tbuckley/cabot-search huggingface dataset:
Abstract 2159: Use of in vitro cell sheet engineering as a chemotherapeutic model for epithelial cancer
Authors: Eun Hye Kim, Jaewang Lee, Daiha Shin, Sunwoo Park, Minsu Kwon, Jong-Lyel Roh
Journal: Cancer Research (2018)

Abstract Epithelial cancer is grown in the in vivo microenvironment mixed of keratinocytes, fibroblasts and matrix, vessels, and immune cells. The current in vitro 2-dimensional (2D) models for anti-cancer drug testing are commonly performed on a physical basis, resulting in significant difference from elucidating the real in vivo effects. To resolve the experimental gap, the 3D models have been developed to mimic the in vivo cancer microenvironment, while there is a lack of specific models for epithelial origin tumors. Therefore, we developed a new 3D model of using the in vitro cell sheet engineering for epithelial cancers and compared the results of several chemotherapeutic drug testing among in the 3D model, spheroid culture, and 2D-dish cell culture. The cell sheet included epithelial and subepithelial layers consisting of keratinocytes overlying the mixture of fibroblasts and endothelial progenitors. The spheroids of green fluorescent protein-tagged epithelial cancers were placed at the interface of epithelial and subepithelial layers. The spheroids with mixture of cancers and fibroblasts or cancer-associated fibroblasts (CAF) were made by the conventional hanging-drop method, and the 2D was simply seeded in the culture dish. The cell growth, viability, and hypoxia were calculated by cell counting kit (CCK), live/dead assay, propidium iodide and LOX-1 staining. The morphology, invasion, and mRNA and protein expressions were also compared among the different in vitro models. The results of live/dead assay and CCK showed higher viabilities in the cell sheet-based models before and after treatment with chemotherapeutic drugs. TGF-β and epithelial-mesenchymal transition-related mRNA and proteins were highly expressed in tumors growing in the cell sheet. Further, the incorporation of CAF into the cancer spheroids appeared to less decrease viable cancer cells by chemotherapeutic agents compared to the use of no or normal fibroblasts. Tumor angiogenesis and hypoxia were also apparently observed in the cell sheet model, which partly contributed to relative resistance to chemotherapeutic drugs. Taken together, the cell sheet-based cancer model might be applied to the in vitro observation of epithelial cancer growth and invasion, and anti-cancer drug testing. Citation Format: Eun Hye Kim, Jaewang Lee, Daiha Shin, Sunwoo Park, Minsu Kwon, Jong-Lyel Roh. Use of in vitro cell sheet engineering as a chemotherapeutic model for epithelial cancer [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 2159.
Abstract 18186: Evaluating the Utility of a Multi-factorial Computational Model and Simplified Multi-factorial Risk Score to Predict Postoperative Atrial Fibrillation Following Cardiothoracic Surgery
Authors: Nathan Harada, Mohammed Saeed, Satinder Singh, Zeeshan Syed
Journal: Circulation (2015)

