tbuckley/cabot-search huggingface dataset:
Abstract 3970: PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping
Authors: Monica E. Wielgos, Petar Jelinic, Douglas A. Levine
Journal: Cancer Research (2019)

Abstract Background: Currently, there are multiple ongoing clinical trials testing the efficacy of various poly (ADP-ribose) polymerase (PARP) inhibitors in combination with immune checkpoint blockade across many cancer types. However, there is no rationale as to which PARP inhibitor is best to use in these studies. Two PARPis (rucaparib and talazoparib) have been reported to activate IFN signaling genes through the stimulator of interferon genes (STING) pathway. The objective of this study is to characterize the effect of all clinically active PARPis on Type I interferon (IFN) regulated genes. We also aim to identify whether this effect is dependent on CHK1, which we have previously reported to be activated by PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) and not by the mainly catalytic inhibitor (veliparib). Methods: CCL5 and CXCL10 gene expression levels were measured using qRT-PCR in 293T after two days of treatment with the PARP inhibitors (velipairb, rucaparib, olaparib, niraparib, and talazoparib). CXCL10 mRNA levels were also measured in HGSOC BRCA wild-type cell lines (OVCAR3 and CAOV3) after two days of treatment with veliparib and talazoparib. We also measured CCL5 and CXCL10 expression after veliparib and niraparib treatment in 293T cells with stable CHK1 overexpression. Results: The four PARP trappers consistently increased CCL5 and CXCL10 expression in 293T cells. Although, veliparib had little to no effect on the expression of these two genes as compared to the other four PARPis. CXCL10 mRNA levels were significantly upregulated after talazoparib treatment (p&amp;lt;0.01) but not affected after veliparib treatment in CAOV3 cells. Similarly, an increase in CXCL10 gene expression was observed in OVCAR3 cells (p&amp;lt;0.05). Although, veliparib also had a modest but not significant effect on CXCL10 levels. CCL5 and CXCL10 gene expression consistently increased when treated with niraparib in 293T cells with stable CHK1 overexpression. This same effect was not observed after veliparib treatment in 293T cells that stably overexpressed CHK1. Conclusions: Our results suggest that all PARP trappers promote expression of IFN Type I regulated genes which may be dependent on CHK1 expression. These findings may better define the most ideal PARP and immune checkpoint inhibitor combination. Citation Format: Monica E. Wielgos, Petar Jelinic, Douglas A. Levine. PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping [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 3970.
Abstract 861: Precise excision of an oncogenic allele of tumor by Adenovirus-based CRISPR/Cas9 system induces tumor regression
Authors: Taeyoung Koo, A-Rum Yoon, Sangsu Bae, Jin-Soo Kim, Chae-Ok Yun
Journal: Cancer Research (2019)

Abstract Approximately 15% of non-small cell lung cancer patients possesses several mutations in the epidermal growth factor receptor (EGFR) gene, which plays a critical role in tumor progression. To this end, we demonstrate that an adenovirus-mediated co-delivery of Cas9 and a guide RNA targeting oncogenic EGFR mutation commonly found in lung cancer can selectively remove oncogenic allele while being inactive against wild-type EGFR allele. An EGFR mutant harboring a single-nucleotide missense mutation (CTG to CGG) was targeted as this mutation leads to generation of protospacer-adjacent motif sequence recognized by the Cas9 protein of S. pyogenes. The CRISPR/Cas9-mediated excision of mutant EGFR allele with high indel rate led to potent lung cancer cell killing. Importantly, intratumoral administration of Ad-based CRISPR/Cas9 system led to potent tumor growth inhibition and complete tumor regressions in number of mice harboring EGFR mutant xenograft tumors. Collectively, our findings show that precise and controlled excision of oncogenic mutation by Ad-mediated expression of CRISPR/Cas9 system offers a powerful genomic surgical strategy to excise oncogenic mutations to treat cancers. Note: This abstract was not presented at the meeting. Citation Format: Taeyoung Koo, A-Rum Yoon, Sangsu Bae, Jin-Soo Kim, Chae-Ok Yun. Precise excision of an oncogenic allele of tumor by Adenovirus-based CRISPR/Cas9 system induces tumor regression [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 861.
A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice
Authors: Kitti Wing Ki Chan, Satoru Watanabe, Jocelyn Y. Jin, Julien Pompon, Don Teng, Sylvie Alonso, Dhanasekaran Vijaykrishna, Scott B. Halstead, Jan K. Marzinek, Peter J. Bond, Bo Burla, Federico Torta, Markus R. Wenk, Eng Eong Ooi, Subhash G. Vasudevan
Journal: Science Translational Medicine (2019)

