tbuckley/cabot-search huggingface dataset:
Abstract 5113: A flexible pipeline for precision medicine biomarker detection and prediction of treatment response
Authors: V Keith Hughitt, Sayeh Gorjifard, Aleksandra M. Michalowski, John K. Simmons, Ryan Dale, Eric C. Polley, Jonathan J. Keats, Beverly A. Mock
Journal: Cancer Research (2019)

Abstract Recent years have seen an explosion in the availability of paired molecular profiling and drug screen data, providing an unprecedented opportunity for the development of targeted therapies based on an individual’s genetic background. Despite a number of recent successes in diseases ranging from cystic fibrosis to cancer, significant hurdles remain in our ability to accurately predict treatments based on molecular profiling data. In particular, few such tools exist that allow the integration of heterogeneous data types (e.g. genomic, transcriptomic, and somatic mutations), along with high-throughput drug screen data to make predictions about treatment efficacy. Here, we describe a generalized open-source pipeline developed for the analysis of precision medicine data, Pharmacogenomics Prediction Pipeline, or “P3”. The modular design of P3 enables the inclusion of arbitrary input data types and the selection from multiple alternative machine learning algorithms, while automated statistical and visualization reporting steps incorporated throughout the pipeline assist in parameter tuning and early detection of problematic data components. Molecular profiling data is further enriched by the incorporation of external biological information in the form of pathway and gene set annotations such and Gene Ontology (GO) and The Molecular Signatures Database (MSigDB). To demonstrate the use of P3 for preclinical biomarker prediction, we applied P3 to an unpublished multiple myeloma dataset consisting of exome, RNA-Seq, CNV, and drug screen data for 1,912 compounds across 47 tumor cell lines. Specifically, P3 was used to predict molecular features associated with response to treatment for all drugs where a differential response to treatment was observed across patients. Furthermore, molecular profiling and drug screen data for 267 drugs and over a thousand cell lines spanning multiple cancer types from the Genomics of Drug Sensitivity in Cancer (GDSC) project were analyzed using P3, providing insights into shared mechanisms of drug sensitivity and resistance across different cancer and treatment types. Citation Format: V Keith Hughitt, Sayeh Gorjifard, Aleksandra M. Michalowski, John K. Simmons, Ryan Dale, Eric C. Polley, Jonathan J. Keats, Beverly A. Mock. A flexible pipeline for precision medicine biomarker detection and prediction of treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5113.
Abstract 3637: Development of a polyethylenimine conjugated liner multiblock polymer to deliver VEGF siRNA for triple negative breast cancer
Authors: Yuanke Li, Zhen Zhao, Kun Cheng
Journal: Cancer Research (2019)

Abstract Vascular endothelial growth factor (VEGF) plays important roles in the angiogenesis process and is correlated with high proliferation and metastasis of breast cancer, particularly in triple negative breast cancer (TNBC). Downregulation of VEGF expression with siRNA in cancer cells is therefore a potential strategy for TNBC treatment. A polyethylene glycol based bio-degradable, linear multiblock polymer was synthesized and conjugated with branched low-molecular-weight poly(ethyleneimine) (PEI) to form nanocomplexes with a VEGF siRNA. The nanocomplex can protect siRNA from serum degradation and deliver the VEGF siRNA into TNBC cells with 72% silencing activity and low cytotoxicity. In vitro activity studies showed that the siRNA nanocomplexes significantly inhibit 64% migration and 67% invasion of TNBC cells. Moreover, the nanocomplex exhibited efficient tumor penetration in a 3D tumor spheroid model, suggesting a good penetration capability of the nanocomplex in tumor microenvironment in vivo. More importantly, the VEGF siRNA nanocomplex efficiently inhibit tumor growth in vivo and successfully downregulate VEGF expression in the tumor. These results suggested that VEGF siRNA is a promising anti-tumor agent for TNBC therapy, and the PEI 1800 conjugated bio-degradable multiblock polymer is a promising system to deliver siRNAs to TNBC cells. Note: This abstract was not presented at the meeting. Citation Format: Yuanke Li, Zhen Zhao, Kun Cheng. Development of a polyethylenimine conjugated liner multiblock polymer to deliver VEGF siRNA for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3637.
Abstract 2507: Genetic alterations affecting treatment response in locally advanced breast cancers
Authors: Andreas Venizelos, Stian Knappskog, Inger Marie Loees, Hans Petter Eikesdal, Per Eystein Lønning
Journal: Cancer Research (2019)