Background: Postoperative atrial fibrillation (PAF) is a frequent complication following cardiothoracic surgery and is associated with increased length of stay and increased morbidity. This study develops a novel multi-factorial computational model to predict PAF, as well as a simplified risk score for PAF based on this model. Methods: A multi-factorial computational model to predict PAF was trained on 592 patients in the MIMIC II database undergoing cardiothoracic surgery at the Beth Israel Deaconess Medical Center, using demographic, comorbidity, laboratory, and echocardiographic parameters. Parameters were chosen using LR stepwise-backward elimination applied to routinely collected covariates via logistic regression. A simplified risk score was created using the retained covariates based on the observed odds ratios (OR). Discrimination for both the model and risk score were calculated using the area under the receiver operating characteristic curve (AUC) via leave one out cross validation. Results: The multi-factorial computational model retained the following parameters: age in years (OR 1.06; p&lt;0.001), serum chloride in mEq/L (OR 0.92; p=0.019), and left atrial diameter categorized from 0-3 (OR 1.84; p&lt;0.001). The model achieved a significantly higher level of discrimination relative to any covariate alone (AUC 0.72; p&lt;0.001 relative to all individual covariates). The simplified risk score is calculated as: +2 for age &gt; 67, +1 for serum chloride &lt; 105, +1 for each categorical increase in left atrial diameter (&gt;40mm, &gt;47.5mm, &gt;52.5mm); and achieved comparable performance to the multi-factorial computational model (AUC 0.71; p&lt;0.001) with a graded increase in risk (Figure). Conclusions: Multi-factorial computational modeling may provide a robust basis for discriminating between patients at high or low risk of PAF following cardiothoracic surgery. This model can be delivered as a simplified multi-factorial risk score for broad use by the bedside.
Abstract 2882: Elucidation of the mechanism of action of the multi-kinase inhibitor midostaurin in NSCLC
Authors: Claudia Ctortecka, Brent Kuenzi, Bin Fang, Natalia Sumi, Victoria Izumi, Fumi Kinose, Eric Haura, John Koomen, Uwe Rix
Journal: Cancer Research (2018)

Abstract Background: Non-small cell lung cancer (NSCLC) constitutes a strong unmet medical need in spite of recent successes with targeted drugs and immunotherapy in some subsets. We had observed the recently FDA-approved drug midostaurin to exhibit potent anticancer activity in a subset of NSCLC cell lines that was unrelated to its known targets FLT3 or PKC. We here explored a new repurposing opportunity and investigated the mechanism of action (MoA) of midostaurin in NSCLC utilizing a multilayered functional proteomics approach. Methods: Chemical proteomics identified kinase targets and global and tyrosine phosphoproteomics generated a network view of intracellular signaling upon midostaurin treatment. Functional validation was performed using RNA interference and selective small-molecule probes. Cell viability assays were carried out using CellTiterGlo and colony formation assays. Induction of apoptosis was determined by immunoblotting and fluorescent microscopy. Flow cytometry assessed cell cycle stages. Signaling changes were determined by immunoblotting. Results: Viability screening confirmed anticancer activity in several midostaurin-sensitive NSCLC cell lines at clinically relevant concentrations independent of its canonical targets. Using chemical proteomics, we identified multiple midostaurin kinase targets. Network-based integration of the chemical proteomics and quantitative tyrosine and global phosphoproteomics data using STRING for protein-protein interactions and NetworKIN for substrate-kinase predictions revealed several nodes to be relevant for the MoA of midostaurin. Subsequent functional validation showed that simultaneous inhibition of TBK1, PDK1 and AURKA was required to mimic midostaurin's cellular effects in these cells. Immunoblotting for downstream targets of these kinases revealed PLK1 as a critical signaling effector. Rational combination of midostaurin with the more potent PLK1 inhibitor BI2536 caused strong synergy. Conclusion: Midostaurin showed activity in a subset of NSCLC cells. Combination of complementary functional proteomics approaches and subsequent network-based integration revealed novel insight into the MoA of midostaurin and NSCLC vulnerabilities. We utilized this mechanistic knowledge for the rational combination of midostaurin with the clinical PLK1 inhibitor BI2536, which is highly synergistic and has strong potential for clinical translation. Citation Format: Claudia Ctortecka, Brent Kuenzi, Bin Fang, Natalia Sumi, Victoria Izumi, Fumi Kinose, Eric Haura, John Koomen, Uwe Rix. Elucidation of the mechanism of action of the multi-kinase inhibitor midostaurin in NSCLC [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 2882.
Abstract 438: Hydrogen Sulfide Promotes Mitochondrial Biogenesis Through the Regulation of AMP-activated Protein Kinase
Authors: Yuuki Shimizu, Rohini Polavarapu, John Calvert
Journal: Circulation Research (2016)

