tbuckley/cabot-search huggingface dataset:
Abstract 5323: Obesity and ovarian cancer survival revisited
Authors: Elisa V. Bandera, Valerie Lee, Bo Qin, Lorna Rodriguez, Bethan Powell, Lawrence H. Kushi
Journal: Cancer Research (2017)

Abstract Research on the impact of obesity on ovarian cancer survival is inconsistent but previous studies did not consider the possible impact of ascites, bowel obstruction, or cachexia, which commonly occur in late-stage disease. We evaluated this association in a cohort study of primary invasive epithelial ovarian cancers diagnosed from 2000-2013 in Kaiser Permanente Northern California (KPNC) (n=1,157). Deaths were identified through December 2014, with median follow-up of 37 months. Proportional hazards regression was used to estimate overall and ovarian cancer-specific mortality, accounting for prognostic variables including age at diagnosis, race, stage, grade, histology, comorbidities, treatment, post-treatment CA125 levels, ascites, and bowel obstruction. There was no evidence of an association between BMI and overall or ovarian cancer-specific survival. However, we found strong effect modification by stage (Pinteraction&amp;lt;.01). Compared to normal pre-diagnosis BMI (18.5-24.9 kg/m2), for women who were obese before diagnosis (BMI≥35 kg/m2) risk of ovarian cancer-specific mortality was increased among those diagnosed at stages I/II (Hazard ratio [HR]: 3.40; 95% confidence interval [CI]: 1.16-9.99), but reduced among those diagnosed with stage IV disease (HR: 0.58; 95%CI: 0.35-0.96). Associations persisted after excluding those diagnosed with cachexia (n=91) and further adjusting for ascites and bowel obstruction, with no evidence of effect modification by these factors. Associations of obesity with ovarian cancer survival differ by stage, with decreased survival among those with localized disease and increased survival among those with late-stage disease. Stage-specific effects of obesity on survival suggest a tailored approach to improve prognosis may be appropriate. Citation Format: Elisa V. Bandera, Valerie Lee, Bo Qin, Lorna Rodriguez, Bethan Powell, Lawrence H. Kushi. Obesity and ovarian cancer survival revisited [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 5323. doi:10.1158/1538-7445.AM2017-5323
Abstract 762: A concordance study of the ArcherDX RevealTMctDNA 28 NGS panel and Biocept’s Target SelectorTMmutation assay using ctDNA collected in Biocept CEE-sureTMblood collection tubes
Authors: Jason C. Poole, Brian Kudlow, Jill Stefanelli, Skyler Mishkin, Anh Pham, Jeff Chen, Veena M. Singh, Josh Stahl, Lyle J. Arnold
Journal: Cancer Research (2017)

Abstract Biocept’s Target Selector technology is a targeted hotspot mutation panel designed to enrich for mutant targets in a large excess of WT DNA. The test is specific to small regions of interest, is highly sensitive, validated down to 7 mutant copies in a background of 14,000 WT at &amp;gt;98% sensitivity. The ArcherDX Reveal ctDNA test is a 28 gene NGS panel that targets key oncogene activating mutations, drug resistance mutations, in addition to full coverage of TP53. The Reveal ctDNA assay utilizes Anchored Multiplex PCR to enrich, tag, and efficiently capture short ctDNA fragments. Both technologies are designed specifically for use with plasma associated ctDNA. We undertook to evaluate the feasibility of using the ArcherDX Reveal ctDNA 28 NGS panel with the DNA extracted from plasma collected with Biocept’s patented blood collection tube which has been validated at room temperature for 4 days for circulating tumor cells and 8 days for ctDNA. The ability to build complex, targeted libraries, free of chemically induced mutations is of major importance for the detection of the vanishingly rare mutations that can be present in the plasma of cancer patients. We found that high quality NGS libraries were produced from plasma collected and stored in the Biocept blood tube, indicating that little damage occurred to the DNA during preservation. In addition, the two methods were found to be highly concordant and complementary when using both mutation positive and negative patient samples. The Target-Selector assay was the more sensitive, however, the ArcherDX panel revealed several additional mutations not targeted by the Biocept Target Selector assay. Citation Format: Jason C. Poole, Brian Kudlow, Jill Stefanelli, Skyler Mishkin, Anh Pham, Jeff Chen, Veena M. Singh, Josh Stahl, Lyle J. Arnold. A concordance study of the ArcherDX RevealTM ctDNA 28 NGS panel and Biocept’s Target SelectorTM mutation assay using ctDNA collected in Biocept CEE-sureTM blood collection tubes [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 762. doi:10.1158/1538-7445.AM2017-762
Abstract 888: Volumetric reconstruction of targeted nanoparticles for superparamagnetic relaxometry
Authors: Sara L. Thrower, Kelsey Mathieu, Wolfgang Stefan, R. Romero Aburto, Zhen Lu, Robert C. Bast, Javad Sovizi, David Fuentes, John D. Hazle
Journal: Cancer Research (2017)

