tbuckley/cabot-search huggingface dataset:
Abstract 920: COP1 E3 ligase regulates response to oncogenic MAPK pathway inhibition
Authors: Manasi K. Mayekar, Luping Lin, Trever G. Bivona
Journal: Cancer Research (2018)

Abstract Oncogenically activated RAS-MAPK pathway is the driver of several cancers including the majority of non-small cell lung adenocarcinomas (NSCLC). RAS-MAPK pathway is activated in NSCLC tumors via diverse genetic alterations in upstream receptor tyrosine kinases such as EGFR and ALK as well as in RAS, BRAF, MEK and RAS GTPase activating protein (GAP) and tumor suppressor, NF1. Molecular targeting of players of RAS-MAPK pathway can elicit an initial tumor response in many patients. However, most patients show an incomplete response and some fail to respond despite the presence of RAS-MAPK pathway activating genetic lesion in the tumor. Hence, it is important to understand the molecular basis of response and resistance to targeted therapies inhibiting the RAS-MAPK pathway in lung adenocarcinomas in order to improve patient survival. We conducted a genetic screen to identify regulators of response to MAPK pathway inhibition in lung adenocarcinomas. Our genetic screen uncovered the E3 ubiquitin ligase COP1/RFWD2 as a novel modulator of response to inhibition of RAS-MAPK pathway. We found that depletion of COP1 and members of its complex, as well as proteasomal subunits, confers resistance to RAS-MAPK pathway inhibition in human lung adenocarcinoma cells with oncogenically activated RAS-MAPK pathway. Interestingly, oncogenic targets of COP1 include MAPK pathway effectors, presence of which has been shown to support the survival of cancer cells with oncogenically activated MAPK upon inhibition of the RAS-MAPK pathway. Hence, we tested if depletion of COP1 alters the levels of those oncogenic substrates. Excitingly, we observed a substantial impact of COP1 depletion on the levels of certain effectors in the presence of RAS-MAPK inhibitors in genetically diverse NSCLC cells and also in oncogenic-BRAF driven melanoma cells. Our studies suggests that depletion of COP1 confers resistance to MAPK pathway inhibition in RAS-MAPK pathway driven cancers through accumulation of specific MAPK pathway effectors. This work has improved our understanding of the molecular basis of tumor cell resilience during initial treatment as well as of primary treatment resistance. Additionally, we are examining if levels of COP1 could be a biomarker for predicting response to RAS-MAPK pathway inhibitor therapy. We will also determine if the resistance-conferring COP1 substrate could be cotargeted along with RAS-MAPK pathway to improve the patient response in RAS-MAPK pathway driven lung adenocarcinomas and other cancers with low levels of COP1. Citation Format: Manasi K. Mayekar, Luping Lin, Trever G. Bivona. COP1 E3 ligase regulates response to oncogenic MAPK pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 920.
Abstract 5038: Comparison of the dose response of malignant peripheral nerve sheath tumor in vitro growth inhibition of 30 drugs to reported Cmax values
Authors: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann
Journal: Cancer Research (2017)