Background: Hydrogen sulfide (H 2 S) possesses numerous cellular actions that account for its cardioprotective effects. A mechanism of particular interest is its effects on the mitochondria. At low concentrations, H 2 S donates electrons to the electron transport chain, whereas at high concentrations it inhibits mitochondrial respiration. H 2 S therapy improves mitochondrial function and prevents the loss of mitochondria following the onset of myocardial ischemia. However, it is not known if these improvements are associated with simply a reduction in injury or if mitochondrial biogenesis is involved. Therefore, the purpose of this study was to determine if H 2 S regulates/induces mitochondrial biogenesis in the heart. Methods and Results: C57BL/6J mice (8 weeks of age) were given an orally active H 2 S donor (SG-1002; 20 mg/kg/day) in their chow for 4 weeks. For these studies we focused our analysis on an AMPK-PGC1α signaling cascade. SG-1002 significantly increased the phosphorylation of AMPK, the serine phosphorylation of PGC1α, and increased the nuclear localization of PGC1α. This was associated with an increase in the gene expression of PGC1α target genes associated with mitochondrial biogenesis, an increase in mitochondrial to nuclear DNA ratios and an increase in citrate synthase activity. SG-1002 failed to elicit these changes in AMPK deficient mice. Therefore, we sought to determine how SG-1002 activated AMPK. SG-1002 did not alter the phosphorylation of LKB1, an upstream kinase of AMPK, and did not alter the levels of AMP (activator of AMPK). SG-1002 did not alter the expression of protein phosphatase 2A (PP2A; dephosphorylates AMPK), but it did significantly decrease the activity of PP2A). This decrease was accompanied by an increase in the sulfhydration of PP2A, suggesting that this modification is inhibitory. Conclusion: These data suggest that H 2 S augments mitochondrial biogenesis in the heart via an AMPK-PGC1α signaling cascade. This is important because mitochondrial abnormalities are associated with a number of disease states (diabetes and heart failure) where H 2 S levels are decreased. Therefore, strategies aimed at increasing H 2 S levels could potentially induce the generation of new, healthy mitochondria.
Abstract 105: CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival
Authors: Edward J. Hartsough, Michele B. Weiss, Shea A. Heilman, Timothy J. Purwin, Curtis H. Kugel, Sheera R. Rosenbaum, Dan A. Erkes, Manoela Tiago, Inna Chervoneva, Andrew E. Aplin
Journal: Cancer Research (2018)

Abstract Metastatic melanoma is the deadliest form of skin cancer; however, patients diagnosed and treated prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion of melanoma cells but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Modulation of CADM1 resulted in significant effects on the migration and invasion of melanoma cells. In addition, elevated CADM1 elicited cell death in non-adherent conditions, an effect that could not be rescued with a pan-caspase inhibitor. Analyses suggest that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Furthermore, clinical data from TCGA indicates that CADM1 expression is correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be a biomarker for improved survival of melanoma patients. Citation Format: Edward J. Hartsough, Michele B. Weiss, Shea A. Heilman, Timothy J. Purwin, Curtis H. Kugel, Sheera R. Rosenbaum, Dan A. Erkes, Manoela Tiago, Inna Chervoneva, Andrew E. Aplin. CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival [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 105.
Three-Year Outcomes After Sirolimus-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease
Authors: MamoruToyofuku, TakeshiKimura, TakeshiMorimoto, YasuhikoHayashi, HiroakiUeda, KazuyaKawai, YoichiNozaki, ShinichiHiramatsu, AkiraMiura, YoshiakiYokoi, ShinichiroToyoshima, HitoshiNakashima, KazuoHaze, MasaruTanaka, ShunsukeTake, ShigeruSaito, TakaakiIsshiki, KazuakiMitsudo
Journal: Circulation (2009)

Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure. Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion re...
Endothelial Dysfunction in Chronic Myocardial Infarction Despite Increased Vascular Endothelial Nitric Oxide Synthase and Soluble Guanylate Cyclase Expression
Authors: JohannBauersachs, AnneBouloumié, DanielaFraccarollo, KaiHu, RudiBusse, GeorgErtl
Journal: Circulation (1999)