Abstract Superparamagnetic relaxometry (SPMR) is an emerging technology that uses the unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) to detect cancer cells. In order to estimate tumor locations from raw MRX data, we developed an L1 reconstruction algorithm under the assumption that early stage disease is sparsely distributed throughout the anatomy. The approach was previously validated in phantom datasets of known signal locations. Advantages of our method are that the solver does not require the user to input prior information regarding the expected number of tumors or their approximate locations. Additionally, the solver reconstructs a volumetric distribution of detected sources within the field of view. To validate the algorithm for use in preclinical settings, SPMR was performed on SKOV3 ovarian tumor bearing mice (n = 3) with the MRX device over time following an intratumoral injection of anti-Her2 antibody-conjugated 25nm SPIONs (Senior Scientific LLC). The SPMR data was reconstructed with our sparse solver and was found to be highly correlated (r = 0.9978) with the results generated by the commercial software that accompanies the MRX instrument (MSA). Additionally, segmentation of the reconstruction revealed a strong signal (2.0·106 pJ/T) in the area of the tumor and almost no signal in areas outside of the tumor (0.077 pJ/T) at four hours after injection. This result was consistent with our prior observations which have revealed that a large fraction of intratumorally-injected nanoparticles remain localized within the tumor for several hours after injection. Furthermore, these results were consistent with SPMR data collected by measuring tissue samples excised 24 hours after injection, of which the tumor had the highest signal. Thus, our sparse reconstruction algorithm was able to return the expected results without prior information regarding the location of nanoparticles. Future work will focus on quantifying the uncertainty in our reconstruction method, as well as characterizing its stability with increasingly complex nanoparticle distributions and detectability limits. In conclusion, this work represents an important advancement of the SPMR technology by allowing for volumetric reconstructions of bound nanoparticles from in vivo data. Citation Format: Sara L. Thrower, Kelsey Mathieu, Wolfgang Stefan, R. Romero Aburto, Zhen Lu, Robert C. Bast, Javad Sovizi, David Fuentes, John D. Hazle. Volumetric reconstruction of targeted nanoparticles for superparamagnetic relaxometry [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 888. doi:10.1158/1538-7445.AM2017-888
THU0601 Cardiovascular screening among patients with inflammatory arthritis: to what extent do patients follow recommendations?
Authors: AH Kjeldgaard, K Hørslev-Petersen, RD Christensen, J Søndergaard, J Primdahl
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with inflammatory arthritis (IA) have a substantially increased risk for cardiovascular (CV) disease and consequently regular screening is recommended (1). <h3>Objectives</h3> To investigate whether patients with known IA and high CV risk follow the recommendation, given in a nurse-led CV risk screening consultation, to consult General Practice in order to reduce their CV risk. Furthermore to investigate the influence of socioeconomic position and gender. <h3>Methods</h3> A register-based cohort study comprising outpatients at King Christian X9s Hospital for Rheumatic Diseases, Graasten, Denmark, diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or spondylo arthritis (SpA), who had participated in at least one screening consultation based on the EULAR recommendations (1) between 1st of July 2012 and 1st of July 2015. The primary outcome was a consultation with their GP and at least one intervention of relevance for CV risk within 3 months after the screening consultation. <h3>Results</h3> 1266 patients, 18–85 years of age, were included; 72.5% with RA and 27.5% with SpA or PsA. Of the 447 (35%) with high risk of CV disease, 60% consulted GP after the screening visit compared to 55% for the 819 patients with low risk of CV disease. Of the 60% of patients with high risk who consulted their GP, 41% had at least one relevant intervention. Education ≥10 years increased the odds for non-compliance (Odds Ratio [Confidence interval]) (0.72 [0.56;0.92], p=0.01) and age above 65 years increased the odds for compliance (1.50 [1.15;1.95], p=0.03). Income, diagnosis, gender, Low Density Lipoprotein level and systolic blood pressure did not significantly influence the odds to consult their GP after the screening consultation. Among high risk patients, 7.4% had their blood glucose checked at a GP consultation and 6.3% had their blood-pressure measured with at-home equipment after the screening consultation as opposed to 4.8% and 1% among low risk patients. <h3>Conclusions</h3> After a screening consultation, 40% of the patients with high risk of CV disease did not consult their GP at all in the following 3 months. At least 33% of the patients with high risk followed the recommendations to consult their GP and 27% consulted their GP for reasons not possible to clarify in this study. Only age and higher education had a significant influence on the outcome. <h3>References</h3> Peters, M.J., et al., EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis, 2010. 69(2): p. 325–31. <h3>Acknowledgements</h3> We would like to thank The Danish Rheumatism Association and the Henrik Henriksens fund for financial support for this study. <h3>Disclosure of Interest</h3> None declared
The Benefit of Early Preventive Dental Care for Children
Authors: Mark Webman
Journal: JAMA Pediatrics (2017)