Abstract In this study we aim to identify drugs that can be repurposed to inhibit malignant peripheral nerve sheath tumor (MPNST), a rare and deadly sarcoma associated with Neurofibromatosis type 1 (NF1). Inhibition of MPNST cell growth in vitro was tested for 30 drugs that have previously been through human clinical trials such that the maximum concentration of compound in human serum (Cmax) at the maximum tolerated dose has been determined. Drugs were compared to the chemotherapeutic doxorubicin. Six MPNST cell lines from human and mouse were tested and dose response curves were compared to Cmax for each drug. For most compounds tested, inhibition of MPNST viability occurred at drug concentrations higher than Cmax. Doxorubicin was one of the best compounds tested. Several compounds with less specific molecular targets appear promising, however, currently available inhibitors of receptor tyrosine kinase signaling pathways required concentrations above Cmax to inhibit MPNST viability. These data suggest that difficulty in developing therapy for MPNST may be due to the requirement for high concentrations of drugs to inhibit MPNST cells. Citation Format: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann. Comparison of the dose response of malignant peripheral nerve sheath tumor in vitro growth inhibition of 30 drugs to reported Cmax values [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 5038. doi:10.1158/1538-7445.AM2017-5038
Inhibition of FAK Exerts Anti-Leukemic Activity and Potentiates ABT-199-Induced Apoptosis in AML
Authors: Xiangmeng Wang, Po Yee Mak, Hong Mu, Xuejie Jiang, Duncan Mak, Jonathan A. Pachter, David T. Weaver, Bing Xu, Michael Andreeff, Bing Z Carter
Journal: Blood (2016)
Abstract 3863: A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas
Authors: Sriram Venneti, Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley Margol, Pooja Panwalkar, Abhijit Paroloia, Melike Pekmezci, Richard Mc Eachin, Marcin Cieslik, Benita Tamrazi, Benjamin Garcia, Gaspare La Rocca, Mariarita Santi, Peter Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B. Thompson, Arul Chinnaiyan, Alexander R. Judkins
Journal: Cancer Research (2017)

Abstract Pediatric posterior fossa ependymomas are poorly understood childhood brain tumors and have no effective treatments. The biology of these tumors is obscure as recent sequencing efforts suggest that they lack recurrent genetic alterations. A subset of these tumors termed PF-A ependymomas exhibits CpG-island hypermethylation implicating epigenetic alterations in their pathogenesis. Through comprehensive analyses of histone modification, we discovered global H3K27me3 reduction in a subset of these tumors. Tumors with lowered H3K27me3 showed many clinical and biologic similarities with PFA-ependymomas. Global reduction in H3K27me3 is likewise observed in pediatric gliomas that bear histone H3K27M mutations termed diffuse intrinsic pontine gliomas (DIPG) that also arise in the posterior fossa of young children. Analyses of ependymomas with reduced H3K27me3 and H3K27M mutant DIPGs showed many similarities in DNA methylation and enrichment of H3K27me3 in many genomic loci important for neuroglial specification. Combined integrative analysis of both tumor types uncovered common epigenetic deregulation of select factors that control radial glial biology and radial glia in the developing posterior fossa showed reduced H3K27me3. Finally, PF ependymomas with lowered H3K27me3 were more invasive radiologically and exhibited poor prognosis in three independent cohorts (P&amp;lt;0.001 in all three cohorts, collective n&amp;gt;300). These data have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymomas. Citation Format: Sriram Venneti, Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley Margol, Pooja Panwalkar, Abhijit Paroloia, Melike Pekmezci, Richard Mc Eachin, Marcin Cieslik, Benita Tamrazi, Benjamin Garcia, Gaspare La Rocca, Mariarita Santi, Peter Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B. Thompson, Arul Chinnaiyan, Alexander R. Judkins. A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas [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 3863. doi:10.1158/1538-7445.AM2017-3863
Abstract 3705: Targeting interleukin-1 to increase cetuximab efficacy in head and neck cancer
Authors: Madelyn Espinosa-Cotton, Ayana J. McLaren, Adam T. Koch, Andrean L Simons
Journal: Cancer Research (2017)