Background—Endothelial dysfunction of the peripheral vasculature is a well-known phenomenon in congestive heart failure that contributes to the elevated peripheral resistance; however, the underlying mechanisms have not yet been clarified. Methods and Results—Dilator responses, the expression of protein and mRNA of the endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and soluble guanylate cyclase (sGC), and superoxide anion (O2−) and peroxynitrite production were determined in aortic rings from Wistar rats 8 weeks after myocardial infarction and compared with those in sham-operated animals. In rats with heart failure, the concentration-response curve of the endothelium-dependent vasodilator acetylcholine (after preconstriction with phenylephrine) was significantly shifted to the right, and the maximum relaxation was attenuated. Determination of expression levels of the 2 key enzymes for NO-mediated dilations, eNOS and sGC, revealed a marked upregulation of both enzymes in aortas from rats w...
Abstract 1576: Clonal diversity revealed by morphoproteomic and copy number profiles of single prostate cancer cells at diagnosis
Authors: Paymaneh D. Malihi, Michael Morikado, Lisa Welter, Anders Carlsson, Carmen Ruiz Velasco, Anand Kolatkar, Mariam Rodriguez-Lee, James Hicks, Peter Kuhn, Sandy T. Liu, Eric T. Miller, Radu M. Cadaneanu, Beatrice S. Knudsen, Michael S. Lewis, Isla P. Garraway
Journal: Cancer Research (2018)

Abstract Tumor heterogeneity is prevalent in both treatment-naïve and end-stage metastatic castration-resistant prostate cancer (PCa), and may contribute to the broad range of clinical presentation, treatment response, and disease progression. To characterize molecular heterogeneity associated with de novo metastatic PCa, multiplatform single cell profiling was performed using High Definition Single Cell Analysis (HD-SCA). HD-SCA enabled morphoproteomic and morphogenomic profiling of single cells from touch preparations of tissue cores (prostate and bone marrow biopsies) as well as liquid samples (peripheral blood and bone marrow aspirate). Morphology, nuclear features, copy number alterations, and protein expression were analyzed. Tumor cells isolated from prostate tissue touch preparation (PTTP) and bone marrow touch preparation (BMTP) as well as metastatic tumor cells (MTCs) isolated from bone marrow aspirate were characterized by morphology and cytokeratin expression. Although peripheral blood was examined, circulating tumor cells were not definitively observed. Targeted proteomics of PTTP, BMTP, and MTCs revealed cell lineage and luminal prostate epithelial differentiation associated with PCa, including co-expression of EpCAM, PSA, and PSMA. Androgen receptor expression was highest in MTCs. Hallmark PCa copy number alterations, including PTEN and ETV6 deletions and NCOA2 amplification, were observed in cells within the primary tumor and bone marrow biopsy samples. Genomic landscape of MTCs revealed to be a mix of both primary and bone metastatic tissue. This multiplatform analysis of single cells reveals several clonal origins of metastatic PCa in a newly diagnosed, untreated patient with polymetastatic disease. This case demonstrates that real-time molecular profiling of cells collected through prostate and bone marrow biopsies is feasible and has the potential to elucidate the origin and evolution of metastatic tumor cells. Altogether, biological and genomic data obtained through longitudinal biopsies can be used to reveal the properties of PCa and can impact clinical management. Citation Format: Paymaneh D. Malihi, Michael Morikado, Lisa Welter, Anders Carlsson, Carmen Ruiz Velasco, Anand Kolatkar, Mariam Rodriguez-Lee, James Hicks, Peter Kuhn, Sandy T. Liu, Eric T. Miller, Radu M. Cadaneanu, Beatrice S. Knudsen, Michael S. Lewis, Isla P. Garraway. Clonal diversity revealed by morphoproteomic and copy number profiles of single prostate cancer cells at diagnosis [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 1576.
Abstract 1580: Separation of circulating biomarkers by nanoDLD lab-on-a-chip technology
Authors: Stacey M. Gifford, Benjamin H. Wunsch, Joshua T. Smith, Navneet Dogra, Sungcheol Kim, Gustavo Stolovitzky
Journal: Cancer Research (2018)

