Lung cancer is often associated with elderly and lower socio-economic populations that may not have a high level of health literacy. As part of a comprehensive needs assessment survey of the lung cancer community, lung cancer patients and their caregivers were asked whether they or their loved ones had undergone molecular testing/biomarker testing as well as asked to report the history of oncologic drugs they had taken. Demographic information and additional cancer treatment history were also collected. Over 300 survey responses were collected. Interim analyses indicated that the majority (68%) of patients currently undergoing active treatment had received molecular testing to help determine their treatment plan. There was a clear improvement in testing rates over time with less than 30% of patients who had completed treatment reporting use of a molecular test. Importantly, there is still an educational gap that needs to be addressed as greater than 20% of patients and greater than 30% of loved ones, including the group who self-identified as the primary caregiver, reported that they did not know whether molecular testing had been performed. In addition, patients reported that they had not received EGFR mutation testing but had taken erlotinib, gefinitib, and/or afatinib. Final results will be presented as well as an analysis of factors that associate with lack of molecular testing. Taken together, these data indicate that there is a critical need for enhanced patient and caregiver education regarding molecular testing. Citation Format: Jennifer C. King, Maureen Rigney. Molecular testing in lung cancer: Patient and caregiver experiences. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3191.
Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus
Authors: Hiddo J.L. Heerspink, Bruce A. Perkins, David H. Fitchett, Mansoor Husain, David Z. I. Cherney
Journal: Circulation (2016)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min –1 ·1.73 m –2 and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate &lt;60 mL·min –1 ·1.73 m –2 ). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and &gt;30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
MDS with Isolated Neutropenia or Thrombocytopenia. Incidence and Characteristics in the Groupe Francophone des Myélodysplasies (GFM) Registry.
Authors: Sophie Park, V. Andrieu, R. Sapena, G. Leroux, A. Stamatoullas, M.P. Callat, O. Beyne-Rauzy, J. Mairesse, M.P. Chaury, Herve Dombret, V. Siguret, Norbert Vey, G. Lepeu, A. Guerci, S. Cheze, Pierre Fenaux, F. Dreyfus
Journal: Blood (2007)
NICE calls for wider supply of condoms to reduce STIs
Authors: Jacqui Wise
Journal: BMJ (2016)

More condoms to tackle rise in STIs

The National Institute for Health and Care Excellence (NICE) has called for free condoms to be given out to men who have sex with men and other high risk groups in order to reduce rates of sexually transmitted infections.1

There were an estimated 435 000 sexually transmitted infections diagnosed in England in 2015, including 200 000 cases of chlamydia. Syphilis and gonorrhoea rates rose by 76% and 53% respectively between 2012 …
Impact of an inpatient palliative consultation in terminally ill cancer patients.
Authors: Radha Krishna Rao Vegunta, Brandon Jamal Blue, Hermina Deepika Fernandes, Satya Upadhyayula, Patricia Burhanna, Miriam B. Rodin, Nishant Poddar
Journal: Journal of Clinical Oncology (2016)

77 Background: Terminally ill cancer patients have complex medical and psychosocial needs at the end of life. Given these complexities, limited data is available to suggest the appropriate timing of palliative care involvement in the treatment of cancer. Our study aims to describe the referral patterns of inpatient palliative care consultations in advanced cancer patients in a tertiary care center. Methods: A retrospective review was performed. Inpatient palliative consultation was obtained in cancer patients from January 1, 2014 to December 31, 2014. Descriptive statistics are used in data analysis. Results: Inpatient palliative care consults (IPCC) were obtained for 245 cancer patients admitted to Saint Louis University Hospital. Of the 245, 130 were male (53.06%), 115 were female (46.93%), 128 were White (52.24%), and 114 were Black (46.53%). Newly diagnosed patients with cancer during the current admission were 79(32.24%). 57 (23.26%) patients were admitted to the Intensive care unit during hospitalization. A total of 39(15.91%) patients died in the hospital; among those who died in the hospital 34 had ICU stay during the hospitalization or died in the ICU (87%). Malignancies most common were lung 71(28.97%) followed by pancreatic-biliary 33(13.4%), lymphoma and leukemia 22(8.9%), hepatocellular carcinoma 18(7.34%), head and neck 16 (6.5%), and upper GI 16 (6.5%). Disposition at discharge included home hospice 67 (28.3%), hospice in facility 27(11%), home without hospice 71(28.9%), facility without hospice 39(15.9%). Conclusions: According to the National Hospice and Palliative Care Organization as of 2013, 7.0% hospice patients die in acute care hospitals. Our data shows 15.9% who received IPCC died in the hospital with 87% dying in ICU. This is likely due to delays in the initiation of palliative care consultation as outpatient leading to increase strain on tertiary referral centers. In another study 22% of eligible Black patients received IPCC. Our rate of IPCC in Blacks was 46.5%. This highlights the disparity in access to outpatient palliative care in this population. Future efforts should be made to promote early outpatient palliative services to reduce ICU admissions, hospital re-admissions and healthcare costs.
Abstract 3331: RP6530, a dual PI3K δ/γ inhibitor attenuates cancer stem cell proliferation in serous adenocarcinoma of ovary
Authors: Sneha S, Nivetha R, Srikant Viswanadha, Swaroop Vakkalanka, Ganesan TS
Journal: Cancer Research (2016)