Abstract Treatment for head and neck squamous cell carcinoma (HNSCC) patients includes the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab. However, response to cetuximab is low and resistance remains a critical issue. Therefore, it is imperative to develop strategies to enhance tumor response to this drug. Inflammation plays an important role in tumor progression by increasing the release of cytokines that promote tumor cell survival. Our prior work has shown that a variety of pro-inflammatory cytokines involved in tumor survival are upregulated upon treatment with EGFR inhibitors in HNSCC cells, suggesting that poor tumor response to EGFR inhibitors may be due to increased tumor-associated inflammation. Our lab has shown that the increased proinflammatory tumor response due to EGFR inhibition may be activated by interleukin-1 (IL-1) signaling, suggesting that the IL-1 pathway may be an important target to enhance the efficacy of anti-EGFR therapy. Here we investigated the effect of IL-1 blockade on HNSCC tumor response to cetuximab treatment. We found that cetuximab induced IL-6 secretion from SQ20B HNSCC cells and knockdown of the adapter protein MyD88, which is essential for IL-1 signaling, suppressed IL-6 secretion at baseline and in response to cetuximab treatment. Similarly, knock down of the IL-1 receptor (IL-1R) decreased baseline and cetuximab-induced IL-6 secretion, although IL-1R knockdown did not improve response to cetuximab in SQ20B xenografts in vivo. We additionally blocked IL-1 signaling using a recombinant IL-1R antagonist (IL-1RA). IL-1RA pre-treatment reduced baseline and cetuximab-induced IL-6 secretion in vitro. Although IL-1RA did not significantly enhance SQ20B tumor response to cetuximab, IL-1RA as a single agent significantly suppressed tumor growth in female mice but not in male mice. Finally, treatment with a human-specific neutralizing IL-1 alpha (IL-1α) antibody (but not IL-1 beta (IL-1β)) reduced baseline and cetuximab-induced IL-6 secretion in vitro, and significantly increased SQ20B tumor response to cetuximab in vivo. Altogether we propose that targeting IL-1α specifically may be a viable strategy to improve HNSCC tumor response to cetuximab. Citation Format: Madelyn Espinosa-Cotton, Ayana J. McLaren, Adam T. Koch, Andrean L, Simons. Targeting interleukin-1 to increase cetuximab efficacy in head and neck 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 3705. doi:10.1158/1538-7445.AM2017-3705
Abstract 16017: Mid-term Outcomes in Persistent and Long-standing Persistent Atrial Fibrillation Patients Undergoing Rotor Ablation
Authors: Carola Gianni, Tamara Metz, Luigi Di Biase, Sanghamitra Mohanty, Chintan Trivedi, Yalçin Gökoglan, Mahmut F Günes, Rong Bai, Amin Al-Ahmad, J D Burkhardt, Joseph G Gallinghouse, Rodney Horton, Patrick M Hranitzky, Javier E Sanchez, Gery Tomassoni, Philipp Halbfaβ, Patrick Müller, Anja Schade, Thomas Deneke, Andrea Natale
Journal: Circulation (2015)

Introduction: Focal impulse and rotor modulation (FIRM)-guided ablation targets localized sources that are thought to sustain AF. We sought to evaluate if acute success of FIRM-guided ablation in patients with non-paroxysmal AF influenced the mid-term ablation outcomes. Methods: This was a multicenter prospective observational study of persistent and LSP AF patients undergoing FIRM ablation in 3 centers. Patients with at least 2 months follow-up were included in the analysis. FIRM was performed alone or in addition to conventional ablation and rotors were ablated as confirmed by their absence during remapping. Acute success was defined as AF termination, organization or slowing 10%. Mid-term success was defined as freedom from AT/AF off antiarrhythmic drugs (AADs) and after a single procedure during the initial follow-up (excluding the 2-month blanking period). Results: A total of 43 patients were enrolled (mean age 62 ± 10; 91% persistent, 9% LSP). Rotors-only ablation was performed in 65% of patients, and in addition to conventional ablation in the remaining 35%. Overall, acute success was achieved in 33% of patients. During a mean follow-up of 5.5 ± 2.4 months, 35% of patients were free of AT/AF off AADs after a single procedure. When comparing patients who underwent rotors-only ablation with those who received additional conventional ablation, mid-term success rates were respectively 25% vs. 53% (P = NS). There was no statistical difference in SR maintenance between patients with and without acute success during FIRM ablation (29% vs. 38%, P = NS). Conclusion: FIRM-guided ablation in persistent and LSP AF was not effective in obtaining AF slowing/organization/termination during the procedure and in preventing mid-term AT/AF recurrences. Acute success did not impact the mid-term success rate.
Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions
Authors: Tiong Yang Tan, Oliver James Dillon, Zornitza Stark, Deborah Schofield, Khurshid Alam, Rupendra Shrestha, Belinda Chong, Dean Phelan, Gemma R. Brett, Emma Creed, Anna Jarmolowicz, Patrick Yap, Maie Walsh, Lilian Downie, David J. Amor, Ravi Savarirayan, George McGillivray, Alison Yeung, Heidi Peters, Susan J. Robertson, Aaron J. Robinson, Ivan Macciocca, Simon Sadedin, Katrina Bell, Alicia Oshlack, Peter Georgeson, Natalie Thorne, Clara Gaff, Susan M. White
Journal: JAMA Pediatrics (2017)

Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.
Abstract 4450: The role of paired-like homeodomain 2B in non-small cell lung cancer progression
Authors: Sheng-Yi Lin, Yu-Han Huang, Yi-Hua Lai, Sung-Liang Yu, Sheng-Fang Su, Tse-Ming Hong, Gee-Chen Chang, Chi-Chung Wang, Jeremy J.W. Chen
Journal: Cancer Research (2017)

Abstract The transcription factor PITX2 (paired-like homeodomain 2) is well known to play an essential role in normal embryonic development. Emerging evidence suggests that PITX2 may be involved in human tumorigenesis. However, the functional role that PITX2 plays in tumor progression remain unclear. In this study, we investigated its function in human non-small cell lung carcinoma (NSCLC). Using real-time quantitative RT-PCR, we demonstrated that PITX2B is the most abundant isoform in lung cancer cells. Enforced expression of PITX2B could promote lung cancer cell morphological change, migration, invasion, anchorage-dependent growth ability and tumorigenesis in xenograft model mice. In addition, nuclear PITX2B localization was correlated with its oncogenic functions and two important nuclear localization signals (NLSs) were identified. Moreover, high expression of PITX2B was associated with poor overall survival (P&amp;lt;0.05) in NSCLC patients. Importantly, silencing of PITX2B by siRNA caused a marked increase in autophagy based on LC3-II, Beclin-1, and p62 protein expression, acridine orange fluorescence of acidic vacuoles and electron microscopic detection of autophagosomes. Furthermore, we found that the autophagy induced by PITX2B knockdown preceded apoptosis in lung cancer cells. Treatment of lysosome inhibitor, NH4Cl, could provide a protective effect that increases cell viability. In conclusion, our studies not only provide new insights into how PITX2B may contribute to the tumor progression in lung cancer but also the autophagy induced by PITX2B knockdown that may be developed as an effective therapeutic strategy for the treatment of lung cancer. Citation Format: Sheng-Yi Lin, Yu-Han Huang, Yi-Hua Lai, Sung-Liang Yu, Sheng-Fang Su, Tse-Ming Hong, Gee-Chen Chang, Chi-Chung Wang, Jeremy J.W. Chen. The role of paired-like homeodomain 2B in non-small cell lung cancer progression [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 4450. doi:10.1158/1538-7445.AM2017-4450
Post-polypectomy bleeding in the English National Health Service Bowel Cancer Screening Programme
Authors: Edmund Derbyshire, Pali Hungin, Claire Nickerson, Matthew Rutter
Journal: Endoscopy (2017)