Abstract Resistance to chemotherapy remains a main cause of death among cancer patients. The primary aim of the present study was to identify genetic alterations predicting resistance to chemotherapy by whole exome sequencing (WES) of tumors subject to neoadjuvant sequential treatment with epirubicin and docetaxel. A long term goal is to identify biomarkers that may be applicable in testing for drug sensitivity prior to commencement of therapy for individual patients, leading to early administration of optimal treatment and sparing patients from side-effects of inefficient treatment. From a total of 100 patients treated with sequential monotherapy in the neoadjuvant setting, we performed WES on 146 tumor samples and matching blood samples from 51 patients. Biopsies for research were taken before treatment start, at the time of treatment switch and at the time of surgery. In the present work, we have analysed WES data to assess the mutational- and the copy number landscape and compared these results between patients having a good or poor response to the two administered drugs. SNV analysis revealed imbalance in several well established breast cancer related genes, between the different response groups. Copy number assessments revealed a general increase in copy number gains in chromosome 16 and increase of copy number losses in chromosomes 1 and X after treatment with epirubicin, indicating that subclones harbouring different types of CNVs are selected for during treatment. Correspondingly, after treatment with docetaxel we found a general increase of copy number gains in chromosome 8 and an increase of copy number losses in chromosomes 1 and 8. Finally, we assessed overall mutational signatures and observed shifts in these profiles during the two treatments. Citation Format: Andreas Venizelos, Stian Knappskog, Inger Marie Loees, Hans Petter Eikesdal, Per Eystein Lønning. Genetic alterations affecting treatment response in locally advanced breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2507.
FEIBA Global Outcome Study (FEIBA GO) Data Read-out: Real World Bleeding Frequency in Inhibitors Patients on Prophylaxis with APCC
Authors: C. Escuriola Ettingshausen, J. Windyga, C. Hermans, A.R. Cid, S. Rangarajan, A. Rocino, A. Gringeri, R. Crea
Journal: Blood (2017)
Abstract P199: Performance of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations by Socioeconomic Status. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Lisandro D Colantonio, April P Carson, Donald M Lloyd-Jones, Joshua S Richman, George Howard, Virginia J Howard, Monika M Safford, Paul Muntner, David C Goff
Journal: Circulation (2016)

Background: The Pooled Cohort risk equations over predict atherosclerosis cardiovascular disease (ASCVD) risk in some contemporary cohorts but not in others. ASCVD risk differs by socioeconomic status (SES) which may influence the performance of the risk equations. We analyzed the performance of the Pooled Cohort risk equations by SES and tested whether adding SES improves the discrimination of the Pooled Cohort risk equations. Methods: We used data from black and white participants enrolled in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study from 2003 to 2007 (all participants ≥45 years of age). The analysis was restricted to participants for whom ASCVD risk may lead to consideration of statin initiation (45-79 years of age without ASCVD or diabetes, LDL cholesterol 70-189 mg/dL, and not taking lipid-lowering medications, N=10,231). SES was assessed using data on living alone, education and household income. Incident ASCVD (fatal/non-fatal stroke, MI or CHD death) was adjudicated through December 2012. Results: The Pooled Cohort risk equations were well calibrated among participants with low SES but over predicted ASCVD risk among participants with higher SES (Table). Discrimination of the equations improved after adding household income (continuous net reclassification improvement: 0.12 [95% CI: 0.03, 0.21]) but not living alone (0.06 [-0.03, 0.14]), or education (-0.04 [-0.13, 0.06]). The continuous net reclassification improvement was 0.10 (95% CI: 0.02, 0.19) after adding the cumulative number of indicators for low SES to the variables in the Pooled Cohort risk equations. Discussion: SES may help explain why the calibration of the Pooled Cohort risk equations has varied across cohorts. Adding information on SES may improve the performance of ASCVD risk equations.
FOLFIRINOX after first-line gemcitabine-based chemotherapy in metastatic pancreatic cancer: a mono-institutional experience
Authors: F. Foschini, L. Formisano, R. Marciano, E. Mozzillo, A. Carratù, F. Napolitano, A. Santaniello, P. De Placido, P. Cascetta, A. Servetto, R. Bianco
Journal: Annals of Oncology (2019)
Abstract 4281: LT-IIc, a bacterial type II heat-labile enterotoxin, induces specific lethality in triple negative breast cancer cells by modulaton of autophagy and induction of apoptosis and necroptosis
Authors: Patricia A. Masso-Welch, Sofia Girald Berlingeri, Natalie D. King-Lyons, Lorrie Mandell, John C. Hu, Christopher Greene, Matthew Federowicz, Peter Cao, Yasser Heakal
Journal: Cancer Research (2019)