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Abstract 325: Pediatric relapsed acute lymphoblastic leukemia patients display enrichment of the PI3K/mTOR pathway and respond to the dual PI3K/mTOR inhibitor PKI-587
Authors: Mohiuddin Gazi, Sausan A. Moharram, Alissa Marhäll, Kinjal Shah, Julhash U. Kazi
Journal: Cancer Research (2017)

Abstract Although significant improvements have been observed in the treatment of acute lymphoblastic leukemia, there is a substantial subset of high-risk T-ALL patients with relatively poor prognosis. T-cell acute lymphoblastic leukemia (T-All) is a hematopoietic malignancy affecting lymphoblast of T-cell lineage which cause lots of hematopoietic cancer related deaths every year all over the world. The current overall cure rates of newly diagnosed childhood ALL are more than 80% in Europe, but approximately 20% of patients relapse due to treatment failure in childhood ALL. Like other leukemia types, alterations of PI3K/mTOR pathway are predominant in T-ALL which is also responsible for treatment failure and relapse. In this study, two different gene expression data sets of relapsed patients also displayed enrichment of the PI3K/mTOR pathway. Out of 88 different inhibitors targeting multiple components of this pathway, we observed that PKI-587 was the most selective to the T-ALL cell line CCRF-CEM. Thus, we characterized the activity of the novel dual PI3K/mTOR pathway inhibitor PKI-587 using CCRF-CEM and Molt3 cells. We observed that PKI-587 blocked proliferation, colony formation and induced apoptosis in the T-ALL cell lines and selectively abrogated PI3K/mTOR without affecting the MAPK signaling. In vivo PI3K/mTOR inhibition delayed tumor progression, and reduced tumor load in a NSG/SCID xenograft mouse model. Since no deceptive body weight decrease was noticed, our conclusion is that this dose is effective and well tolerated. The beneficial effects of PKI-587 on T-ALL cells that has been observed in this study both in vitro and in vivo warrant further investigation. Citation Format: Mohiuddin Gazi, Sausan A. Moharram, Alissa Marhäll, Kinjal Shah, Julhash U. Kazi. Pediatric relapsed acute lymphoblastic leukemia patients display enrichment of the PI3K/mTOR pathway and respond to the dual PI3K/mTOR inhibitor PKI-587 [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 325. doi:10.1158/1538-7445.AM2017-325
Abstract 4721: Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer
Authors: Xue Gong, Zurab Siprashvili, Okyaz Eminaga, Zhewei Shen, Yusuke Sato, Haruki Kume, Yukio Homma, Seishi Ogawa, Paul A. Khavari, Jonathan R. Pollack, James D. Brooks
Journal: Cancer Research (2017)

Abstract Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort (P=0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.4 (CI, 2.1-5.4), P &amp;lt; 0.001; Tokyo HR=9.2 (CI, 2.2-43), P = 0.003], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation. Citation Format: Xue Gong, Zurab Siprashvili, Okyaz Eminaga, Zhewei Shen, Yusuke Sato, Haruki Kume, Yukio Homma, Seishi Ogawa, Paul A. Khavari, Jonathan R. Pollack, James D. Brooks. Novel lincRNA SLINKY is a prognostic biomarker in kidney 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 4721. doi:10.1158/1538-7445.AM2017-4721
Abstract 3934: Bladder cancer tumor heterogeneity: development of a system-level mutation assay
Authors: Katherin Patsch, Naim Matasci, Anjana Soundararajan, John Nicoll, Jonathan Katz, Antonio Sanchez, Erika Feierstein, Christina Van Loy, Zhao Xu, David B. Agus, Mitchell E. Gross, Daniel Ruderman
Journal: Cancer Research (2017)