The T164S mutation in the NS1 protein of dengue virus increases disease severity in mice through complement activation.
Abstract 1866: Sea cucumber (Stichopus japonicas) F2 enhanced TRAIL-induced apoptosis via XIAP ubiquitination-ER stress in colorectal cancer cells
Authors: Jung lim Kim, Seong Hye Park, Soyeon Jeong, Bo Ram Kim, Yoo Jin Na, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Dae Yeong Kim, Bu Gyeom Kim, Sang Cheul Oh, Dae-Hee Lee
Journal: Cancer Research (2019)

Abstract Natural products have shown great promise in sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy. Sea cucumber (SC) extracts possess antitumor activity, and hence their potential to sensitize CRC cells to TRAIL therapy was evaluated. This study used Western blotting to evaluate the combination effects of SC and TRAIL in CRC and determined the molecular mechanism underlying these effects. SC fractions and TRAIL alone had no effect on apoptosis; however, combined treatment dramatically induced apoptosis of CRC cells, but not normal colon cells. Combined treatment induced expression of apoptotic proteins (poly (ADP-ribose) polymerase (PARP), caspase 3, and 8), and this effect was markedly inhibited by ubiquitination of X-linked inhibitor of apoptosis protein (XIAP). SC did not affect the mRNA levels, but increased proteasomal degradation and ubiquitination of XIAP protein. Furthermore, SC induced reactive oxygen species (ROS) production, thereby activating c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress-related apoptotic pathways in CRC. Taken together, our results demonstrate that the SC fraction may sensitize CRC cells to TRAIL-induced apoptosis through XIAP ubiquitination-ER stress. Citation Format: Jung lim Kim, Seong Hye Park, Soyeon Jeong, Bo Ram Kim, Yoo Jin Na, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Dae Yeong Kim, Bu Gyeom Kim, Sang Cheul Oh, Dae-Hee Lee. Sea cucumber (Stichopus japonicas) F2 enhanced TRAIL-induced apoptosis via XIAP ubiquitination-ER stress in colorectal cancer 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 1866.
Abstract 2678: A clonal expression biomarker improves prognostic accuracy: TRACERx lung
Authors: Dhruva Biswas, Nicolai J. Birkbak, Rachel Rosenthal, Crispin T. Hiley, Emilia L. Lim, Krisztian Papp, Marcin Krzystanek, Dijana Djureinovic, Yin Wu, David A. Moore, Marcin Skrypski, Christopher Abbosh, Maise Al Bakir, Thomas B. Watkins, Selvaraju Veeriah, Gareth A. Wilson, Mariam Jamal-Hanjani, Arul M. Chinnaiyan, Patrick Micke, Jiri Bartek, Istvan Csabai, Zoltan Szallasi, Javier Herrero, Nicholas McGranahan, Charles Swanton
Journal: Cancer Research (2019)

Abstract At the point of cancer diagnosis, molecular biomarkers aim to stratify patients into precise disease subtypes predictive of outcome independent of standard clinical parameters such as tumour stage. Although prognostic gene expression signatures have been derived for many cancer types, seldom have they been shown to improve therapeutic decision making, limiting their clinical use. While intra-tumour transcriptomic heterogeneity (RNA-ITH) has been shown to bias existing biomarkers, efforts to control for this biological parameter have not been considered in biomarker development. Here, we analyse multi-region RNA-seq and whole-exome data for 156 tumour regions from 48 TRACERx patients to explore RNA-ITH in NSCLC. We show that chromosomal instability is a major driver of RNA-ITH, through the generation of heterogeneous copy number events within tumours, and that existing prognostic gene expression signatures are vulnerable to sampling bias. To address this issue, we develop the Outcome Risk Associated Clonal Lung Expression (ORACLE) assay, comprised of genes expressed homogeneously within individual tumours but heterogeneously between patients. These genes are enriched in modules associated with cell proliferation, such as mitosis and nucleosome assembly, that are often selected for through copy number gain events occurring early in tumour evolution. Our approach to identify “clonal” transcriptomic biomarkers in NSCLC overcomes tumour sampling bias, improves survival risk forecasting over current clinicopathological risk factors, and may be generalised to other cancer types, whilst revealing the early evolutionary selection of high risk DNA copy number events driving poor clinical outcome. Citation Format: Dhruva Biswas, Nicolai J. Birkbak, Rachel Rosenthal, Crispin T. Hiley, Emilia L. Lim, Krisztian Papp, Marcin Krzystanek, Dijana Djureinovic, Yin Wu, David A. Moore, Marcin Skrypski, Christopher Abbosh, Maise Al Bakir, Thomas B. Watkins, Selvaraju Veeriah, Gareth A. Wilson, Mariam Jamal-Hanjani, Arul M. Chinnaiyan, Patrick Micke, Jiri Bartek, Istvan Csabai, Zoltan Szallasi, Javier Herrero, Nicholas McGranahan, Charles Swanton. A clonal expression biomarker improves prognostic accuracy: TRACERx lung [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 2678.
Assessment of the impact of the extension of vaccination mandates on vaccine coverage after 1 year, France, 2019
Authors: Daniel Lévy-Bruhl, Laure Fonteneau, Sophie Vaux, Anne-Sophie Barret, Denise Antona, Isabelle Bonmarin, Didier Che, Sylvie Quelet, Bruno Coignard
Journal: Eurosurveillance (2019)