Abstract Despite the recent advances in breast cancer treatment, triple negative breast cancer (TNBC) remains a serious health problem with limited treatment options. Poor prognosis is due to the development of chemoresistance. To discover novel therapeutic approaches to treat TNBC, we screened cholera toxin (CT) and the members of the bacterial type II heat-labile enterotoxin family (LT-IIa, LT-IIb, and LT-IIc) for their capacity to induce cell death in TNBC cells. LT-IIc, but not the other toxins, significantly reduced viability of the TNBC cell lines BT549 and MDA-MB-231 (IC50 = 82.32 nM). LT-IIc had no significant cytotoxic effects on MCF10A (IC50 = 2600 nM), a non-tumorigenic breast epithelial cell line, and minimal effects on MCF7 and T47D, ER+ breast cancer cells, or SKBR-3, HER2+ cells. LT-IIc stimulated autophagy through inhibition of the mTOR pathway, while simultaneously inhibiting autophagic progression, as observed by the accumulation of LC3B-II and p62 proteins. Morphologically, LT-IIc induced accumulation of enlarged LAMP2+ autolysosomes selectively in TNBC cells. Bafilomycin A1, an inhibitor of autophagic flux, blocked the formation and/or retention of these autolysosomes. The increase in caspase 3, 7 activity and annexin V staining indicated that LT-IIc induced an apoptotic response. Co-treatment with necrostatin-1, however, demonstrated that the lethal response to LT-IIc is elicited, at least in part, by concomitant induction of necroptosis. Collectively, these experiments demonstrate that LT-IIc acts bifunctionally, inducing autophagy while simultaneously blocking autolysosomal progression in TNBC cells, resulting in specific cytotoxicity in this breast cancer subtype. Citation Format: Patricia A. Masso-Welch, Sofia Girald Berlingeri, Natalie D. King-Lyons, Lorrie Mandell, John C. Hu, Christopher Greene, Matthew Federowicz, Peter Cao, Yasser Heakal. LT-IIc, a bacterial type II heat-labile enterotoxin, induces specific lethality in triple negative breast cancer cells by modulaton of autophagy and induction of apoptosis and necroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4281.
Rapid reduction of peripheral blasts in older patients with refractory acute myeloid leukemia (AML) using reinduction with single agent anti-CD45 targeted iodine (<sup>131</sup>I) apamistamab [Iomab-B] radioimmunotherapy in the phase III SIERRA trial.
Authors: Ben Kent Tomlinson, Vijay Reddy, Mark S. Berger, Jennifer Spross, Renee Lichtenstein, Boglarka Gyurkocza
Journal: Journal of Clinical Oncology (2019)

7048 Background: The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial for patients aged ≥55 years with active, relapsed/refractory (R/R) AML evaluating allogeneic hematopoietic cell transplantation (HCT) versus conventional care (CC). Recent preliminary data demonstrated robust donor engraftment in all patients treated with Iomab-B (Blood 2018 132:1017) despite active disease. We hypothesize that successful engraftment was due to rapid disease reduction with Iomab-B. Methods: Patients are randomized to receive Iomab-B and HCT or to a CC therapy including approved targeted agents followed by HCT if in remission. Majority of patients (79%) in the CC arm did not achieve CR and the study allowed crossover to receive Iomab-B. Results: Data were evaluated for the first 25% of patients (N=38). Twenty-nine patients received Iomab-B, either directly (N=19) or via crossover (N=10). Median baseline marrow blasts were 30% (4-74) for Iomab-B and 24% (6-70%) for CC, which increased to 45% (10-70%) at crossover. Peripheral blast data was available in 16 patients (Iomab 7, Crossover 9). By day 3 post-Iomab, blasts were reduced by 98% with 100% reduction by day 8 (assuming 0% blasts due to lack of differential at WBC 0.1; Table). All patients engrafted with ANC at a median of 13 days (9-22 days). Conclusions: Targeted re-induction radioimmunotherapy with single agent Iomab-B rapidly decreases peripheral blasts in chemotherapy refractory AML. This significant reduction of leukemia burden followed by successful engraftment after HCT is encouraging in this underserved population. Clinical trial information: NCT02665065. [Table: see text]
Orbitofrontal Circuits Control Multiple Reinforcement-Learning Processes
Authors: Stephanie M. Groman, Colby Keistler, Alex J. Keip, Emma Hammarlund, Ralph J. DiLeone, Christopher Pittenger, Daeyeol Lee, Jane R. Taylor
Journal: Neuron (2019)