Abstract Survival rates for patients with muscle-invasive bladder cancer have not improved in the past 20 years, and new therapies are imperative. Intratumor heterogeneity can complicate molecular profiling attempts to optimize therapy for cancers harboring several actionable tumor subclones. To develop personalized treatment strategies, there is a need for assays to measure intratumor heterogeneity in bladder cancers. We conducted a pilot study of two muscle invasive high-grade transitional cell carcinoma cases. We used a comprehensive cancer panel (Thermo Fisher) covering &amp;gt;400 cancer genes to analyze distinct tumor loci and matched normal tissues. Based on the identified somatic mutations, we designed a bladder-specific panel to (1) validate our results with increased coverage, and (2) analyze liquid biopsy samples. Using the comprehensive cancer panel, we sequenced 6 tumor loci to an average sequencing depth of approximately 100x. We detected intratumor heterogeneity in both patients: By applying a combination of frequency-based (minor allele frequency &amp;gt;10%) and probabilistic (probability of difference between observed frequencies due to sampling) filters, we identified 44 credible somatic SNVs, including mutations that were not shared among all three loci. We used these SNVs to design a custom amplicon panel covering 42 SNVs across 38 genes that is suitable for highly fragmented DNA. The custom panel was used to validate the SNVs in the same tumor regions and in liquid biopsy samples from plasma and urine (approximate coverage 6,000x). In both cases, we identified private mutations reported in The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) data collection, reflecting tumor evolution. Liquid biopsy samples from urine revealed all trunk mutations but only 1 out of 5 private mutations. We conclude that tumor evolution can affect distinct loci within bladder tumors, which may not be fully represented in liquid biopsy samples. These results suggest the need for analyzing multiple tumor regions to identify all actionable driver mutations. In the future, we plan to apply our assay to additional foci and patients in order to identify optimal bladder tumor sampling strategies. Citation Format: Katherin Patsch, Naim Matasci, Anjana Soundararajan, John Nicoll, Jonathan Katz, Antonio Sanchez, Erika Feierstein, Christina Van Loy, Zhao Xu, David B. Agus, Mitchell E. Gross, Daniel Ruderman. Bladder cancer tumor heterogeneity: development of a system-level mutation assay [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 3934. doi:10.1158/1538-7445.AM2017-3934
Abstract 5334: Destabilization of EWS-Fli1 protein by deubiquitinase inhibition in Ewing Sarcoma
Authors: Shan Wang, Ralf Kittler
Journal: Cancer Research (2017)

Abstract Background: Ewing Sarcoma is a malignant tumor in bone or soft tissue, and typically in teenagers and young adults. Genetically, 85% of Ewing’s Sarcoma contains the chromosomal translocation [t(11;22)(q24;q12)], which fuses EWSR1 gene from chromosome 11 and Fli1 gene from chromosome 22 and generates an aberrant chimeric protein EWS-Fli1. EWS-Fli1 is essential for cell growth and development in EWS-Fli1 positive Ewing Sarcoma cells. Therefore, targeting EWS-Fli1 could be a promising therapeutic strategy for Ewing Sarcoma. Methods and Results: Currently, the compounds of targeting EWS-Fli1 mainly interfere its interaction with partner or DNA. However, it could be a more potent way to manipulate its protein stability. Firstly, the proteasome inhibitor MG132 could retard the degradation of EWS-Fli1 protein in EWS502 cells and A673 cells, and increase its ubiquitination, which hints the degradation of EWS-Fli1 is through the ubiquitin (Ub)-proteasome pathway (UPP). Then, to identify the protein that interact with EWS-Fli1 and modulate its stability, we selected the candidate deubiquitinase according to literatures and the protein homology. And by co-immunoprecipitation assay, we identified a deubiquitinating enzyme (DUB) binding to EWS-Fli1. RNAi-mediated knockdown or inhibition of EWS-Fli1-DUB with a small molecule compound caused a marked increase in EWS-Fli1 ubiquitination, decreased levels of EWS-Fli1 in a proteasome-dependent manner, and further inhibited the growth of Ewing Sarcoma cells. Conclusion: The findings indicate that EWS-Fli1 could be ablated by inhibiting its specific deubiquitinase in Ewing Sarcoma, which could be a novel treatment approach for Ewing Sarcoma. Citation Format: Shan Wang, Ralf Kittler. Destabilization of EWS-Fli1 protein by deubiquitinase inhibition in Ewing Sarcoma [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 5334. doi:10.1158/1538-7445.AM2017-5334