One year after the extension of the childhood vaccination mandates to the 11 routine vaccinations for children under 2 years old, we estimated vaccination coverage through vaccine reimbursement data. Coverage for children born in 2018 has notably increased. Moreover, vaccine coverage for children and for vaccines not concerned by the law have also shown an increasing trend, supporting a positive impact of the ongoing communication strategy on vaccination, beyond the extension of vaccination mandates.
Alterations of the bile microbiome in primary sclerosing cholangitis
Authors: Timur Liwinski, Roman Zenouzi, Clara John, Hanno Ehlken, Malte C Rühlemann, Corinna Bang, Stefan Groth, Wolfgang Lieb, Marcus Kantowski, Nils Andersen, Guido Schachschal, Tom H Karlsen, Johannes R Hov, Thomas Rösch, Ansgar W Lohse, Joerg Heeren, Andre Franke, Christoph Schramm
Journal: Gut (2019)

Background Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC. Methods Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20). Results The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10 −5 ) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021). Conclusion PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
Abstract 16744: Global Two-Dimensional Strain as a New Prognostic Factor in Patients With Reperfused Acute Stemi
Authors: Myung-Jin Cha, Goo-Yeong Cho, Yeonyee E Yoon, Seong Hwan Kim, Jae-Hyeong Park, Kyoung-Ha Park, Hyun-Sook Kim, Seung-Pyo Lee, Hyung-Kwan Kim, Yong-Jin Kim, Dae-Won Sohn
Journal: Circulation (2013)

Objectives: We sought to evaluate whether global 2-dimensional (2D) strain offers additional benefit over left ventricular ejection fraction (LVEF) to predict clinical events in successfully reperf...
Abstract 1831: Role of autophagy in lymphangiosarcoma initiation and progression
Authors: Fuchun Yang, Shaogang Sun, Jun-Lin Guan
Journal: Cancer Research (2019)

Abstract Lymphangiosarcoma is a rare malignant vascular tumor which is formed from aberrant proliferation of endothelial cells (ECs). We previously established a vascular tumor mouse model by conditional knockout of Tsc1 gene in ECs and revealed that hyper-activated mTORC1 and increased VEGF autocrine are required for lymphangiosarcoma development and progression. However, we also found that there are other unknown factors which contribute to vascular tumor development besides mTORC1 hyper-activation. Autophagy has been shown to play an important role in tumor initiation and progression. However, the role of autophagy in mTORC1-dependent vascular tumor development is unclear. In this study, we studied the potential role and mechanism of autophagy in promoting lymphangiosarcoma development. FIP200 (FAK family interacting protein of 200 kDa) was identified as an essential autophagy gene, which was shown to play a key role in breast cancer development and progression. By crossing Tsc1f/f, Scl-Cre mice with Fip200f/f mice, we generated Tsc1/Fip200 double cKO mice. We found that Fip200 deletion blocked lymphangiosarcoma development induced by mTORC1 hyper-activation in mice. We established an immortalized lymphangiosarcoma cell line named Tsc1ΔEC from Tsc1 cKO mice and examined their growth in xenograft transplant models following CRISPR-Cas9 knockout of Fip200, Atg5 or Atg7 in Tsc1ΔEC cells. Our data showed that KO of each of these autophagy genes impaired vascular tumor growth in nude mice. Mechanistically, we found that Fip200 KO suppressed mTORC1 signaling activation under glucose starvation condition. In addition, we found that both Fip200 KO and lipase inhibitor Orlistat treatment in Tsc1ΔEC inhibited mitochondria respiration and decreased ATP content by seahorse assay. We also found that deletion of Fip200, Atg5, Atg7 or LAL in Tsc1ΔEC blocked lipid droplets (LDs) degradation and decreased glycerol release. Collectively, our data suggest that autophagy is required for lymphangiosarcoma initiation and progression through mTORC1 hyper-activation maintenance under stress conditions and supplying energy consumption by regulating lipid metabolism. Note: This abstract was not presented at the meeting. Citation Format: Fuchun Yang, Shaogang Sun, Jun-Lin Guan. Role of autophagy in lymphangiosarcoma initiation and progression [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 1831.
Mobile apps help me manage my tics
Authors: Thomas Daly
Journal: BMJ (2019)