Adaptive decision making in dynamic environments requires multiple reinforcement-learning steps that may be implemented by dissociable neural circuits. Here, we used a novel directionally specific viral ablation approach to investigate the function of several anatomically defined orbitofrontal cortex (OFC) circuits during adaptive, flexible decision making in rats trained on a probabilistic reversal learning task. Ablation of OFC neurons projecting to the nucleus accumbens selectively disrupted performance following a reversal, by disrupting the use of negative outcomes to guide subsequent choices. Ablation of amygdala neurons projecting to the OFC also impaired reversal performance, but due to disruptions in the use of positive outcomes to guide subsequent choices. Ablation of OFC neurons projecting to the amygdala, by contrast, enhanced reversal performance by destabilizing action values. Our data are inconsistent with a unitary function of the OFC in decision making. Rather, distinct OFC-amygdala-striatal circuits mediate distinct components of the action-value updating and maintenance necessary for decision making.
Abstract 5087: Carvedilol prevents skin cancer independently of its antioxidant property
Authors: Mengbing Chen, Sherry Liang, Bradley Andresen, Ying Huang
Journal: Cancer Research (2019)

Abstract Carvedilol is an FDA approved β-blocker traditionally prescribed for cardiovascular diseases. Our previous work demonstrated that carvedilol has preventive activity against ultraviolet radiation (UVR)-induced skin damage, inflammation, and carcinogenesis. However, the photoprotective mechanism for carvedilol remains unknown. Interestingly, not all β-blockers have cancer preventive activity, suggesting that targeting the β-adrenergic receptors may not be responsible for carvedilol’s anticancer activity. Since carvedilol has been shown as a potent antioxidant and such property is not shared by majority of other β-blockers (e.g., metoprolol), we hypothesized that the antioxidant property may be, in part, responsible for carvedilol’s protective activity against photocarcinogenesis. The nontumorous mouse epidermal JB6 P+ cells were subjected to various doses of UVR exposure and H2O2 treatment to identify the optimal doses to examine protective activity. UVR and H2O2dose-dependently reduced cell viability. 25mJ/cm2 UVR and 100 μM H2O2 reduced cell viability detected by Trypan blue exclusion assay to 58.1% and 60.6%, respectively. 25mJ/cm2 UVR and 300 μM H2O2 increased the formation of intracellular fluorescent 2',7'-dichlorofluorescein (DCF) fluorescence, a marker of reactive oxidative species (ROS) detected by flow cytometry, to 5- and 4-fold compared to non-treated control, respectively. The cells were treated before or after UVR and H2O2 exposure with metoprolol, carvedilol or 4-hydroxycarbazole (4-OHC). 4-OHC is an intermediate compound for carvedilol synthesis that possesses an identical UV absorption profile as carvedilol. Additionally, the carbazole moiety is likely responsible for the antioxidant activity of carvedilol. Carvedilol, but not metoprolol and 4-OHC, was able to inhibit EGF-induced JB6 transformation in soft agar. Carvedilol, but not metoprolol and 4-OHC, also attenuated UVR and H2O2 induced cell death. Carvedilol, but not 4-OHC, inhibited UVR-induced NF-κB and AP-1 promoter activity. In addition, unlike carvedilol, 4-OHC failed to prevent chronic UVR induced skin carcinogenesis in SKH-1 mice. However, 4-OHC and carvedilol similarly attenuated UVR- and H2O2-induced ROS formation in JB6 P+ cells, while metoprolol had no effect. These results indicate that the photoprotective effects of carvedilol are primarily due to an unknown mechanism that is independent of β-adrenergic receptors and reactive oxygen species scavenging. Citation Format: Mengbing Chen, Sherry Liang, Bradley Andresen, Ying Huang. Carvedilol prevents skin cancer independently of its antioxidant property [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5087.
Abstract 17185: Sympathetic Reinnervation is Required for Mammalian Cardiac Regeneration
Authors: Ian A White, Julie Gordon, Wayne Balkan, Joshua M Hare
Journal: Circulation (2015)