Abstract The overall survival of patients with advanced serous adenocarcinoma of the ovary (EOC) has not significantly improved for the past 3 decades despite advances in treatment. In part, this is due to resistance of malignant cells and it is currently hypothesized that this could be due to persistence of cancer stem cells (CSC). Elimination of these cells may improve the survival of patients. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor that demonstrated high potency against PI3Kδ (IC50 = 25 nM) and γ (IC50 = 33 nM) enzymes with selectivity over α (&amp;gt;300-fold) and β (&amp;gt;100-fold) isoforms. A Phase-1 dose-escalation study to evaluate the safety and efficacy of RP6530 in patients with hematological malignancies in currently underway at several sites in Europe. The objective of this study was to test the efficacy of RP6530 against the CSC of EOC. A spheroid assay enriched for CSC was employed for this study. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5 μM RP6530. In addition, MTT assay for cell viability was performed for the molecule to evaluate for non-selective cytotoxicity. To confirm that the target was CSC, we performed analysis of Side population (SP) based on H33342 dye exclusion. In the screening assay (triplicate and repeated thrice), RP6530 significantly inhibited spheroid formation in PEO4 and OVCAR-5 (p&amp;lt;0.05) and CAOV-2 (p&amp;lt;0.0005). In the cell viability assay, RP6530 had no cytotoxic effect in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of SP cells with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a reduction in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Further in vitro and in vivo experiments are ongoing to conclusively prove this effect. Citation Format: Sneha S, Nivetha R, Srikant Viswanadha, Swaroop Vakkalanka, Ganesan TS. RP6530, a dual PI3K δ/γ inhibitor attenuates cancer stem cell proliferation in serous adenocarcinoma of ovary. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3331.
Abstract 5270: The UCSC Xena system for integrating and visualizing functional genomics
Authors: Mary Goldman, Brian Craft, Jingchun Zhu, Teresa Swatloski, Melissa Cline, David Haussler
Journal: Cancer Research (2016)

Abstract UCSC Xena (http://xena.ucsc.edu/) is a bioinformatics tool to visualize functional genomics data from multiple sources simultaneously, including both public and private data. The Xena system consists of a set of federated data hubs and the Xena browser, which integrates across hubs, providing one location to analyze and visualize all data. The lightweight Xena data hubs are straightforward to install on Windows, Mac and Linux operating systems and easily allow hub administrators to authenticate users, ensuring that only authorized users have access to secure data. Loading data into a Xena hub is easy using either our application or command line interface. Hosting public data from major projects, such as TCGA, on public Xena hubs gives users access without having to download these large datasets. The Xena system makes it easy to aggregate across many hubs, allowing users to integrate public datasets and private secure data together or view them separately. This system of the browser and hubs helps researchers combine new or preliminary results from their laptops or internal servers, or even data from a new paper, securely with vetted data from the public sphere. The largest public Xena hub, based at UCSC, currently hosts an expanding set of searchable data, including 806 public datasets from several large consortiums including TCGA (The Cancer Genome Atlas), ICGC (International Cancer Genome Consortium), Treehouse Childhood Cancer Project, CCLE (Cancer Cell Line Encyclopedia), and more. Xena hubs are flexible enough to handle most data types, including gene, exon, miRNA and protein expression, copy number, DNA methylation and somatic mutation data along with phenotypes, subtype classifications and genomic biomarkers. Dynamic Kaplan-Meier survival analysis helps investigators to assess survival stratification by any information while scatter plots and bar graphs offer new insights into the data. Integration with Galaxy gives users access to a myriad of bioinformatics tools for further analysis and hypothesis testing. Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, Teresa Swatloski, Melissa Cline, David Haussler. The UCSC Xena system for integrating and visualizing functional genomics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5270.
Abstract 2991: Inhibition of Rac1 GTPase activity by SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10
Authors: Rodney Balhorn, Arjan J. van Adrichem, Saphon Hok, Monique C. Balhorn
Journal: Cancer Research (2016)

Abstract SH7139, the first in a series of selective high affinity ligand (SHAL) therapeutics designed to treat non-Hodgkin's lymphoma, has been shown to be selectively cytotoxic to lymphoma cells over-expressing HLA-DR10. Recent efforts to elucidate the mechanisms of action of SH7139 show that the small molecule drug functions similar to both an antibody drug conjugate and a pro-drug. SH7139 is comprised of three small molecule recognition elements that, when linked together, collectively target the drug to HLA-DR10. Following its binding to HLA-DR10, SH7139 is shuttled into the interior of the lymphoma cell where the subsequent metabolism of these recognition elements releases a series of metabolites that inhibit multiple activities required for tumor cell growth and replication. Studies performed using the Burkitt's lymphoma cell line Raji have shown that SH7139 is metabolized by Raji cells, and the metabolic cleavage of two of the recognition elements (Ct and Dv) produce cytotoxic compounds that contribute to tumor cell killing. While the third recognition element, Cb, is not cleaved off the SHAL scaffold or hydrolyzed to release a cytotoxic metabolite, its structural similarity to known inhibitors of the GTPase activating protein (GAP) MgcRacGAP suggested that it might be active in this pathway. MgcRacGAP functions as a switch that stimulates by many orders of magnitude the activity of the Rac1 GTPase, which is required for cleavage furrow formation, ingression, and the completion of cytokinesis. Experiments conducted with the MgcRacGAP-Rac1 complex have shown that the intact SH7139 molecule (IC50 = 10.6±1.6μM) as well as SH7139 fragments containing the Cb recognition element is effective in inhibiting the GTPase activity of the MgcRacGAP:Rac1 complex. These results confirm that one mechanism action of SH7139 is the inhibition of the Rac1-dependent effector pathways that control the rounding of cells undergoing mitosis, confine Rho activation to the equator of the cell for proper cleavage furrow formation and other processes involved in the completion of cytokinesis. This research was supported by the National Cancer Institute Phase II SBIR award R44CA159843 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. Citation Format: Rodney Balhorn, Arjan J. van Adrichem, Saphon Hok, Monique C. Balhorn. Inhibition of Rac1 GTPase activity by SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2991.