Mobile apps help me manage my ticsThomas Daly describes what it is like to live with Tourette's syndrome and how he manages his tics Thomas Daly I received a diagnosis of complex tics at the age of 6 and have experienced involuntary tics throughout my life-these include blinking, head shaking, shoulder movements, and vocalisations.My condition made my childhood challenging.Different movements present with varying intensities-for example, I feel the greatest urge for shoulder movements, and satisfaction once the tic has occurred.
Abstract 18084: Assessment of Echocardiogram Report Interpretation by General Providers
Authors: Amanda Trang, June Kampangkaew, Arunima Misra, Ihab Hamzeh, Alvin Blaustein, David Aguilar, Tina Shah, Christie Ballantyne, Miguel Quinones, Sherif Nagueh, Hisham Dokainish, Salim Virani, Anita Deswal, Vijay Nambi
Journal: Circulation (2017)

Introduction: Echocardiograms (echo) are the second most commonly ordered cardiac test after ECGs with 56% of them ordered by general medicine providers (GP). Thus, initial interpretation of the re...
Abstract 25: P2Y14 Purinergic Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ’See’ Again
Authors: Farid G Khalafalla, Waqas Kayani, Arwa Kassab, Kelli Ilves, Roberto J Alvarez, Monica Chavarria, Benjamin Norman, Mark A Sussman
Journal: Circulation Research (2017)

Heart failure (HF) is a leading cause of death due to limited regenerative capacity of adult mammalian heart following injury. Autologous stem cell therapy holds promise for promoting cardiac regeneration. However, stem cells derived from aged/diseased organs exhibit poor growth and survival capabilities. Empowering cardiac progenitor cells (CPC) with prosurvival genes has been attempted. Nonetheless, the molecular mechanisms by which stem cells initially detect stress signals to stimulate appropriate regenerative responses are poorly understood. This study aims to explore the physiological responses mediated by purinergic receptors, which represent a major detector for extracellular nucleotides released during injury/stress, with a focus on P2Y 14 nucleotide receptor (P2Y 14 R) activated by extracellular UDP-conjugated sugars. P2Y 14 R mediates proliferation of keratinocytes and chemotaxis of neutrophils and hematopoietic stem cells (HSCs). In addition, P2Y 14 R enhances HSC resistance to stress-induced senescence and maintains regenerative capacity after injury. However, the physiological roles of P2Y 14 R in CPCs are largely unknown. Preliminary data show striking correlations between P2Y 14 R expression in human CPCs derived from HF patients (hCPCs) and patients’ ejection fraction (EF), where low EF corresponds to low P2Y 14 R expression hCPCs. Moreover, hCPCs with relatively slower growth kinetics and enhanced senescence exhibit dramatic decreases in P2Y 14 R expression compared to fast-growing hCPCs. P2Y 14 R overexpression improves hCPC proliferation, migration, survival under stress stimuli and reverses senescent-associated phenotypes. Furthermore, P2Y 14 R-overexpressing hCPCs show remarkable upregulation in the expression of paracrine factors critical for cardiac repair. Preliminary studies will be extended in vivo to assess whether P2Y 14 R overexpression in hCPCs improves their reparative potential for injured mouse myocardium. Overall, this study introduces a novel interventional molecular approach to improve the therapeutic outcome of hCPCs by enhancing their capability to detect stress-induced extracellular nucleotides and initiate proper regenerative responses through augmenting P2Y 14 R expression.
Abstract 2494: Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways
Authors: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh
Journal: Cancer Research (2019)

Abstract The therapeutic outcome of colon cancer (CoCa) is often compromised due to the development of chemoresistance and toxicities associated with current therapeutics. Hence, identification of less toxic and efficacious agent is needed to treat CoCa. In this study, we tested the effect of natural agent, Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) isolated from Asian plant rhubarb, on CoCa cell death and survival. Effects of Emodin on CoCa (DLD-1 and COLO-201) cell viability and death was determined by MTT and Annexin-V assays, respectively. Apoptosis-specific protein antibody array was used to define the Emodin induced molecular mechanisms involved in cell death vs. survival and results were confirmed by western blot analysis. Mitochondrial membrane potential and the expression/localization of Bcl-2 family protein were assessed via flow cytometry and WB, respectively. Our data show Emodin decreased the viability of CoCa cells and induced apoptotic cell death in a time and dose-dependent manner. Emodin-induced apoptosis resulted in increased death receptor expression, modulated caspase activation, and an imbalance in the Bax/Bcl-2 ratio. Changes in Bcl-2 family protein expression and localization correlated with loss in mitochondrial membrane potential. Emodin also negatively impacted MAPK/JNK, PI3K/AKT, NF-kB and STAT signaling pathways, which are associated with cell growth, differentiation, and Bcl-2 family expression or function. Modulation of cell survival and apoptotic pathways by Emodin and specifically the impact on Bcl-2 projects Emodin significance as promising therapeutic agent for CoCa treatment. Citation Format: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh. Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways [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 2494.