Rationale: Established animal models of tissue and limb regeneration demonstrate a critical dependence on concurrent reinnervation by the peripheral nervous system. The abundance of autonomic nerves in the mammalian heart suggests they play a similar role in the response to cardiac injury. Objective: To test the hypothesis that reinnervation is required for innate neonatal cardiac regeneration. Methods and Results: Crossing Wnt1:cre transgenic mice with a double-tandem (td) tomato reporter strain identified all neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. Whole mount epi-fluorescence microscopy facilitated the clear resolution of subepicardial autonomic nerves in the mouse ventricles providing unprecedented detail of the subepicardial neuroanatomy of the mouse heart. We confirmed that sympathetic nerve structures envelop the entire heart, and importantly, exhibit robust re-growth into the regenerating myocardium following resection of the left ventricular apex in neonatal mice. While innervated hearts regenerate with minimal scarring to the left ventricular myocardium, we report that innate cardiac regeneration was inhibited following sympathectomy, as determined by cross-sectional percentage of viable LV myocardium (n=9, 0.87±1.4% vs. n=6, 14.05±4.4% ; p&lt;0.01). Conclusions: Ablation of post-ganglionic sympathetic nerves blocks the innate regenerative capacity of neonatal mouse hearts. Therefore, the innate ability of the neonatal mouse heart to undergo regeneration in response to injury is dependent on sympathetic innervation of the ventricular myocardium. This finding has significant implications for adult regeneration following myocardial infarction where nerve growth is hindered by age related influences and scar tissue.
Abstract 3798: Acetate supplementation eliminates hypoxia mediated resistance to differentiation therapy in neuroblastoma cells
Authors: Yang Li, Yiren Zhou, John M. Maris, Amato J. Giaccia, Jiangbin Ye
Journal: Cancer Research (2019)

Abstract Neuroblastoma is the most common extracranial solid tumor in childhood. Retinoic acid (RA) leads to cell cycle arrest and induces cell differentiation in neuroblastoma cells, thus it has been used to treat neuroblastoma as differentiating agent for decades. However, therapy resistance often occurs and the overall survival remains low. Hypoxia, a common metabolic stress existing in tumor microenvironment, increases tumor resistance to RA by promoting dedifferentiation of neuroblastoma cells. The aim of this study was to elucidate the mechanisms underlying hypoxia-mediated therapy resistance and develop therapeutic approach to improve the response to differentiation therapy. By RNA-Seq analysis, we identified a group of neuron-specific differentiation markers that induced by RA treatment, while the induction was diminished under hypoxia. Associated with the silencing of differentiation markers expression, a significant loss of histone acetylation of H3K9, H3K27 and total H3 was observed under hypoxia. Metabolomics analysis indicated hypoxia inhibited mitochondrial oxidative phosphorylation to decrease intracellular acetyl-CoA and citrate, which provides acetyl-CoA for histone acetyltransferase. Importantly, acetate supplementation restored cellular acetyl-CoA level, histone acetylation, and the expression of differentiation markers under hypoxia. Differentiation morphology was also restored by acetate supplementation under hypoxia. In conclusion, our finding suggested hypoxia contributed to the resistance to RA-induced differentiation by reprogramming cellular metabolism and inducing histone hypoacetylation. Acetate supplementation is an efficacious therapeutic approach to improve the sensitivity of hypoxic tumor to RA-based differentiation therapy. Citation Format: Yang Li, Yiren Zhou, John M. Maris, Amato J. Giaccia, Jiangbin Ye. Acetate supplementation eliminates hypoxia mediated resistance to differentiation therapy in neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3798.