Abstract Efficient isolation of circulating biomarkers is key for enabling liquid biopsies for cancer diagnosis and prognosis. Circulating biomarkers such as exosomes and cell-free DNA hold promise for non-invasive early cancer diagnosis, determining cancer stage and prognosis, as well as monitoring treatment progression and the development of drug resistance. However, isolation of these biomarkers has proven challenging in the clinic. Exosomes range in size from approximately 30 to 150 nm and the current gold standard isolation method includes large-scale ultracentrifugation, which is time-consuming and lacks reproducibility. Circulating cell-free DNA is found in a variety of sizes and states and while clinical applications for prenatal testing have emerged, applications in oncology remain elusive in part due to high background and challenges in isolating relevant molecules. We have developed a lab-on-a-chip technology based on deterministic lateral displacement at the nanoscale (nanoDLD) which separates and concentrates particles as small as 20 nm from smaller particles in continuous flow. Analysis of nanoDLD isolation of exosomes and DNA show improved resolution, recovery, and concentration compared to standard techniques. Current efforts to scale nanoDLD technology to clinically relevant volumes will provide a reproducible and automated tool for isolation, study, and clinical use of these important non-invasive biomarkers. Citation Format: Stacey M. Gifford, Benjamin H. Wunsch, Joshua T. Smith, Navneet Dogra, Sungcheol Kim, Gustavo Stolovitzky. Separation of circulating biomarkers by nanoDLD lab-on-a-chip technology [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 1580.
Abstract 14667: Endothelial-specific Loss of Primary Cilia Exacerbates Cardiac Fibrosis
Authors: Krishna K Singh, Pratiek N Matkar, Jonathan W Yau, Yi Pan, Adrian Quan, Jean-François Desjardines, Thomas G Parker, Mohammed Al-Omran, Subodh Verma
Journal: Circulation (2016)

Introduction: Cardiac fibrosis after injury, which significantly compromises heart function, is in part due to proliferation of fibroblasts of unclear cellular origin. Primary cilia are cellular pr...
Abstract 4294: SUMOylation promotes nuclear import and stabilization of polo-like kinase 1 to support its mitotic function
Authors: Donghua Wen, Jianguo Wu, Lei Wang, Zheng Fu
Journal: Cancer Research (2018)

Abstract As a pivotal mitotic regulator, polo-like kinase 1 (PLK1) is under highly coordinated and multi-layered regulation. However, the regulatory pathways that control PLK1's activity and function have just begun to be elucidated. PLK1 has recently been shown to be functionally modulated by post-translational modifications (PTMs), including phosphorylation and ubiquitination. Herein, we report for the first time that a novel PTM, SUMOylation, plays an essential role in regulating PLK1's mitotic function. We found that Ubc9 was recruited to PLK1, upon initial phosphorylation and activation by CDK1/cyclin B. By in vivo and in vitro SUMOylation assays, PLK1 was identified as a physiologically relevant SUMO-targeted protein, preferentially modified by SUMO-1. We further showed that K492 on PLK1 was the lysine residue essential for SUMOylation. SUMOylation not only led to PLK1's nuclear import, but also significantly increased its protein stability by preventing the recruitment of APC/Ccdh1, the ubiquitin E3-ligase of PLK1. Resembling Ubc9 deficiency, cells expressing PLK1-K492R mutant exhibited mitotic aberrations characterized by prolonged mitotic progression, and misaligned and/or mis-segregated chromosomes, which could be rescued by reintroducing SUMOylation modification to PLK1. Collectively, our findings suggest that SUMOylation is another important regulatory mechanism governing PLK1's mitotic function to ensure normal mitotic progression and genomic integrity. Citation Format: Donghua Wen, Jianguo Wu, Lei Wang, Zheng Fu. SUMOylation promotes nuclear import and stabilization of polo-like kinase 1 to support its mitotic function [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 4294.