Abstract Background and study aims Colonoscopic polypectomy reduces colorectal cancer incidence, but is associated with complications including post-polypectomy bleeding (PPB). PPB ranges in severity from minor to life-threatening, making interpretation and comparison difficult. No previous studies have examined PPB rate according to a standardized severity grading system. We aimed to determine the PPB rate stratified by severity grading, explore factors that contribute to PPB severity grading, and describe PPB management. Methods Data relating to PPB were prospectively collected from all colonoscopies performed in one region of the English NHS Bowel Cancer Screening Programme (BCSP) from 06/12/2010 to 15/07/2014. PPB was defined and stratified into major, intermediate, and minor according to BCSP standardized definitions based on the American Society for Gastrointestinal Endoscopy adverse events lexicon. Results A total of 15 285 colonoscopies (23 766 polypectomies) were analyzed. The PPB rate per colonoscopy was 0.44 % (95 % confidence interval [CI] 0.34 – 0.54) and the rate per polypectomy was 0.29 % (95 %CI 0.20 – 0.38); 2.9 % of PPBs were major and 42.6 % were intermediate. Repeat endoscopy occurred in 27.9 % and was the most common reason for bleeding being categorized as of intermediate severity, although therapy was applied in only 36.8 % of these cases. A therapeutic intervention was significantly more common in patients with PPB who had either a hemoglobin drop ≥ 2 g/dL and/or a blood transfusion (P = 0.04, relative risk 3.47, 95 %CI 1.05 – 11.52). Conclusions This study specifically examined colonoscopic PPB rate, stratified using standardized criteria. The rates of PPB were low, with the majority of PPB being of minor severity. Current stratification of PPB severity combines measures of bleed severity with interventions. Using only hemoglobin drop ≥ 2 g/dL and/or blood transfusion as markers of PPB severity may simplify stratification, and allow a better assessment of the necessity and impact of an intervention.
Abstract 3743: Magnetic resonance imaging shrinkage patterns after neoadjuvant chemotherapy for breast carcinomas: Correlation with molecular subtypes
Authors: Tsuyoshi Mori, Kaori Tomida, Mina Kitamura, Sachiko Sakai, Yuki Kawai, Tomoharu Shimizu, Tomoko Umeda, Tomoyuki Ueki, Sachiko Kaida, Toru Miyake, Hiroya Iida, Hiroya Akabori, Naomi Kitamura, Tsuyoshi Yamaguchi, Hiromichi Sonoda, Shigeyuki Naka, Masaji Tani
Journal: Cancer Research (2017)

Abstract Background: Neoadjuvant chemotherapy (NAC) is widely performed for patients with locally advanced breast carcinomas. It is important to obtain precise information using imaging modalities about the distribution of residual carcinomas after NAC to predict the success of breast conserving surgery. However, the relationship between magnetic resonance imaging (MRI) shrinkage patterns and molecular subtypes of breast carcinomas has not yet been investigated. Methods: We analyzed the MRI shrinkage and pathological patterns of residual carcinomas after NAC in 54 consecutive breast carcinomas. The shrinkage patterns were classified into five categories: Type I and II (concentric shrinkage with or without any surrounding lesion), type III (shrinkage with residual multinodular lesions), type IV (diffuse contrast enhancement in the entire quadrant), and non-visualization. Results: The most common MRI shrinkage pattern was type I (39%) followed by non-visualization (26%). The most common pathological shrinkage pattern was type III (33%), followed by type II (28%) and non-visualization (22%). The concordance rates of the MRI patterns of non-visualization and type I were significantly lower than those of the MRI patterns of type II, III, and IV (p = 0.018). Moreover, in the luminal subtypes, the concordance rates of the MRI patterns of non-visualization and type I were significantly lower than those of the MRI patterns of type II, III, and IV (p = 0.026); however, in the non-luminal subtypes, this correlation was not significant. Conclusions: The results of the present study suggest that the cases with MRI shrinkage patterns of non-visualization and type I require caution regarding the surgical margins compared with the other types, especially the luminal subtypes. Citation Format: Tsuyoshi Mori, Kaori Tomida, Mina Kitamura, Sachiko Sakai, Yuki Kawai, Tomoharu Shimizu, Tomoko Umeda, Tomoyuki Ueki, Sachiko Kaida, Toru Miyake, Hiroya Iida, Hiroya Akabori, Naomi Kitamura, Tsuyoshi Yamaguchi, Hiromichi Sonoda, Shigeyuki Naka, Masaji Tani. Magnetic resonance imaging shrinkage patterns after neoadjuvant chemotherapy for breast carcinomas: Correlation with molecular subtypes [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 3743. doi:10.1158/1538-7445.AM2017-3743